• May be positive in PUD, mesenteric ische-  mia, carcinoma of colon, Crohn's disease, and  diverticulitis.   • Sustained elevation of serum alkaline  phosphatase and presence of HBsAg or anti-  HCV in hepatocellular carcinoma may be seen   • Serum amylase and lipase elevated significantly  (three times normal) in acute pancreatitis,  perforated ulcer, and mesenteric thrombosis.   • To assess the state of hydration, and to rule  out renal disease.   • Indicated in all women of childbearing age  to exclude normal (before imaging proce-  dures) or ectopic pregnancy.   • In general right upper quadrant pain is best  evaluated initially by US, such as due to  hepatobiliary diseases   • It is also helpful in evaluating appendicitis,  gynecological disease, intra-abdominal fluid,  abscesses, and pregnancy — both normal  and ectopic   • Transvaginal Doppler US may be indicated  to further confirm or exclude ectopic  pregnancy   • Although US remains the primary modality  by which complaints specific to the pelvic  pain in women are evaluated, in many  instances, CT and MRI imaging, due to their  improved technology have become equal to  that of ultrasound in diagnosing causes of  pelvic pam m women. '   • In general, nonenhanced HRCT scanning of the  entire abdomen and pelvis is proved to be the  single most accurate factor for identifying need  for urgent intervention in patients with acute  nontraumatic abdominal pain, including those  associated with retroperitoneal structures.  Many inflammatory, ischemic, and mass  lesions such as appendicitis, cholecystitis,  diverticulitis, hernia, obstructed or perforated  bowel, pancreatitis, renal colic, and acute  bowel ischemia can be evaluated with high  degree (>90%) of sensitivity and specificity   • A contrast enhanced CT scan is invaluable  in the work-up of patients with hepatic,  pancreatic, and renal disorders   • HRCT can be considered a better alternative  than IVU because it has a higher diagnostic  accuracy, faster, less expensive and less risky  than IVU. In addition, it also has the capa-  bility of detecting various additional renal  and extrarenal pathologies 5   • CT scan is also helpful to guide biopsies and  other minimally invasive procedures.   • Provides diagnostic information in the work  up of patients with hepatic, adrenal, pan-  creatic disease, and lesions associated with  mesenteric circulation.   • EGD may be indicated in the diagnosis of  upper GI bleeding (PUD, esophageal varices)   • In patients with visceral perforation, free  intraperitoneal air can be seen as a crescent  of lucency under the right diaphragm (as this  is at a higher level). The amount of air as  little as 1 to 2 ml is detectable   • Parenchymal consolidation, CHF, or pleural  lesion that may be the cause of referred pain  to the abdomen can also be confirmed   • Those who cannot maintain upright position,  lateral decubitus view, and across the table  view may be helpful. In lateral decubitus  view, free air can be viewed between the right  edge of the liver and the lateral right  diaphragm. In across the table view, air may  be viewed just behind the parities   • US of abdomen is shown to be superior to  the erect CXR for the detection of free intra-  peritoneal gas. 6 ' 7   • Supine plus erect or decubitus views to  primarily evaluate GI gas pattern, i.e. air  Linder diaphragm or multiple air-fluid levels,  indicative of perforated ulcer or viscus, or  bowel obstruction'   • Other lesions such as renal calculi; gallstones,  gas in biliary tree in gallstone ileus; aortic  calcification (aneurysm); and obliteration of    #Numerous signs are described for pneumoperitoneum  on plain radiographs. The Rigler sign, or the double-wall  or bas-relief sign, is a visualization of the outer surface of  a bowel loop wall as a result of free air in the peritoneal  cavity. The intraluminal gas provides negative contrast  and outlines the internal wall. The cupola sign, typically  seen on supine radiographs, is an inverted cup-shaped  arcuate lucency overlying the lower thoracic spine and  projecting caudally to the heart. This sign is formed as air  accumulates anteriorly in the median subphrenic space  under the central leaf of the diaphragm. The football sign,  typically seen in pediatric patients, is a visualization of  the entire peritoneal cavity as an oval gas shadow, with  the vertically oriented falciform ligament representing  the seam of an American football.   • This has largely replaced the invasive  diagnostic ERCP in delineating the cause of  obstructive jaundice.   • This is a recent innovation in the world of  endoscopy. Its advantage over conventional  endoscopy is its ability to provide trans-  mural details. Also, it is extremely useful  in small tumors that cannot be properly  assessed by CT scan. The option of EUS-  guided fine needle aspiration cytology  (FNAC) and brush cytology is an added asset  in selected situations.   • Liver-spleen scans, HIDA scans, and gallium  scans may be useful in localizing intra-  abdominal abscesses (now replaced by CT  scans)   • 51Cr labelled erythrocyte scans may be useful  to identify the source of intermittent or slow  GI bleeding   • " m Technetium pertechnetate scans are  helpful in the diagnosis of Meckel's diverti-  culum.   • Percutaneous invasive angiography or  magnetic resonance angiography (MRA) is  indicated if intra-abdominal intestinal ische-  mia or ongoing hemorrhage is suspected.  Selective visceral angiography is a reliable  method of diagnosing mesenteric infarction.   • Upper GI barium series or enema with  double contrast media, and IVP are rarely    indicated (time consuming and excess  radiation exposure). However, where CT  scan facility is lacking, a barium enema will  confirm the diagnosis of volvulus of sigmoid  colon ('beaked' appearance). IVP may be  needed occasionally when it is difficult to  differentiate right sided ureteric colic and  acute appendicitis. In such cases a single film  IVP is found to be useful. In ureteric colic  there may not be secretion of dye on the  affected side, or there may be hold up in the  line of ureter. Intravenous cholangiography  is now replaced by US and HIDA scans in  the diagnosis of jaundiced patients and those  suspected with cholangitis.   • Histopathological or exfoliative cytology of  superficial lesion, e.g. in patients suspected  with lymph node tuberculosis, or metastasis;  or ultrasound/CT guided biopsies of abdo-  minal organs; or endoscopically obtained  specimen in inflammatory or malignant  disease, e.g. abdominal TB, hepatocellular  carcinoma, metastatic liver disease, adeno-  carcinomas, lymphomas, and neoplastic  lesions of retroperitoneal organs like kidneys  and adrenals.   • In patients with SBP, TB peritonitis, chylous  ascites, and for peritoneal cytology.   • A less invasive procedure for the diagnosis  of extraluminal, intra-abdominal solid  lesions which cannot be visualized by  endoscopic procedures.   • May be required in a few complicated or  undiagnosed cases, e.g. intestinal adhesions.    obstruction, perforation; acute biliary disease,  ectopic pregnancy, etc. particularly if there is  preoperative diagnostic uncertainty. Biopsy  of the pathological organ may be performed.   • Perhaps in no other situation is the history  and physical examination more important  in arriving at a rapid diagnosis than in the  acute abdomen.® Decisions have to be made  quickly with minimum investigations.  Therapeutic efforts have to be instituted often  within minutes. A structured date sheet* ** is  now widely used in many health services as  aide-memoire to minimize diagnostic errors   • Special points to note in the general examination  in a patient with an acute abdomen include:  general appearance (well looking, or ill, thin,  emaciated); alertness or state of consciousness;  hydration; temperature-pulse-respiration; and  blood pressure. Life-threatening causes (Table  2.5) should always be ruled out before focussing  on less serious diagnosis. Periodic examination  and critical assessment of the changes in the  condition of the patient, including vital signs  and appearance are clues to risk stratification  and appropriate diagnosis   • A careful examination of hernial sites,  scrotum, pelvis, and rectal examination is  mandatory in every patient with abdominal  pain— especially in acute cases to rule out  intestinal obstruction.    *Dr Zachary Cope in the classical text Cope's Early Diagnosis  of the acute Abdomen, reminds us that, "the general rule can  be laid down that the majority of severe abdominal pains  that ensue in patients who have been previously fairly  well, and that last for as long as six hours, are caused by  conditions of surgical import".   hunger; pallor; shock;  increasing distension; pulsatile  (aneurysm) or tender (ectopic  pregnancy) mass; rectal  bleeding (occasionally)   vomiting (in high obstruction);  constipation (in low  obstruction); Distension;  hyperperistalsis (early); visible  peristalsis (late); 'silent  abdomen' (late); diffuse pain  without rebound  tenderness   distension; palpable  sigmoid colon (like a pneumatic  tyre) in left lower abdomen; or  in a female palpable, freely  mobile, cystic swelling in the  lower abdomen   Patient elderly; atherosclerosis  or valvular heart disease; post-  prandial acute pain but little  tenderness; not distended (till  late); rectal bleeding  (occasionally)   Patient motionless; fever;  tachycardia; cough and  rebound tenderness; board-like  rigidity (late); absent bowel  sounds   Patient pale, anxious, lies still in  bed; vomiting; rising pulse;  hypotension; tenderness,  rigidity (early); increasing  distension; diffuse tenderness  (late); loss of liver dullness;  absent bowel sounds    • Biliary diseases such as cholecystitis,  cholelithiasis occur commonly in a fatty,  flatulent, fertile, and female of forty    In a woman with abdominal pain a detailed  gynecological history, including the timing of  LMP, pregnancy history, and vaginal discharge  or dysmenorrhea should be obtained  Pregnant women with abdominal pain, in  addition to all other causes of abdominal  pain, may present with atypical locations of  abdominal conditions. 8,9 Also, prior to  examination of the abdomen, the patient  should empty the bladder  History of collapse or fainting in a patient  with abdominal pain is suggestive of an acute  vascular catastrophe such as internal  hemorrhage, ruptured ectopic pregnancy,  acute pancreatitis, torsion, strangulation, or  mesenteric vascular thrombosis or embolism  Past history of abdominal surgery makes  intestinal obstruction from adhesions more likely  In elderly patients with history of CAD or  presence of cardiac risk factors with abdominal  pain, especially upper abdominal pain of acute  onset, obtain an ECG to rule out MI  In elderly patients with abdominal pain  associated with skin xanthomas and  generalized atherosclerosis, the possibility of  MI, AAA, and mesenteric ischemia must be  excluded by obtaining ECG, US, or CT scan  Drug history should include prescription and  illicit drug use as well as alcohol. NSAIDs,  steroids and immunosuppressants facilitate  perforation or peritonitis. Anticoagulants  enhance bleeding and hematoma formation.  Alcohol predisposes to pancreatitis. Purgatives  may ease perforation in a case of acute  appendicitis. Sulpha, steroids, barbiturates,  estrogen, beta-blockers are known to  precipitate porphyria. Megadoses of vitamin A  and D, diuretics, lithium, oral calcium intake  lead to hypercalcemia which may present with  acute abdominal pain   There are specific signs associated with  certain specific diagnosis (Table 2.6); these  should be elicited where applicable.   Intraperitoneal  hemorrhage (due to hemorr-  hagic pancreatitis, ruptured  ectopic pregnancy); retro-  peritoneal hemorrhage   Tenderness located 2/3 distance  from anterior iliac spine to umbilicus  on right side   • Catastrophic abdominal emergencies such as  perforated peptic ulcer or internal hemorr-  hage may be associated with minimal or no  detectable pain or muscle spasm in frail elderly,  seriously ill patients, and in patients with HIV  infection, or those taking immunosup-  pressants. A thorough work up and ad-  mission is usually warranted   • Intrathoracic diseases that most often  masquerade as abdominal emergencies (MI,  PE, pneumonia, pericarditis, and esophageal  disease) must be considered in every patient  with abdominal pain, especially if the pain  is in the upper part of the abdomen   • Whenever the cause of abdominal pain is  obscure, a metabolic or vascular origin (diabetes  mellitus, Addison's disease, mesenteric ischemia,  and porphyria) must always be considered   • Beware of silent abdomen — the temporary  improvement (easing of pain) in a patient    with perforated appendix or peptic ulcer  with peritonitis; it could be misleading   • Screen any women in the reproductive age  with history of missed period and presenting  with abdominal pain, vaginal bleeding, or  spotting for pregnancy — normal or other-  wise. An ectopic pregnancy can present even  before a missed period   • In a patient with recurrent abdominal pain  with repeated negative work up — rule out  three Ps, i.e. pancreatitis, porphyria, and  psychiatric disorder.   Mittelschmerz pain (pronounced mitel-  schma’rts). It is the ovulation pain or midcycle  pain — pain associated with ovulation. The  pain may occur just before, during, or after  ovulation. Symptoms include lower-  abdominal pain that is:    • Typically lasting minutes to a few hours, but  may extend as long as 24-48 hours   • May switch sides from month to month or  from one episode to another   Signs and tests: A pelvic examination shows no  abnormalities. Other diagnostic procedures  (such as an US abdomen) may be performed to  rule out other causes of ovarian pain if ovulatory  pain is prolonged.   Munchausen syndrome (pronunciation: Mun-  chau-zen) was named after the Baron Karl  Friedrich Hieronymus Freiherr von Munchau-  sen, who was a German cavalry officer and  known as a tremendous liar. Patients with  Munchausen syndrome go from physician to  physician dramatically presenting very  plausible symptoms and histories and receiving  care, up to and including surgery. They fake  physical signs of illness and abnormal  laboratory findings. The person may:   • Claim that he or she has symptoms, when  none exist.   • Produce false test results, such as by sticking  a thermometer in hot water to mimic a fever  or by putting bacteria or something else in  laboratory test samples.   • Say that symptoms are worse than they  really are, such as claiming to have severe  pain or bleeding when a milder condition is  actually present.   • Request surgical procedures.  Approximately 50% of those with Munchau-  sen syndrome are subject to drug abuse, and  many have borderline personality disorder. The  disorder generally starts during early adult-  hood, but may begin during childhood.    Myofascial pain syndrome (MPS) — Myofascial  pain is a chronic, painful condition that affects  the fascia, i.e. the connective tissue that covers  the muscles-either a single muscle or a muscle  group. Myofascial pain symptoms usually  involve muscle pain with specific "trigger" or  "tender" points. Trigger points can be identified  by pain that results when pressure is applied  to an area of the patient's body. The pain can be  made worse with activity or stress. In addition  to the local or regional pain associated with MPS,  people with this disorder also can suffer from  depression, fatigue, and behavioral distur-  bances. No specific lab tests confirm the  diagnosis of MPS, but lab tests can be helpful in  looking for predisposing conditions, such as  hypothyroidism, hypoglycemia, and vitamin  deficiencies. Chronic infections and sleep  deprivation have been cited as causative factors,  as have radiculopathy, visceral diseases, and  depression. The pathogenesis likely has a central  mechanism with peripheral clinical mani-  festations.    1. Dietrich CF, et al. Acute abdomen, gastroentero-  logists view. Praxis (Bern 1994), 2007; 96(16):645-  59. [PMID: 17474291: Abstract],   2. Heikkinen M, et al. GPs' ability to diagnose  dyspepsia based only on physical examination  and patient history. Scand J Prim Health  Care 2000;18(2):99-104. [PMID: 10944064:  Abstract],   3. Kalish CM, et al. Computed tomographic and  magnetic resonance features of gynecologic  abnormalities in women presenting with acute or  chronic abdominal pain. Ultrasound Q. 2007;  23(3):167-75. [PMID: 17805165: Abstract],   4 . Patel MD, et al. Reimaging the female pelvis with  ultrasound after CT: General principles.  Ultrasound Q. 2007;23(3):177-87. [PMID:  17805166: Abstract],   5. Pfister SA, et al. Unenhanced helical computed  tomography vs intravenous urography in patients  with acute flank pain: Accuracy and economic  impact in a randomized prospective trial. Eur  Radiol 2003;13(ll):2513-20. Epub 2003 Jul 24.  [PMID: 12898174: Abstract],    6. Yen HP, et al. Ultrasonography is superior to  plain radiography in the diagnosis of  pneumoperito-neum. British J of Sur 2002;89(3)  :351-4. [Abstract].   7. Okkes Ibrahim Karahan, et al. New method for  the detection of intraperitoneal free air by sono-  graphy: Scissors maneuver. J of Clinical Ultra-  sound 2004;32(8):381-5. [Abstract],    8 . Cappell MS, et al. Abdominal pain during pregnancy.  Gastroenterol Clin North Am 2003;32(l):l-58.  [PMID: 12635413: Abstract],   9. Gray J, et al. Abdominal pain, abdominal pain in  women, complications of pregnancy and labour.  Emerg Med J 2004;21(5):606-13. [PMID: 15333547:  Free full text].   Normal menstruation depends on the integrated  hypothalamic-pituitary-ovarian (HPO) axis and  endometrial function, and a patent lower genital  outflow tract. Briefly the pulsatile hypothalamic  gonadotropin releasing hormone (GnRH)  stimulates release of pituitary gonadotropins  luteinizing hormone (LH) and follicle-stimulating  hormone (FSH), which stimulate ovarian pro-  duction of estrogen (17-(3 estradiol) and pro-  gesterone. Sequential endometrial stimulation by  estrogen initially, followed by progesterone, cause  uterine endometrial proliferation (in preparation  for possible nidation of fertilized ovum). Cyclical  withdrawal of these hormones (in the absence of  nidation) results in sloughing of the endometrium  and menstrual bleeding.   In normal healthy women, the cyclical men-  struation is mostly constant with an average  rhythm of 28 ± 7 days, inclusive of 4 to 6 days of  bleeding which persists throughout the  reproductive period of life.   Amenorrhea indicates the absence of men-  struation; its onset may be primary or secondary.  Primary amenorrhea is arbitrarily defined as failure of  onset of menstruation beyond the age of  16 years regardless of development of secondary    sexual characteristics.* Secondary amenorrhea refers  to absence of menstruation for 3 consecutive months  in women who have previously menstruated.® 1   Amenorrhea may be physiological such as  during pregnancy, lactation, and after meno-  pause. Pathological amenorrhea results from  disorders of the HPO — uterine axis, endo-  crinopathies, psychological factors, drug usage,  and other rare causes such as anatomic abnor-  malities, and genetic factors.   In clinical practice, it is helpful to consider  amenorrhea as an abnormality in one of the four  areas based on the underlying anatomic or  endocrine dysfunction; viz. the hypothalamic,  the anterior pituitary, the ovaries, and the  outflow tract, including the uterus, cervix, and  vagina. Investigating and treating the cause for  amenorrhea can prove challenging because  disorders at any of the above several hormonal  levels can disturb the normal function and alter  the pattern of menstruation or prevent it  entirely. However, in the majority, diagnosis  and management is usually straightforward,   * For the purpose of evaluation, absence of any menses  and secondary sexual characteristics by age 14 is defined  as primary amenorrhea.   @ Menopause is defined as the terminal episode of naturally  occurring menses; it's a retrospective diagnosis, usually  made after 6 months of amenorrhea.    and a few need detail investigations, especially  if fertility is desired but impaired.   The causes for amenorrhea are grouped into  primary and secondary, but these are shared  between the two categories   • Disorders of anterior pituitary (prolacti-  noma, Cushing's disease, Frohlich syndrome,  Laurence-Moon-Biedl syndrome, empty  sella syndrome)   • Disorders of ovary (Turner's syndrome,  polycystic ovarian syndrome, i.e. PCOS)   #Causes 'false' or 'cryptomenorrhea' — menstruation is  taking place but the patient is unaware of it as the outflow  is obstructed.   • Functional hypothalamic amenorrhea (due to  emotional, physical, social stress; depression)   • Disorders of genital outflow tract ( Asherman's  syndrome, Rokitansky-Kuster-Hauser  syndrome)   • All patients require an initial pregnancy test  (serum or urine hCG). Any woman with  amenorrhea is considered pregnant until proven   Pelvic ultrasound-bilateral enlarged  ovaries, subcapsular cysts; altered  FH:FSH ratio >3:1; Testosterone  >200 ng/ml   Hypogonadotropic hypogonadism  (constitutional delay, stress, weight loss,  systemic disease, hypothalamic/  pituitary disorder, etc.)   » Histamine H 0 receptor blockers ml; Hyperprolactinemia = serum prolactin >40 ng/ml    otherwise; false-positive testing may occur vary  rarely with ectopic hCG secretion (e.g. chorio-  carcinoma or bronchogenic carcinoma).   • Anatomic abnormalities should be excluded  before performing an endocrine evaluation.  Pelvic ultrasound will evaluate for the  presence or absence of pregnancy, ovarian  cysts (PCOS), ovarian tumor, uterine lesions  such as hematometra, Asherman's synd-  rome, and uterovaginal disorders.   • Hypothyroidism, including subclinical  hypothyroidism, may affect menstruation,  leading to amenorrhea. Besides, abnormal  thyroid hormone levels can affect prolactin  levels; therefore, measuring TSH, FT4 levels  is indicated in patients with amenorrhea.   • Elevated in autoimmune disorders; may be of  significance in patients associated with POF.   • Diabetes mellitus type 1 is associated with a  higher incidence of hypogonadotrophic  amenorrhea, secondary to chronic systemic  illness, possibly due to derangement in FFPO axis.   • For evidence of autoimmune disease  associated with resistant ovarian syndrome.   • For evidence of structural abnormality of the  genital tract, it should be performed earlier  in investigation of primary amenorrhea.   • May include serum LH, FSH, serum prolactin,  estradiol, free testosterone, 1 7-hydroxy -  progesteron, and dehydroepian-drosterone  sulfate (DEHA-S).   • Level up to 100 ng/ml suggests hyperpro-  lactinemia; more than 100 ng/ml occurs in  the presence of a tumor. PRL levels fluctuate  periodically, therefore, several measure-  ments may be necessary to confirm hyper-  prolactinemia.   • Elevated LH and FSH (>40 ml IU/ml) are  suggestive of ovarian failure, e.g. POF,  resistant ovary syndrome, or autoimmune  ovarian failure. If FSH and LH levels are  elevated, POF is the most likely cause   • An increased ratio of LH: FSH exceeding 3:1  suggests PCOS, and helps differentiating  patients of PCOS from hypothalamic  dysfunction   • Low LH and FSH values (<20 ml IU /ml)  suggest physiological hypothalamic ame-  norrhea (stress, anxiety, diet, exercise) or  pituitary disease (GnRH deficiency).   • Elevated values are seen in PCOS, ovarian  tumor, adrenal tumor, and Cushing's syndrome.   • This test is performed to confirm the presence  of adequate endogenous estrogen (>50 pg /  ml). Medroxyprogesterone acetate 10 mg is  given orally once daily for 5-7 days or  injection progesterone in oil 100 mg  intramuscularly. Any withdrawal bleeding  occurring within 2 days to 2 weeks  following the final dose indicates that the    patient has sufficient estrogen, suggesting  that the major components of the  hypothalamic, pituitary, ovarian, and  uterine pathways are at least minimally  functioning. The amenorrhea is likely caused  by anovulation. The common underlying  causes are hypothalamic dysfunction and  PCOS. Absence of with-drawal bleeding  during the week following after the final dose  indicates estrogen deficiency or possibly  outflow tract abnormality.   • This test helps to differentiate outflow  abnormalities from estrogen deficiency.  Estrogen is given for 21-25 days and a  progestational agent for the final 5-7 days of  estrogen therapy to stimulate withdrawal  bleeding. If no bleeding occurs, an outflow  tract abnormality (uterine agenesis, imper-  forate hymen) is present. If bleeding occurs,  estrogen deficiency (due to hypothalamic,  pituitary cause) is present and further  testing is necessary.   • To screen for Cushing's syndrome and to  differentiate disorders causing hypercorti-  solism without Cushing's syndrome (i.e.  pseudo-Cushing's syndrome) such as in  alcoholism, depression, anorexia nervosa,  and antiseizure drugs.   • Hyperprolactinemia (i.e. serum prolactin  >100 ng/ml) warrants MRI of the brain.  Various tumors such as craniopharyn-  giomas and meningiomas may cause  hyperprolactinemia, but pituitary adeno-  mas are the most common.   • If LH and FSH levels are high, POF is the most  likely explanation. In patients <30 years age or  stigmata of Turner's syndrome, karyotyping  is indicated to determine the chromosomal sex.  If a Y chromosome is found, the chance of a  gonadal malignancy is greatly increased.   • In PCOS, laparoscopy reveals bilateral en-  larged ovaries with thickened tunica albu-  ginea and multiple cystic follicles.   • The clinical evaluation of the patient should  include careful history, and should always  include the following:   • Menstrual history, including dates of last  menstrual period — Age of menarche is  important and separates primary amenorr-  hea from secondary amenorrhea. A history of  cyclical abdominal colicky pain, retention of  urine suggests cryptomenorrhea presenting  as primary amenorrhea. Sudden missed  menses preceded by regular menses suggests  pregnancy in reproductive-age woman.  Oligomenorrhea progressing gradually to  amenorrhea characterizes PCOS   • Additional history may include symptoms of;  Pregnancy (nausea, breast tenderness, weight  gain); menopause or premature ovarian failure  (hot flushes, vaginal dryness, mood changes);  headache, visual disturbances, galactorrhea  (prolactinoma); seborrhea, acne, excessive  coarse hair growth, voice change  (hyperandrogenism, mostly caused by PCOS);  anosmia (Kallmann's syndrome)    • Medications (Table 3.2) may induce hyper  prolactinemia. Post-pill amenorrhea may  persist for several months   • Vigorous exercise — A history of excessive  activity level suggests the female athlete triad  (i.e. amenorrhea, eating disorder, and  osteoporosis: vide infra -li)   • Social history includes — Dietary habits,  'crash' dieting, nutritional status, weight  loss, emotional and physical stress, and  sexual activity   • Family history includes— Family pattern of  sexual development (menarche of mother  and sisters), genetic anomalies, and endo-  crinopathies (diabetes, thyroid dysfunction)   • Past history includes — Trauma, surgery  (hysterectomy), endometrial curettage,  infection (TB), chemotherapy, and irradiation   • Physical examination — This is guided by  history and should address the following:   • The type and stage of development of secon-  dary sexual characteristics such as breast  and areola development, axillary and pubic  hair growth, provide most important guide  to diagnostic work-up in patients with  primary amenorrhea   • Associated symptoms and signs as clues to  the diagnosis include:   > Signs of hirsutism (acne, excessive facial  and body hair), virilization (voice change,  temporal baldness) are suggestive of  PCOS and ovarian or adrenal tumor.   • B2 (age 11, range 8-13) •  breast bud, papilla and  areola elevate, increased  areolar diameter   • B5 (age 15, 13-18)  mature, areolar mound  recedes into general  contour of breast, papilla  continues to project    PH 1 preadolescent, no  pubic hair, fine vellus hair  covers genital area  PH 2 (age 11) sparse  distribution of long slightly  pigmented straight hair  bilaterally along medial  border of labia majora  PH3 (age 12) pubic hair  increases in pigmentation,  begins to curl and spread  sparsely over mons pubis  PH4 (age 13) pubic hair  continues to curl and  becomes coarse, increase  in number   • Systemic examination— For evidence of Tur-  ner 's syndrome, hypo- and hyperthyroi-  dism, Cushing's disease, panhypopitui-  tarism, chronic hepatic or renal disease.  Evidence of autoimmune disorder (RA, SLE,  and myasthenia gravis) is suggestive of  autoimmune ovarian failure   • Primary amenorrhea with normal secon-  dary sexual characteristics is commonly due    ^Menstruation fails to occur regularly if BMI falls below  18-19 kg/m 2 and it is estimated that 22% of female body  weight should be fat to ensure ovulatory cycle.    Clitorimegaly defined as a length times width product  of greater than 40 mm 2 .    to anatomical defects and rarely due to  androgen insensitivity syndrome, i.e. patient  phenotypically female but genetically male  with undescended testes. A karyotype  analysis is needed to determine proper  treatment. If testes are present, they should  be removed because of the high risk of  malignant transformation after puberty   • Primary amenorrhea with hypoplastic  secondary sexual characteristics is com-monly  due to HPO axis disorders; Turner's syndrome  is the commonest type of dysgenetic gonad.   • Although primary pregnancy before men-  arche is extremely rare, it's not impossible.  "Although the first few menstrual cycles  after menarche are often anovulatory, this  is not always the case. Because it is no longer  uncommon for girls to be sexually active in  their early to mid teens, a sensitive dis-  cussion of this subject and a pregnancy test  are necessary in the initial investigation of  amenorrhea in women of almost any age " 5   • Although 'constitutional delay of menarche  and puberty' is a common cause for primary  amenorrhea, it should not be assumed to  account for amenorrhea; periodic follow up  to evaluate other pathological causes for  delayed puberty (e.g. growth velocity for  skeletal age) is indicated   • In patients with secondary amenorrhea,  physical and pelvic examinations must rule out  pregnancy before diagnostic testing begins   • Oral contraceptives do not cause amenorrhea  after discontinuation. Amenorrhea occurring  after discontinuation of oral contraceptive  therefore needs the same investigations as  amenorrhea temporarily unrelated to  previous use of an oral contraceptive.    secondary amenorrhea and shortened luteal  phases is much higher among women partaking  in athletics, specifically in sports requiring low  body weight for per-formance and aesthetics. The  hormone pattern seen in these amenorrheic  athletes includes a decrease in GnRH pulses from  the hypo-thalamus, which results in decreased  pulsatile secretion of LH and FSH and shuts down  stimulation of the ovary. The recently dis-covered  hormone leptin may also play a large role as a  significant mediator of reproductive function. The  prevalence of eating disorders is high among female  athletes who practice sports which emphasize  leanness. Consequently, the cause of menstrual  irregularities is not due to the exercise alone, but  to chronic inadequate or restrictive caloric intake  that does not com-pensate for the energy  expenditure. The most dangerous risk associated  with amenorrhea for the female athlete is the  impact on the skeleton. Complications associated  with amenorrhea include compromised bone  density, failure to attain peak bone mass in  adolescence and increased risk of stress fractures.  The diagnosis of exercise-associated menstrual  dysfunctions is one of exclusion. The most effective  treatment is to decrease the intensity of the  exercise and increase the nutritional intake.  Hormone replacement has also been under  investigation as a possible treatment ". 6   1 . Tierney Lawrence M Jr, et at. Current Med Diag  and Treat 2006; 45th ed. 1184.   2. Kaplowitz PB. Link between body fat and the  timing of puberty. Pediatrics 2008; 121 Suppl  3:S208-17. [PMID: 18245513: Abstract],   3. Baker ER. Body weight and the initiation of  puberty. Clin Obstet gynecol 1985;28(3): 573-9.  [PMID: 4053451: Abstract],   4. Child Marriage: Girls 14 and Younger At Risk.  Web site - http://www.iwhc.org/resources/  youngadolescents/childmarriage.cfm. Accessed  on 11-09-08.   5. Bryan M, et al. Evaluation and Management of  Amenorrhea, Mayo Clin Proc 1997;72:1161-9.   6. Warren MP, et al. Exercise-induced endocrine  pathologies. J Endocrinol Invest 2003 Sep;  26(9) :873-8. [PMID: 14964440: Abstract],   In clinical practice, a significant number of patients  presenting with psychiatric symptoms seek an  acceptable explanation and relief from symptoms  or illness. These symptoms are either quantit-  atively excessive (compared with normal reaction  to stress), or qualitatively abnormal (they do not  usually occur as understandable reaction to stress).  For many patients such episodes of illness represent  major disruption to life; they may even express  fears for their own mortality. All these are  essentially normal and understandable responses  to the illness and the context in which they occur,  and a normal individual deals with such fears or  apprehensions effectively by utilizing his inherent  defence mechanisms that produce a natural 'fight-  or-flight' adaptive response. However, in some the  defensive mechanism is inadequate, leading to a  maladaptive response, resulting in overt emotional,  behavioral and physical manifestations, which can  vary enormously from feeling tense or tired to panic  attack. Thus, the experience of an Lin pleasant and  inappropriate affective state (i.e. fear or apprehension  out of harmony with the idea, thought, or object  accompanying it) with the expectation of, but not  the certainty of something untoward happening is  defined as anxiety *. A definition which is briefer and  to the point is: 'a fear for no adequate reason. 1    Anxiety is always accompanied by distur-  bances of autonomic functions, and because the  patients are not aware of the relation between  their anxiety and other symptoms, the latter  usually dominate the clinical picture. Patients  may present with any of the complaints (Table  4.1), but particularly common are headache,  dizziness, chest pain, palpitation, abdominal  cramps, diarrhea, tremor, fatigue, and emotional  upset. There is often an increase in tone in  voluntary muscles, so that the patient has a  sense of tension and complains of feeling tense,  keyed-up, on edge, unable to relax, lack of  concentration, irritable, and insomnia. When  anxiety becomes intense, chaotic motor  behavior may occur, which is usually called  panic ; the patient may experience chocking or  smothering, feeling of dead or threat, which may  lead the patient to associated comorbid  disorders. 1    * Anxiety is sometimes differentiated from fear, as anxiety  is a feeling of unease or dread in response to an internal  stimulus, in contrast to fear, which is based on an external  threat.   tin certain individuals anxiety may extend beyond the  single issue of their worry and may lead to phobias,  obsessive compulsive disorder, panic disorders, hypo-  chondriasis, and somatization.   can be challenging because patients present with  distress and concern about disease in the absence  of objective evidence. However, "...central to the  whole issue of diagnosing anxiety disorders, it is  usually not the illness that is masked but the  doctor who is blind. By confining enquiries to  physical systems, the correct questions are not  asked, and consequently the correct diagnosis is  missed..."." Also, anxiety and anxiety-like  symptoms may be consequent to a variety of  medical aliments and their treatment (Table  4.2). J Therefore, a comprehensive, emphatic  understanding, and time to listen to the patient  permits a reasoned and often a therapeutically  effective approach to the difficult problem.   • Acute stress reaction (death; accident;  traumatic diagnosis: HIV, ESRD, end-stage  COPD; cancer; assault; rape)   • Psychiatric disorder (generalized or chronic  anxiety state, depression, hyperventilation  syndrome)   • Acute systemic illness (acute coronary  syndrome, bronchial asthma, stroke,  seizure, migraine)   Hypertensive medication  Withdrawal from alcohol  ADHD medications  (amphetamine)  Withdrawal from  benzodiazepines  (Diazepam)   • Chronic systemic disease (diabetes mellitus,  cardiac arrhythmia, hyperthyroidism,  rheumatoid arthritis, hepatitis B and C, post-  herpetic neuralgia)   • Psychiatric disorders (panic, phobia, obs-  essive compulsive disorder, post traumatic  stress disorder, hysteria, psychosis, demen-  tia).   • In diabetic patients on insulin and/or  sulfonylureas, plasma glucose <50 mg/dl  causes hypoglycemic episodes leading to  adrenergic symptoms such as anxiety,  palpitations, and tremor   • Decreased levels of TSH with increased  levels of FT4 suggest thyrotoxicosis.   • Useful to evaluate possible tachyarrhy-  thmias, coronary syndromes, and to screen  for drug-induced QT prolongation.   • Increased levels of VMA and HMMA in urine,  or increased levels of free metadrenaline in urine  and blood (soon after episode of anxiety symp-  toms) is suggestive of pheochromocytoma.   • May be useful to detect pancreatic (3 cell  tumor, e.g. insulinoma.   • Patients with intermittent anxiety with  period of remission in between the episode  should have a wake-and-sleep EEG (and  possibly a CT) to rule out cerebral tumor.   • Anxiety is a normal human emotion. Dis-  tinguishing normal anxiety from pathologic  anxiety and anxiety disorders* often requi-  res systematic evaluation and a thorough  understanding of the individual patient's  physical and psychological status   • Also, it cannot be assumed that physical  symptoms are simply secondary to an  anxiety disorder because anxiety may be the  consequence of a physical illness such as in  the cardiac or hyperthyroid patient. Anxiety  may also coexist with other psychiatric  disorders as in bipolar depression. Hence it  is important to be certain about the  diagnosis of anxiety per se   • Typical features of pathological anxiety include  excessive, unrealistic, and persistence of its  somatic and physical symptoms (Table 4.3)  for more days than not, for at least six months,  in the absence of an objective stimulus. The focus of  anxiety may be everyday trifle activities (e.g.  appointment, communication) or life events  (e.g. job performance, marriage relationship,  financial stability, and retirement)   • Diagnosis of anxiety is based on the history —  It is vital to listen carefully to what patients'  say; it helps to determine whether their    *As outlined in the Diagnostic and Statistical Manual of  Mental Disorders 4th edition (DSM-IV), anxiety  disorders include generalized anxiety disorder (GAD),  social anxiety disorder (SAD, also known as social  phobia), specific phobia and panic disorder (PD), with  and without agoraphobia, obsessive-compulsive disorder  (OCD), somatization and post-traumatic stress disorder  (PTSD).   Muscle tension or ache  Tension headaches  Tremors, twitches,  and jitters  Tiredness/fatigue    anxiety is dysfunctional, i.e. whether it is  excessive and sustained and interferes with  daily living. History also helps to ascertain if  medications, substance abuse, a medical  illness, or associated psychiatric disorder is  aggravating patient's anxiety. Historical data  from family members may indicate the cause  of acute anxiety   • History of intermittent anxiety — Suggests  cardiac arrhythmia such as PSVT or AF,  psychomotor epilepsy, insulinoma, and  pheochromocytoma   • Age— The young and the middle-aged patient  is more likely to suffer from a psychiatric  disorder, while older patient may be suffering  from vascular or some other form of dementia   • Physical examination— Patient with anxiety  is restless, agitated; vital signs reveal tachy-  cardia and increased blood pressure and  respiration; neurologic examination usually  shows brisk tendon reflexes and tremors.  Sustained tachycardia with weight loss makes  hyperthyroidism a very likely possibility.  Presence of a thyroid bruit, auscultatory  systolic click indicates hyperthyroidism and  mitral valve prolapse respectively   • Exclusion of other psychiatric disorders,  especially depression — The Mini Mental  State Examination (MMSE) protocol is useful  to screen patients for this purpose. It is    critical to diagnose depressive disorders  because they are common, treatable, carry a  high risk of morbidity and mortality, and  frequently coexist with anxiety. In addition  DSM IV criteria may be used to determine  specific psychiatric disorder.   Anxiety and depression frequently occur together,  which can complicate the clinical picture,  including suicidal attempts or self-medication  with alcohol or other illicit drugs . 4 " 7   Cardiac arrhythmias, endocrinopathies  (insulinoma), and medication reactions consti-  tute significant number of undiagnosed psy-  chiatric referrals for 'anxiety'.   3. Harter MC, et al. Associations between anxiety  disorders and physical illness. Eur Arch  Psychiatry Clin Neurosci 2003; 253(6):313-20.  [PMID: 14714121: Abstract],   4. Katon W, et al. The association of depression and  anxiety with medical symptom burden in patients  with chronic medical illness. Gen Hosp  Psychiatry 2007; 29(2):147-55. [PMID: 17336664:  Abstract],   5. Sareen J, et al. Anxiety disorders and risk for sui-   cidal ideation and suicide attempts: A population-  based longitudinal study of adults. Arch Gen  Psychiatry 2005; 62(ll):1249-57. [PMID:   6. Hawgood J, et al. Anxiety disorders and suicidal  behaviour: An update. Curr Opin Psychiatry 2008;  21(l):51-64. Review. [PMID: 18281841: Abstract],   7. Petry NM, et al. Comorbidity of DSM-IV patho-  logical gambling and other psychiatric disorders:  Results from the National Epidemiologic Survey  on Alcohol and Related Conditions. J Clin Psychia-  try 2005; 66(5):564-74. [PMID: 15889941:  Abstract],   Arthralgia is pain or discomfort in one or more  joints. Apart from tenderness, abnormalities of  the joint cannot be identified.   Arthritis is painful joint with associated signs  of inflammation such as erythema, swelling,  tenderness, effusion, and limitation of move-  ments of the joint. Often, both arthralgia and  arthritis coexist in the same joint; arthralgia  being an early symptom whose clinical signs is  not yet apparent or too subtle for detection.   Joint pain can be a manifestation of disorders  confined to the joint and also of a number of  systemic disorders. Identifying the cause of joint  pain, therefore, can be difficult because of  extensive differential diagnosis. In some cases  the diagnosis may be hindered by atypical  presentation (as in the elderly or immunocom-  promised), or masked in those with multiple  comorbidities and/or symptoms. Consequently,  it is prudent to keep the diagnosis open in  patients who present with pain in multiple  joints. For instance, what may begin as a  monoarthritis may in course of time become  polyarthritis, thereby necessitating a review of   *The term arthrosis is sometimes used to describe a  degenerative lesion of a joint.    alternative diagnostic possibilities. Similarly, an  elderly woman, diagnosed initially as RA, may  later develop a molar rash and oral ulcer which  would change the diagnosis to SLE.   A careful history and physical examination  are essential which will help guide appropriate  investigations and management. The most  relevant aspects to decide are threefold:   1. Whether the underlying disorder is infla-  mmatory or not (Table 5.1).   2. Establish the type of onset (acute or other-  wise), and its subsequent evolution (i.e.  self-limiting, monoarticular, polyarticular  symmetrical, or polyarticular nonsymme-  trical: Table 5.2).   3. The presence of associated extra- articular and  systemic manifestations (e.g. fever, rash, eye  involvement, bowel symptoms, Raynaud's, etc.)  The majority of conditions are benign and self-   limiting, but a minority (trauma, sepsis, gout) may  require an urgent assessment and treatment.    observed, i.e. pain and  stiffness lasting few  minutes after a period of  joint immobility, and  improves with mild to  moderate activity.    chikungunya, dengue; bacterial — gonoco-  ccal, nongonococcal, e.g. staphylococcal,  streptococcal; tubercular)   • Spondyloarthropathies (ankylosing spon-  dylitis, i.e. AS; Reiter's syndrome; Psoriatic  arthritis, IBD)   1 Of historical interest is the fact that this diagnosis shares  its name with the man who first described it, Hans Reiter, a  Nazi physician who tested unapproved vaccines and  performed experimental procedures on victims in  concentration camps. The infamous legacy of Reiter's name  has led to the proposal that the syndrome be referred to by  another, more descriptive name such as Reactive arthritis.   Gout (due to uric crystal deposition)  Pseudogout (due to calcium pyrophosphate  cry-stal deposition)   Sjogren's syndrome (primary)  Antiphospholipid syndrome  Dermatomyositis/polymyositis  Polyarticular septic arthritis  Poncet's disease (vide infra 1-k)   • Hb reduced in inflammatory arthritis;  leukocytosis in osteomyelitis, reactive  arthritis, and acute gout; and eosinophilia  in collagen arthropathies, e.g. SLE, PAN.   • Most useful in the assessment of patients  with RA, PMR, and giant cell arthritis;  however, their values are elevated in a wide  variety of disorders, including infections,  trauma, inflammatory arthritides and  various neoplasms.   • IgM RF may be positive in the majority of  patients with RA.   • Values are elevated at some point during  acute attack, though a single estimation is  normal in up to 25% of acute gouty patients.   • Bone and/or joint X-rays are indicated in all  cases of major trauma to exclude fracture; to  diagnose pathological fracture such as in  osteomalacia, bone metastasis, and to  diagnose stress fracture. Other radiological  features of common arthritic disorders are  given in Table 5.3.   • In patients with rheumatic fever the ASO  titer is useful to document evidence of a  preceding streptococcal infection.   Initially normal; localized soft-tissue  swelling, bone destruction, involu-  crum, sequestrum, cloaca formation  seen as disease advances  Joint space narrowing; subchondral  sclerosis, osteophytes, cysts; effusion;  varus or valgus deformities in weight-  bearing joints. Growth of osteophy-  tes is one of the best indicators of  disease progression.   Target areas include all five MCP, PIP  joints, and all wrist compartments  and feet. Joint space widening is the  earliest and very transient finding (due  to effusion).   Other early features include peri-  articular swelling, regional osteo-  porosis, and erosion near joint capsule.  Late signs are joint space narrowing,  periarticular erosion, extensive des-  truction of bone ends, bony fusion,  and cyst formation.   Psoriatic arthritis Almost always accompanies skin dis-  ease, especially nail changes; mostly  involves DIP joints of hand, classical  deformity is called "cup-and-pencil  deformity".   Often unremarkable early in disease.  Later "punched-out" lytic bone  lesion with sclerosis, interosseous  tophi, and calcium deposits in soft  tissues.   Most frequent in the knees; calcifi-  cation in the hyaline and fibroc-artilage  (chondrocalcinosis) is present.  Sacroiliac joint involvement. Sacroi-  liitis occurs early with "saw-teeth"  appearance. Initially the joint may  look widened; squaring of the lumbar  vertebral bodies is charac-teristic;  followed by "bamboo-spine"  appearance.   • A positive ANA does not confirm diagnosis  of SLE; a negative value virtually excludes  the diagnosis of SLE and drug induced lupus.   • Almost diagnostic of SLE; occasionally found  in other conditions, e.g. RA, drug-induced  lupus, autoimmune hepatitis and lupus  nephritis.   • In the initial diagnosis of RA; its presence is  associated with poor prognosis.   • Helpful in imaging small structures or subtle  abnormalities such as partial ligament  or tendon tears; synovial inflammation,  hypertrophy, or effusions; and articular    cartilage lesions. High-resolution ultrasono-  graphy (HRUS) allows detailed 'real time'  imaging of joint and tendon morphology,  and structural changes involving the hand  in patients with several rheumatic diseases,  including RA, SLE, and gout, even in clini-  cally silent joints . 3 " 5   • CT to diagnose fractures, infection, neoplasm,  and vascular necrosis; MRI is best for assessing  soft-tissue and spinal-cord elements.   • Provides valuable information, especially in  patients with monoarthritis and joint effusion.  Gouty arthritis is definitely diagnosed in the  presence of urate crystals. Other parameters  such as cell count and culture studies help to  differentiate inflammatory arthritis from non-  inflammatory and septic arthritis.   • May be essential in the diagnosis of granulo-  matous arthritis such as tuberculosis,  sarcoidosis, amyloidosis, synovial tumors, or  mycotic infections.   • When an individual presents with com-  plaints of musculoskeletal aches and pains,  it is prudent to ascertain that the symptoms  confirm to 'arthritis', because what may  apparently look like an arthritic condition  may actually be a manifestation of ‘soft tissue  rheumatism (STR)*, also known as 'non-  articular rheumatic pain syndrome'. For   ^ STR is a collection of nonarticular pain generators that  result from pathology of extra-articular and extraosseous  periarticular structures. These soft tissue structures  include bursae, tendons and their synovial sheaths,  entheses, muscles and fasciae.    example, 'pain in the knee' as the patient may  complain, may actually be due to pain  because of bursitis over the knee; 'pain in  the shoulder' may be due to adhesive  capsulitis as against arthritis in the shoulder  joint. The main features that differentiate  arthritis and STR are explained in Table 5.4.   • The most useful information in evaluating  joint pain comes from history and physical  examination. The relevant aspects are age;  whether the underlying condition is  inflammatory or degenerative; type of onset  (i.e. acute or otherwise); subsequent evolution  (i.e. self-limiting, monoarticular, polyarti-  cular symmetrical, or polyarticular non-  symmetrical); and presence of associated or  complicating extra-articular features.    • Age— Infectious causes as well as trauma have  no particular age association. SLE presents  between second and forth decades of life; RA is  more common between fourth and sixth decades;  and OA peaks in the seventh and eighth decades   • Duration— Joint disorders are acute or chro-  nic, i.e. either less or more than six weeks  respectively. Acute disorders are often  traumatic, infectious, metabolic (gout), or  reactive; chronic disorders often include  noninflammatory and immunologic dis-  orders such as OA and RA. However, an acute    episode may be a harbinger of a chronic  polyarticular disease, and a chronic condi-  tion can present as an acute episode. There-  fore, chronic conditions such as RA, SLE, and  gout should be considered, at least initially,  in patients who present with acute poly-  articular or monoarticular joint pain  Inflammatory or degenerative etiology —  Inflammatory features include the presence  of all or some of the cardinal signs of  inflammation (i.e. erythema, warmth, pain,  swelling, and morning stiffness), and generally  associated with systemic symptoms (e.g. fever,  fatigue, weight loss). Common examples are  infections, RA, gout, and reactive arthritis.  Degenerative (i.e. noninflammatory) features  include pain without swelling or warmth,  activity-related pain, minimal or absent  morning stiffness, and absence of systemic  symptoms. Common examples are OA,  fibromyalgia, and neoplasms  Affected joints — Early OA can present in one  joint, most commonly the knee. Podagra, or  pain in the first metatarsophalangeal joint,  is the classic presentation of gout, appearing  suddenly at night. Gout most commonly  affects joints in the feet, ankles, hands, wrists,  elbows, and knees; less commonly affected  areas include the sacroiliac, sternoclavicular,  and shoulder joints. Gout rarely affects the  hip and spine. Symmetrical involvement of  metacarpal phalangeal, proximal interpha-  langeal joints, wrist, and feet is more  common in RA; involvement of knees and  hips is unusual. OA favors knees, ankles, feet,  and spinal column, but involvement is not  necessarily symmetrical. Depending upon  the underlying cause, the pattern of arthritis  may change overtime   Lifestyle factors— Diet rich in purine foods  (liver, kidney, red meat) and alcoholism can  precipitate an attack of gout in susceptible  individuals. High-risk behaviors, intravenous    drug use, past history of STD are risk factors  for infectious arthritis, including viral  hepatitis and HIV   • Medications — Diuretics, chemotherapeutic  agents, niacin, and aspirin can precipitate gout.  Hydralazine, isoniazid, methyldopa, procaina-  mide, chlorpromazine, and quinidine are  known to cause a lupus-like syndrome   • Family history — RA, SLE, OA, ankylosing  spondylosis, and (primary) gout have a familial  component. SLE is also found in families with  other autoimmune disorders such as hemolytic  anemia, thyroiditis, idiopathic thrombocyto-  penic purpura, vitiligo, and antiphospholipid  antibody syndrome   • Extra-articular symptoms and systemic  manifestations are often helpful in narrowing  the differential diagnosis (Table 5.5).   • Arthritis caused by alpha viruses, especially  Ross River, Chikungunya and Pogosta  disease is increasing, and these should be  kept in mind as a possibility, especially in  those cases where the disease starts with  flu-like symptoms, and rash is involved   • Beware of the red-hot joint (Table 5.6), i.e. a  single acutely inflamed, swollen joint that  may present a diagnostic problem. For  example, acute gout is often confused with  cellulitis; joint aspiration and bacteriological  studies are indicated for precise diagnosis   • Pain in wrists and ankles in a middle-aged  or elderly smoker with new onset of digital  clubbing strongly suggests HPOA caused by  underlying bronchogenic carcinoma   • Persistent underlying bone or skeletal pain,  nocturnal pain, swelling, and spontaneous  fracture warrants prompt evaluation to  exclude malignancy (usually secondaries)  and leukemic arthritis.    • Presence of HIV infection should be ruled out  in a patient with Reiter's syndrome, (i.e.  Reactive arthritis — a clinical tetrad of  urethritis, conjunctivitis or uveitis, muco-  cutaneous lesions, and aseptic arthritis),  who belong to high risk group for HIV  infection.   Poncet's disease — In 1897, Poncet described  polyarthritis in patients suffering from tuber-  culosis which was not caused by tuberculosis  infection of the joints. It is characterized by  polyarthritis that occurs during acute tuber-  culosis infection that affects persons with visceral  or disseminated tuberculosis. No mycobacterial  involvement can be found or other known cause  of polyarthritis detected. Therefore Poncet's    disease remains a diagnosis of exclusion. Poncet's  disease is postulated to be an immunologic  reactive form of polyarthritis, and associated  with an excellent prognosis with rapid resolution  on commencing antituberculous therapy and no  sequelae. Therefore, recognition of Poncet's  disease can be important.    1. Toivanen A. Alphaviruses: An emerging cause  of arthritis? Curr Opin Rheumatol 2008; 20(4):486-  90. [PMID: 18525365: Abstract],   2. McGill PE. Viral infections: Alpha-viral arthro-  pathy. Baillieres Clin Rheumatol 1995;9(1):145-  55. [PMID: 7728877: Abstract],   3 . Szkudlarek M, et al. Ultrasonography of the meta-  tarsophalangeal joints in rheumatoid arthritis:  Comparison with magnetic resonance imaging,  conventional radiography, and clinical exami-  nation. Arthritis Rheum 2004;50(7):2103-12.  [PMID: 15248207: Abstract],   4 . Wright SA, et al. High-resolution ultrasonography  of the first metatarsal phalangeal joint in gout:  A controlled study. Ann Rheum Dis 2007;  66(7):859-64. Epub 2006;21. [PMID: 17185326:  Abstract].   5. Wright S, et al. Hand arthritis in systemic lupus  erythematosus: An ultrasound pictorial essay.  Lupus 2006; 15(8):501-6. [PMID: 16942002:  Abstract].   Back pain is one of the most common complaints  and cause of disability in people seen in practice.  More than 80% of the adults have had at least  one episode of back pain, and many have had  recurrent episodes since adolescence. Despite  the frequency of low back syndrome, it is poorly  understood and physical examination is often  unrewarding in locating the etiopathogenesis  of backache because low back pain may  originate from many spinal structures,  including ligaments, facet joints, the vertebral  periosteum, the paravertebral musculature  and fascia, blood vessels, the anulus fibrosus,  and spinal nerve roots. Although advanced  imaging tools such as CT, MRI, and nuclear  scans have made it possible to distinguish wide  variety of spinal aliments, their association  between symptoms and imaging results is  weak. 1   Because of the high prevalence and high cost  of dealing with this problem, and also because  many experts believe the problem has been  'overmedicalized', resulting in rapidly rising  workers' compensation claim burden being  imposed on state budgets by low back pain  (LBP) management, it is now clear, from the    findings of many extensive studies that,  "uncomplicated acute LBP is a benign, self-  limited condition that does not warrant any  imaging studies. The vast majority of these  patients are back to their usual activities within  30 days. The challenge for the clinician, therefore,  is to distinguish that small segment within this  large patient population that should be  evaluated further because of suspicion of a more  serious problem". 2 ' 3 The history and  examination will identify both the majority of  patients with self-limiting disease and also the  minority who have a potentially serious  conditions that may present as back pain  needing further evaluation (Table 6.1).  Diagnostic testing should not be a routine part  of the initial evaluation, but used selectively  based upon the history, examination, and initial  treatment response. 4   > Upper back Pain (i.e. UBP or Thoracic or  Dorsal Pain) related to the thoracic (T 1 to T  12) segments, and   > Low back pain (i.e. LBP or Lumbosacral Pain)  related to the lumbosacral region (L 1-L5 +  S1-S5), which may be associated with lower  extremity symptoms.    Table 6.1: Potentially serious conditions that may  present as back pain   • History of even a minor trauma or strenuous  lifting in an older or osteoporotic patient   • Failure to improve after 4 to 6 weeks of  conservative low back pain therapy   > Acute backache— Usually lasting <4 weeks of  duration; mostly due to injury, strain, or  faulty posture; symptoms such as pain, and  restricted movements often confined to lower  back, which are aggravated on coughing,  straining, or bending. The main task is to  watch on events, e.g. any neurological deficit,  and address them as indicated.   > Chronic backache— Lasting >4 to 8 weeks of  duration. At this point it is appropriate to  reassess the patient's symptoms and physical  findings; perform selective investigations,  evaluate psychosocial barriers (Table 6.2), and a  surgical referral should be considered.   genesis and management between the UBP, LBP,  acute, and chronic disorders, their causes are  considered together for the purpose of practical  clinical approach.   • Problems at work, e.g. heavy work, unsociable  hours, low job satisfaction    * Spondylolisthesis, i.e. anteroposterior movement of  one vertebral body upon another body or the sacrum,  commonly L4 on L5, occasionally L5 on SI.   • Required when back pain is likely to be due  to infection, inflammation, or malignancy.   • Including c/s may be indicated to rule out  UTI and pyelonephritis as referred causes  complicating low back pain.   • Not useful in mechanical pain. Required if  pain is associated with red flags (Table 6.3)  indicating more serious problems.   Table 6.3: Lumbar spine X-rays should be  limited to red flag indications   Note: Generally AP and LAT X-rays are adequate; Oblique  X-rays are not recommended; they add only minimal  information in a small percentage of cases, and more  than double the exposure to radiation (Ref. Table 6.4).   • Serum acid phosphate is commonly elevated  in prostate carcinoma with bone secondaries.   • Tophaceous gout may mimic epidural/extra  epidural infection, abscess, or may coexist  with other rheumatological disorders.   • Backache may be an uncommon presenta-  tion of metastasized carcinoma of the pro-  state   • Prostate carcinomas with established malig-  nant potential are more likely to be identified  with PSA threshold >4.0 ng/ml.   • Useful in the diagnosis of plasma cell neo-  plasms, e.g. multiple myeloma, and lym-  phoma.   • A solitary pulmonary nodule or metastatic  deposits, usually from thyroid, or breast  may be an associated lesion in elderly with  chronic back pain.   • Intra-abdominal disorders such as aortic  aneurysm, renal, and uterine disease are an  occasional cause of referred pain to thoracic    or lumbar region which can be demon-  strated on US of abdomen and pelvis.   • CT scanning is considered the imaging  modality of choice to evaluate patients for  spinal trauma and vertebral fractures.   • To confirm abdominal US findings, and /or for  evidence of pancreatic, aortic, or pelvic lesions.   • MRI is noninvasive, does not involve radia-  tion, covers a large area of the spine, and can  show changes within the disk and vertebral  body. It has become the imaging modality of  choice in the diagnosis of radiculopathy, spinal  cord abscesses, spinal cord tumors, spinal  stenosis, and nontraumatic vascular lesions.   • In patients suspected with GI causes, e.g.  gastric or duodenal ulcer.   • To confirm CNS infections — bacterial,  tubercular, fungal, or viral.   • Such as NCS, needle EMG evoke potential  studies are usually not necessary in a clear-  cut radiculopathy or in patients with isolated  mechanical low back symptoms. These studies  are helpful in the evaluation of patients with  limb pain in whom the diagnosis remains  unclear, e.g. peroneal neuropathy vs. radi-  culopathy and motor neuron disease.   • The radiation dose of one lumbar spine is equivalent to 150 chest X-  rays and potential of gonadal irradiation.   • Even in well-established metastatic disease, the tumor must erode  more than half of the vertebra before it is visible on plain X-ray.   • Several X-ray findings are of questionable clinical significance  and may be unrelated to back pain. These findings include:   *** Diagnostic imaging practice guidelines for musculoskeletal  complaints in adults - an evidence-based approach. Part 3: spinal  disorders. Web site:   • Myelography has been largely replaced by  CT myelography or MRI.   • Discography and/or nerve blockade are  indicated in selective chronic back pain  patients in an attempt to either locate or  abolish the exact source of back pain.   • In conditions undetectable by conventional  methods, e.g. granulomatous bone disease,  lymphomas, myelomas, and metastatic  disease.   • A careful history taking and physical  examination should address the following  three aspects of back pain, which are mostly  sufficient to arrive at a working diagnosis:  > Is the back pain due to any systemic    > Is there a neurological deficit that may  entail surgical evaluation?   > Is there a psychosocial distress that is  aggravating or prolonging the pain (see  below)?   • The vast majority of LBP are mechanical, i.e.  muscular and ligamentous strains. They are  self-limiting and not severe   • Diagnostic testing should not be a part of  their initial evaluation. However, a patient's  failure to improve with conservative  treatment (within 4-6 weeks) is an  indication for further evaluation   • Absence of history of trauma does not exclude  mechanical causes, IVDP, or vertebral  fractures. A seemingly insignificant episode,  such as a minor fall, may be a red flag for  fracture in an elderly   • Examine the spine after its adequate  exposure and in good light. Sometimes an  unexpected finding such as midline mole, tuft  of hair, dimpling, or hemangioma will spot  the diagnosis of spina bifida occulta   • Palpation is an important component of  examination. Unlike the lumbar spine, the  thoracic vertebrae are superficial and it is  relatively easy to locate affected (painful)  segment   • Sciatica usually involves L4 - L5, L5- SI nerve  roots, either alone or together (Table 6.5)   • Thoracic spine pain is frequently associated  with the lower cervical spine lesions   • The thoracic spine is the commonest site in  the vertebral column for metastatic deposits   • Back pain that is unilateral may have a  urologic etiology such as pyelonephritis, or  obstructive nephropathy   • Only congenital abnormalities which may  cause back pain are spina bifida and spon-  dylolisthesis. Sacralization^ of L5 is gene-  rally asymptomatic   • The pain of myocardial ischemia, from angina,  or myocardial infarction can be referred to    the interscapular region of the thoracic spine.  A clinical rule is to consider the cause of  thoracic pain as cardiac until the examination  and investigations prove otherwise   • Beware of herpes zoster in the thoracic  segments especially in old and immunocom-  promised persons   • Beware of spinal canal stenosis, especially  in middle-aged or elderly patient, with  history of neurogenic claudication * such as back  pain referred to hips, paresthesias worsened  by back extension, walking and relieved by  sitting, or lying with the trunk flexed (finds  hills easier to climb than to descend)   • In chronic cases, exclude significant pathology.  Focus on counseling; discussing preventive  measures and patient education for self-  management of future episodes improves  prognosis. Avoid unnecessary, costly investi-  gations   • Suspect malingering, especially in patients  with legal, or mediclaim issues. False-positive  physical findings such as positive SLR tests  may be seen, yet the person may not have  any problem while walking, sitting, or  climbing. However, when the diagnosis of  malingering is doubtful, it is safest to assume  a person is not, unless a contradictory sym-  ptom or sign is witnessed (Table 6.6) 5   • Although any one episode of back pain may be  started by a physical problem in the back, its  prognosis is vastly influenced by psychosocial  factors. The added morbidity of depression and  anxiety with chronic pain is strongly associated  with more severe pain, greater disability, and  poorer health-related quality of life/ 1   • Back pain associated with severe or pro-  gressive neurological deficit is a medical  emergency; suspect IVDP, cord compression,    Table 6.6: What physical exam techniques are  useful to detect malingering?   The Diagnostic and Statistical Manual of Mental  Disorders (DSM-IV) defines malingering as:   " The intentional production of false or grossly exaggerated  physical or psychological symptoms motivated by external  incentives such as avoiding military duty, avoiding work,  obtaining financial compensation, evading criminal  prosecution, or obtaining drugs."   Malingering is not considered a mental disorder  because symptoms are intentionally produced for  external incentives.   Several exam tests are commonly thought to detect  nonorganic causes of low back pain such as Waddell's  signs, Mankopf's test, Hoover's test. Arm Drop test.  Midline Split test, etc. which have low diagnostic yield.   Since no examination technique objectively proves  malingering, the DSM-IV recommends suspicion of  malingering for patients who present with 2 or more of  the following:   vertebral fracture, and viral myelitis (her-  pes, polio, HIV). Hospitalization is indicated.  • In a patient with acute back pain, who is  withering with pain and clinically unstable,  suspect intra-abdominal or vascular  process. Hospitalization is indicated.    • Cauda equina syndrome — Back pain with  bladder or bowel incontinence, saddle area  perineal numbness, disturbed gait is an  emergent condition.   • Beware of patients, especially elderly, with  weight loss, pain at rest, or constant pain at  night; significant pathology, especially  malignancy, must be ruled out.   • In elderly men, especially over age 50 with  back pain, per rectal examination is man-  datory; associated PSA estimation may be  indicated to rule out prostate malignancy.   • Chronic back pain before the age of 20 years  is an indication to rule our primary spinal  tumors, e.g. osteosarcoma.    1 . Mulconrey DS, et al. Interobserver reliability in  the interpretation of diagnostic lumbar MRI and  nuclear imaging. Spine J 2006;6(2):177-84.  [PMID: 16517390: Abstract],   2. National Clearing House. Clinical Practice Guide-  line. Web site - http://www. guideline, gov/  summary/summary, aspx? doc_id=8599 and nbr =  004786 and string = low + and + back + and + pain.  Accessed on 03.10.08.   3. Carragee E, et al. Are first-time episodes of  serious LBP associated with new MRI findings?  Spine J. 2006;6(6):624-35. [PMID: 17088193:  Abstract],   4. Chou R, et al. Clinical Guidelines: Diagnosis and  treatment of low back pain: A joint clinical practice  guideline from the American College of Physi-  cians and the American Pain Society. Ann  Intern Med. 2007;147(7):478-91. [PMID:  17909209: Abstract],   Web site: http://www.annals.org/cgi/content/  abstract/147/7/478? maxtoshow = and hits = 10  and hits = 10 and Resultformat = and fulltext =  Diagnosis + and + Treatment + of + Low + Back +  Pain% 3A + Recommendations + from + the +  American + College + of + Physicians% 2F  American + Pain + Society and searchid Back = 1  and first index = 0 and resource type = HWCIT.  Accessed on 04.10.08.   5. American Psychiatric Association. Diagnostic and  Statistical Manual of Mental Disorders, Fourth  Edition, Text Revision (DSM-IV-TR). Washington  DC: American Psychiatric Press Inc; 2000:683.   6. Bair MJ, et al. Association of Depression and  Anxiety Alone and in Combination with Chronic  Musculoskeletal Pain in Primary Care Patients.  Psychosom Med. 2008. [Epub ahead of print],  [PMID: 18799425: Abstract],   A breast Jump* is a swelling or a protuberance in  the breast which feel different from surroun-  ding breast tissue.   Although breast lumps may appear at all  ages— infants, young girls, and teenage boys —  they are transitory and disappear on their own  over a period of months. It is the breast lump in  an adult woman that raises concern for breast  cancer, even though most lumps turn out to be  benign breast lesions.   Frequently, it is the patient who has noticed  the 'lump' herself and expects reassurance or  early evaluation. Not infrequently, a lump may  have been detected on routine mammographic  screening* called as a 'mammographic lesion '*.   "The terms breast 'lump' and breast 'mass' are used  interchangeably; however, since the term 'mass' is also  used in the context of breast imaging modalities , the term  'lump' may be preferred to avoid confusion.   + ' Screening ' is performed in the absence of symptoms;  when symptoms exist, the evaluation may dictate going  beyond screening procedures.   ^Screening mammographic 'lesion' could be a lump,  architectural distortion, asymmetric parenchyma, calci-  fication, or skin changes. These findings are further defined  by diagnostic mammographic imaging modalities as  benign or malignant as per the Breast Imaging-Reporting  and Data System protocol.    In either case, however, the importance of  correctly diagnosing a breast lump early can  not be understated irrespective of woman's age,  clinical status, and risk factors. Goodson WH et  al states, "The leading cause of physician delay  in diagnosis of breast cancer continues to be  inappropriate reassurance that a mass is benign  without biopsy. Reducing delay in diagnosis  will require less willingness to rely on clinical  examination to decide that a mass is benign,  less reliance on benign mammography reports  to decide not to biopsy a mass, and a require-  ment that fine-needle aspiration biopsy be done  by persons with demonstrated competence for  the procedure ". 1   As most women who present with breast  lump are emotionally distressed, the goal of the  evaluation is not only differentiating a benign  breast disease from cancer, but also addressing  the patient's symptoms and alleviating the  anxiety about breast cancer.   • Anemia in chronic infection and malignancy;  leukocytosis in breast abscess.   • To detect underlying lung disease, e.g. TB,  secondary deposits in lungs and ribs.   • Indicated as an initial screening procedure to  evaluate a breast lump in women aged 30  years and more. The purpose is to evaluate a  palpable or dominant ** mass, or to define the  presence or absence and extent of nonpalpable  lesion associated with the mass; and also to  identify additional abnormalities in the  ipsilateral or contralateral breast that may  influence further management. The purpose  of the mammogram is not to diagnose the  palpable findings, and normal mammogram  does not ensure absence of malignancy   • Because the breasts are relatively radiodense  in women under 30 years of age, mammo-  graphy is rarely of value in this age group. In  older women some amount of fatty dis-  placement of breast tissue makes mammo-  graphic evaluation more informative   • Mammographic findings that suggest  malignancy include increased density,  irregular margin, speculation, and clustered  irregular microcalcifications.   • This procedure greatly facilitates the use of  computer-aided-detection (CAD), which  allows further evaluation of an abnormal  mass or some breast lesion that may have  missed on initial evaluation. CAD is used  selectively especially in women with a  genetic predisposition for breast cancer,  where intensified early detection programs  may have to start from 25 to 30 years of age. 2    **Dominant mass is a palpable mass which persist through-  out the menstrual cycle. These masses may be discrete  or poorly defined, but they differ in character from the  surrounding breast tissue and the corresponding area in  the contralateral breast.   • The material aspirated, either fluid from the  cyst or samples of solid lesions, are subjected  to cytological examination. Any finding that  is suspicious for malignancy on FNA is  subjected to surgical excision for definitive  diagnosis   • This procedure can be combined with US,  i.e. US guided FNAC, to further assess poorly  defined palpable masses   • If FNA is done before mammography, the  diagnostic mammography should be de-  layed for 2 weeks after needle aspiration so  as to avoid false-positive results due to  trauma and possible hematoma formation.   • Indicated as an initial procedure to evaluate  palpable masses in women under 30 and  lactating or pregnant women   • Helps to differentiate a benign simple cyst, a  complex cyst, or any suspicious mammo-  graphic solid density   • It has high sensitivity for breast cancer  besides aiding in its (TNM) staging and  management. MRI is also found to be an  optimum method of imaging breast implants  and detecting implant leakage and rupture.    Screening MRI may be helpful for women for  whom mammography is not optimal, such  as young women at substantially increased  risk for breast cancer because of known  BRCA1 or BRCA2 mutations. 3   • Mostly used to evaluate small or difficult-  to-palpate lesions, or nonpalpable breast  masses identified on mammogram with  ultrasound guidance. A minimum of four  core samples are taken to achieve greater  histologic accuracy.   • Indicated if FNAC or core Biopsy is  inconclusive and there is clinical suspicion  of malignancy; the other possible indications  are: a discrete lump which is increasing in  size, and when the patient is not willing to  'wait-on-events' and anxious to have a rapid  diagnosis.   • It's a combination of clinical breast exami-  nation (CBE), imaging studies, and FNAC,  used as an alternative to surgical excision to  establish that the breast mass is benign.   • If the above three parameters indicate a  benign process, the breast mass is considered  as benign. If biopsy is deferred after triple  diagnosis, careful follow-up is warranted. If  any of these three modalities suggests  malignancy, excisional biopsy is mandatory.   • Woman with personal history of breast cancer  at young age; family history of breast cancer  in two or more close relatives, such as  parents, siblings and children; a family  history of breast cancer in more than one    generation; a family member who has both  breast and ovarian cancers; a male relative  with breast cancer; or a positive BRCA1 or  BRCA2 genetic test in a relative; may  undertake genetic testing after proper genetic  counselling to see if she actually do have a  mutated gene. If a woman has mutations in  either of two breast cancer susceptibility  genes (BRCA1 and BRCA2), her risk of breast  or ovarian cancer is significantly higher than  that of a woman without such a mutation. 1 "   • Any exposure to hormone therapy or oral  contraceptive pills (age when began, duration,  dosage)   • Family history of breast cancer (including in relat-  ives), and other carcinomas, e.g. ovarian   • Breast lump — Duration of the mass; how and  when it was first noticed; change in its size,  shape, and consistency; its relation to  menses; changes in surrounding skin; and  trauma should be questioned.   • Presence of risk factors (Table 7.2) indicates  highest risk for breast carcinoma.    ,# FDA has approved the TOP2A FISH pharmDx device to  test for the TOP2A (topoisomerase 2 alpha) gene in cancer  patients. Web site - http://www.fda.gov/bbs/topics/  NEWS/2008/NEW01 774.html   • Family history in first degree relative (i.e. mother,  sister, daughter)   • Previous history of breast cancer, breast biopsy  showing atypical hyperplasia   • Minor risk factors include: alcohol intake, obesity  (BMI >= 30 kg per rrr), high economic status,   • Breast pain (mastalgia), breast lump, and  nipple-discharge are the most common  symptoms   • The most common causes of breast pain are  fibrocystic disease, i.e. cyclical mastalgia  (pain increases before the menstrual period  and settles afterwards), and mastitis   • A breast lump in a woman in the ages of 15 and  25 years suggests fibrocystic condition, or  fibroadenoma; cysts tend to occur commonly  and frequently around the fourth decade of life  and in the perimenopausal period. In any  woman with breast lump, no matter what her  age, the probability of developing breast cancer  increases throughout life   • Characteristics of discharge — May be  physiological (pregnancy or lactation, i.e.  galactorrhea). Purulent discharge may be  caused by mastitis, breast abscess, or duct    ectasia; unilateral blood stained discharge  increases the concern for malignancy;  spontaneous persistent discharge may  indicate hyper-prolactinemia and warrants  endocrine work-up   Skin changes overlying the lump such as  orange peel appearance, retraction, inver-  sion, and ulceration of the nipple strongly  indicate breast cancer  CBE of the breast lump is done in at least two  positions: Sitting (i.e. upright) and supine with  the woman's arms behind her head.  Although CBE can detect a variety of abnor-  malities, by far the most common are those  detected by palpation. The entire breast  tissue, i.e. the four quadrants, is palpated  gently, systematically and individually,  including the tail of Spence, by applying  varying pressure. This is clinically significant  because abnormalities can arise in the 'tail'  region (e.g. axillary extension of ipsilateral  breast cancer) just as they can in other areas  of the breast   Normal breast tissue is dense, firm, and elastic.  Generalized nodularity and tenderness is  common during the menstrual cycle. It is  important to differentiate between a dominant  lump and areas of nodularity which can occur  at any age   A dominant mass or lump is distinct from  surrounding tissues, asymmetrical relative  to the other breast, and persist throughout  a menstrual cycle   In a premenopausal woman, CBE is ideally  performed 3 to 10 days after the onset of  menstruation (when ovarian hormones  exert least influences; breast engorgement  and nodular structure of breast tissue is  usually decreased)   Examination of the regional lymph nodes,  i.e. axillary, cervical, and supraclavicular, for  their site, size, and associated features such    as pain, tenderness, and consistency is a  critical component of the examination   • Any breast lump must be evaluated to  determine whether it is cystic or solid;  neither the CBE nor mammography can  make this distinction   • Although benign masses are often mobile,  soft, or cystic, these features are not specific  enough to exclude malignancy   > Changes in the breast that include dis-  tortion, puckering of the skin and nipple  retraction.   > Lump that may be firm or hard with  varying degree of fixity to surrounding  tissues, overlying skin, or underlying  pectoral muscles.   > Malignant ulcer may be present, and the  nipple discharge is usually bloody.   • Symptoms suggestive of metastasis disease  are— bone pain, back pain, cough, dyspnea,  headache, personality changes, seizures, and  abdominal symptoms and jaundice   • If the CBE yields findings suspicious of  carcinoma, the American Joint Committee  on Cancer (AJCC) 3 clinical staging should be  included in the medical records.   • Never ignore a women's insistence that an  area of her breast is different or has changed   • An asymptomatic breast mass is the most  common presentation of the breast cancer   • Any eczematous rash appearing on the  nipple or areola indicates underlying breast  malignancy   • A negative mammogram does not replace the  need for biopsy of the palpable mass    • Tuberculosis of the breast, though an  uncommon disease, is still present and is also  misdiagnosed with carcinoma or bacterial  abscesses. Moreover, simultaneous occurrence  of these two major illnesses in the breast, i.e.  tuberculosis and carcinoma has been reported  in the literature which can lead to many  problems regarding diagnosis and treatment . 6,7   1 . Goodson WH, et al. Causes of physician delay in  the diagnosis of breast cancer. Arch Intern Med.  2002;162(12):1343-8. [PMID: 12076232: Free full  text].   2. Bick U, et al. Digital mammography: What we do  and what we don't know? Eur Radio 2007;   3. Joann G, et al. Screening for Breast Cancer. JAMA  2005;293:1245-56.   5 . Singletary SE, et al. Revision of the American  Joint Committee on Cancer staging system  for breast cancer. J Clin Oncol 2002;20(17):  3628-36. [PMID: 12202663: Free full text],  Web site - http://jco.ascopubs.org/cgi/content/  full/20/17/3628 (accesses on 09-07-2008).   6. Fadeei-Araqqhi M, et al. Breast tuberculosis:  Report of eight cases. Arch Iran Med 2008;  1 1(4) :463-5. [PMID: 18588382: Free full text],   7. Alzaraa A, et al. Coexistence of carcinoma and  tuberculosis in one breast. World J Surg Oncol  2008;6:29. [PMID: 18318914: Free full text].   Chest pain— broadly defined as any discomfort  in the anterior thorax occurring above the  epigastrium and below the mandible— can be  one of the most challenging problem managed  by the physicians. The typical patients' concern  with the first bout of chest pain is their  apprehension of the onset of cardiac pathology,  such as CAD. However, of the patients' referred  to the Rapid Access Chest Pain Clinic, 52% did  not have cardiac chest pain. 1 In another study  statistics show that more than 50% of patients  referred to cardiologists for chest pain are  ultimately found to have noncardiac chest pain;  that is, their chest pain is not shown to be caused  by cardiac ischemia. ~ Further, patients with  chest pain who present for the first time to  ambulatory care or to the emergency room, only  11 to 39% are ultimately diagnosed with  coronary artery disease. 3 The balance of patients  (approx. 50-60%) experience noncardiac chest pain. 4  Thus, although for the patient with chest pain, the  possible underlying (notably cardiac) cause is the  chief concern, for the physician, the cause, cardiac  or otherwise, is often unrelated to the complaint of  chest pain.    When a person complains of chest pain as  'crushing, retrosternal pain, or substernal  pressure', it usually suggests a cardiac source  of chest pain. However, only 50% of patients  with acute coronary syndrome (ACS) describe  their pain in classic terms such as crushing or  pressure-like; it is often experienced more as a  'nonspecific' sensation of discomfort than actual  pain. Many other descriptive terms are also  used to convey chest pain, such as dull, aching,  tightness, squeezing, soreness, burning, or 'gas'.  Diabetic and elderly people who may have  cardiac pain are more likely not to experience  chest pain, or to have nonspecific symptoms  such as dyspnea, nausea and vomiting, unusual  fatigue, or syncopal attacks. Moreover, in  women, the presentation of chest pain of cardiac  origin is frequently atypical than in men.  Therefore, the physician has to be aware of both  the typical and atypical presentations of chest  pain, especially of cardiovascular origin.   The differential diagnosis of chest pain  includes conditions affecting organs throughout  the thorax, neck, jaw, shoulder, arm, forearm,  and upper abdominal viscera (i.e. the area  covered by six dermatome — T1 to T6 - sensory  nerves), with prognostic implications that vary    from benign to life-threatening, including death.  Nora Goldschlager, MD, Professor of Medicine,  University of California, San Francisco states,  "evaluation of chest pain is really all about not  missing CAD*, and in particular not missing  things that could be ACS + , and calling  them something else and sending the patient  home". 5-8   The extent of evaluation of the chest pain is  chiefly determined by the patient's age, family  history, cardiac risk factors' estimation, total  ischemic burden, and cost-effective analysis of  noninvasive and invasive procedures, so that  unnecessary tests, procedures, anxiety, and  hospitalization are minimized or avoided.  However, chest pain is not always of cardiac  origin. In some patients, further workup may  reveal a noncardiac cause of chest pain, while  in others, the results may be inconclusive. It is  in this latter population that diagnosis can be  particularly challenging. Despite test results  that are negative for CAD, they may still have  cardiac or systemic diseases. 9   “'Coronary artery disease (CAD) may manifest as: stable  angina; unstable angina, non-Q wave MI (NQMI), non-  ST segment elevation MI (NSTEMI); ST segment  elevation MI (STEMI); heart failure; sudden death; and as  an incidental finding (asymptomatic).   + The term acute coronary syndrome (ACS) refers to a  range of acute myocardial ischemic states. It encompasses  unstable angina, non-ST segment elevation myocardial  infarction (ST segment elevation generally absent), and  ST segment elevation infarction (persistent ST segment  elevation usually present). — BMJ 2003; 326:1259-61.   • Intercostals neuritis (herpes zoster: prior to  the eruption; diabetes mellitus).   Pain with tenderness of anterior thoracic wall, burning  in nature, observed mostly in post CABG patients.   • When obvious ST-segment elevation is present  in patients with acute chest pain, the diagnosis  of myocardial injury is straight forward.  However, significantly more than 50% of  patients with AMI have nondiagnostic ECG  changes. The ECG becomes even less sensitive  with increasing age and in those with a previous  MI. Also, many ECG patterns interfere with the  diagnosis of AMI. These include left bundle-  branch block, WPW syndrome, early  repolarization ST changes, left ventricular  hypertrophy, hyperkalemia, digoxin effect, etc   • Further, ST-T changes in patients with chest  pain due to MI, PE, and pericarditis can be  similar; therefore, the clinical history and  physical examination, as well as ECG clues,  must be considered before making a diagnosis   • As patients with initially normal ECG are  still at risk for life-threatening complications  and death, it is important to obtain serial  ECGs for any evaluation.   • PA projection provides valuable information  about pneumonia, pneumothorax, media-  stinal disease, pulmonary hypertension,  aortic dissection, spine disease and trauma    • Dilatation of individual cardiac chambers  and cardiomegaly is seen in hypertension,  valvular heart disease and chronic CHF.   • Levels of creatine kinase MB isoenzyme (CK-  MB) usually rise above the normal range  within 4 hours after the onset of myocardial  infarction, and serial sampling of CK-MB over  a period of 12 to 24 hours permits the detection  of virtually all acute myocardial infarctions.  However, CK-MB elevations can result from  causes other than myocardial injury   • The cardiac troponin T and I markers are  more specific than CK-MB for myocardial  injury. After myocardial injury, the levels of  cardiac troponins rise after approximately  the same amount of time as CK-MB levels  and remain elevated for up to 2 week;  therefore, they are not useful in detecting  episodes of reinfarction. However, the assay  for CK-MB permits the detection of  reinfarction   • The most appropriate strategy followed at  many hospitals is the combined use of the  CK-MB and Troponin I and T   • Although troponin has greater specificity  than myoglobin and CPK-MB for myocardial  damage, elevated levels may be present in  patients with nonischemic heart disease or  noncardiac disease. Cardiac causes, such as  heart failure, myocarditis, and the use of  cardiotoxic drugs, such as doxorubicin,  5-fluorouracil, and trastuzumab can produce  nonischemic troponin elevations. Non-  cardiac causes, such as pulmonary embolism,  sepsis, high-dose chemotherapy, stroke,  subarachnoid hemorrhage, pre-eclampsia,  and renal failure can also produce such  elevations. Therefore, elevated troponin levels  do not invariably signify myocardial  damage.   • The overall sensitivity and specificity is  about 50-70% in patients with CAD. The  ECG is monitored for ST-depression and any  ventricular arrhythmias. The patient is also  monitored for any fall in blood pressure, or  complaints of chest discomfort, or dyspnea.  The test is performed if diagnosis is in doubt,  for prognostic reasons, or to aid in the  timing of additional investigations, e.g.  Coronary angiography. A normal stress ECG  does not rule out CAD; both false-positive  and false- negative results are common.   • In patients with acute chest pain due to MI,  this technique can be performed at the  bedside, and is very useful for assessing right  and left ventricular function, wall motion  abnormalities, identification of vegetations  in endocarditis, and for detecting important  complications such as mitral regurgitation,  ventricular septal defects, pericardial  effusion, and cardiac rupture.   • In aortic dissection, Doppler echo may show  aortic regurgitation, a dilated aortic root  and, occasionally, the flap of the dissection.   • In patients presenting with atypical chest  pain, suspected to be due to MVP, 2-D cardiac  echo findings of > 2 mm superior displacement  of the mitral leaflets into the left atrium during  systole, with a leaflet thickness of at least  5 mm can be diagnostic.   • Particularly useful in imaging the aorta in  suspected aortic dissection   • HRCT with contrast has been shown to have  sensitivity and specificity comparable to  that of contrast pulmonary angiography.    and in recent years, HRCT has been accepted  both as the preferred primary diagnostic  modality, and also as the criterion standard  for making or excluding the diagnosis of  pulmonary embolism.   • V/Q scan remains an important part of  the evaluation for detecting pulmonary  thromboembolism when HRCT angio-  graphy is not available.   • Intravenous administration of a radioiso-  tope (e.g. 201 thallium or tetrafosmin) at rest  and during stress provides additional  information about myocardial perfusion.  Areas of decreased uptake during exercise,  followed by normal uptake at rest suggest  ischemia; whereas areas of persistent defect  indicate infarction.   • This technique, which delineates coronary  artery anatomy, is the gold standard and  indicated in those patients who are at high  risk for CAD by noninvasive tests, and for  those with persistent symptoms despite  medical therapy, i.e. medical vs. surgical  management, including stenting and CABG.   • Coronary angiography, although generally  accepted to be the gold standard of diagnosis,  is not 100% sensitive for exclusion of coronary  artery disease. Coronary angiography detects  the later stage of atherosclerosis (negative  remodeling stage), when larger plaques  significantly impinge on the coronary lumen.  Angiography may fail to detect the early stage  of atherosclerosis (positive remodeling stage),  when smaller plaques cause minimal or no   • Multislice computed tomography coronary  angiography (MSCT-CA) has emerged as a  powerful noninvasive diagnostic modality  to visualize the coronary arteries and to  detect significant coronary stenoses. The  latest generation 64-slice computed tomo-  graphy (CT) scanners are a robust technique  which allows high-resolution, isotropic,  nearly motion-free coronary imaging.  Coronary stenoses are detected with high  sensitivity and a normal scan accurately  rules out the presence of a coronary stenosis.  With the introduction of further novel  concepts in CT-technology one may expect  that MSCT-CA will become a clinically used  diagnostic tool. 12   • Common GI causes of acute noncardiac chest  pain include esophageal spasm, reflux eso-  phagitis, peptic ulcer, pancreatitis, cholecystitis,  and esophageal perforation. According to one  study, GI disease is the most common cause for  which patients are admitted to a coronary care  unit to have MI ruled out, accounting for 42%  of all cases of chest pain. 13   • Esophagogastroduodenoscopy, 3 hours  monitoring of esophageal pH, esophageal  mano-metry, Bernstein test, and ultrasonic  examination of the abdomen may be indi-  cated where symptoms are atypical, or  cardiac evaluation is normal.   • Can be helpful in patients with pulmonary  chest pain, in differentiating obstructive vs.  restrictive disease and its severity.   • Both hyper- and hypothyroidism can  precipitate CAD. Low or undetectable TSH  in hyperthyroidism may contribute to  anxiety associated chest pain.   • Regardless of where care is given - primary  or emergency department— the critical first  step in managing patients with chest pain is  to explore the possibility of potentially life-  threatening causes of the symptoms,  including ACS, aortic dissection, and PE   • A focussed, expeditiously performed phy-  sical examination should include: heart  rate, palpation of peripheral pulses, BP  measure-ment in both arms, and  estimation of oxygen saturation. Other  salient features are listed in Table 8.1.  Besides coronary risk factors' stratific-  ation, few key investigations to search for  evidence of CAD (a 12-lead ECG, CXR, and  serial measurements of cardiac enzymes)  may be indicated in patients with acute  undifferentiated chest pain   • Physical examination usually does not reveal  any abnormality in the diagnosis of aortic  dissection and PE; thus clinical suspicion  must be heightened in order to diagnose these  conditions   • If acute CAD seems unlikely to be the cause  of the chest pain, the possibility of pul-  monary, GI, and musculoskeletal conditions,  as well as pericarditis and other cardio-  vascular causes (e.g. cardiomyopathy, CSX)  should be investigated   • For clinical evaluation, patients with chest  pain can be classified into three broad  groups, namely: acute pain of recent onset;  recurrent pain - lasting for minutes; and  persistent pain - lasting for hours or even  days (Table 8.2).    Altered mental state; cold  extremities; pulsus altemans;  tachycardia; hypotension; S 4  Dyspnea; tachycardia; hypoxia;   BP difference between two arms;  murmur of aortic insufficiency;  neurological deficit  Tachypnea; hypotension;   elevated JVP; right ventricular  lift; accentuated P 2 ; pulmonary  rales, consolidation, effusion  Dyspnea, dysphagia, hypoxia;  elevated JVP; hypotension;  tachycardia; pulses paradoxus;  muffled heart sounds;  pericardial rub   Dyspnea; hypoxia; tachycardia;  mediastinal shift; hyperresonance;  absent/diminished breath sounds;  subcutaneous emphysema  Hamman's sign (crunching,  rasping sound, synchronous  with heartbeat)    Table 8.2: Classification and examples of  chest pain based on duration    Cardiac: ACS; HCM; aortic stenosis;  pericarditis Vascular: Aortic  dissection; PE; PH Pulmonary:  pneumonia; tracheobronchitis;  pleuritis; pneumothorax; mass lesion  GI: GERD; PUD; biliary disease;  pancreatitis   Others: breast disorders; herpes zoster;  anxiety; emotional  Cardiac: (same as in above)  vascular: PE; PH    • Careful assessment of patient's history and  cardiac risk factors is often the most helpful  starting point. Historical features generally useful  in the diagnosis of cardiac origin of chest pain  include:   • Common features of atypical chest pain are  listed in Table 8.3   • Coronary risk factors include— Age, family  history of heart problems, diabetes,  hypercholesterolemia, smoking, hyper-  tension, obesity, sedentary lifestyle, and  stress or competitive occupation   • Although cardiac risk factors are common  in patients with ACS, they are not a pre-  requisite; absence of such risk factors does  not lower the risk of ACS 14   • The key distinctive point in the clinical  diagnosis of chest pain caused by CAD is in  its relation to physical exertion. If the chest  discomfort is not precipitated by physical  exertion, it is highly unlikely that coronary  artery disease of any significant degree is  present (Table 8.4)   • Occasionally, effort-induced ischemic pain  disappears while the activity continues; this  is known as walkthrough or second wind angina   • Occasionally, diagnosis based solely on  history may not be possible; e.g. descriptions  of chest pain of cardiac, upper gastroin-  testinal, or gallbladder origin can be identical.  Hence, although patient's history is usually a  valuable starting point, it may not provide a  definite diagnosis because of their poor  specificity in diagnosis of chest pain 13   • Symptoms of angina equivalents, i.e. cardiac  ischemia without chest pain, such as   • Features suggesting atypical, also called as non-  cardiac/ nonanginal pain includes:   • Pain — dull ache, sharp, shooting/ knife-like', pleuritic,  pain brought on by respiratory movements or cough.   • Aggravating factors - body movements, respiration,  swallowing, palpation of chest.   • Duration - brief episodes lasting a few seconds, or  constant lasting for days.    Table 8.4: Questions to differentiate patients with non-  cardiac chest pain from those with coronary heart  disease #   If you go up a hill (or other stressor) on 10/10 <10/10   10 separate occasions on how many  do you get the pain?   Of 10 pains in a row, how many occur at rest? <2/10 >2/10   When answers to all three questions are "atypical" the chance of  coronary disease is only 2% in patients aged <55 years and 12% in  those aged >55   ^Christopher Bass et al. Clinical review ABC of psychological  medicine chest pain. BMJ 2002; 325:588-91.   breathlessness; profound, unexplained,  sudden-onset fatigue, especially in the  elderly and diabetic patients is common   • Pain that radiates to the left arm and  shoulder is often assumed to indicate  coronary ischemia, whereas pain that  radiates to the right shoulder is thought to  suggest a biliary source. However, chest pain  that radiates to the right shoulder is more  specific for pain of cardiac origin than pain  that radiates to the left shoulder. Radiation  of chest discomfort to the right arm is also  consistent with the diagnosis of acute IHD 16   • Acute, sudden and severe chest pain described  as ripping or tearing that is maximal at onset  and radiates to interscapular area raises the  possibility of aortic dissection. Important  diagnostic feature is the inequality in the pulses,  e.g. carotid, radial and femoral, and a blood  pressure differential of greater than 20 mm Hg    • The pain of diffuse esophageal spasm may  mimic that of angina pectoris, including that  the relief in many cases is obtained with  nitroglycerine   • Severe chest pain, retrosternal, accompanied  by dyspnea, cough, and hemoptysis deve-  loping in a patient who has been immo-  bilized or bedridden is suggestive of  pulmonary embolism   • Pulmonary hypertensive pain may resem-  ble angina in that it is precipitated by effort.  Associated moderate or severe dyspnea and  evidence of signs of pulmonary hypertension  suggest its diagnosis   • Chest discomfort due to pericarditis is typi-  cally retrosternal, aggravated by coughing,  deep respiration, or change in position; worse  in supine, and relieved in sitting upright and  leaning forward   • The acute onset of pleuritic pain and dyspnea  in a patient with a history of asthma or  emphysema is suggestive of pneumothorax   • Psychogenic chest pain is often associated  with hyperventilation and other somatic  symptoms such as chronic headache, diz-  ziness, sweating, paresthesia, and a sense of  'impending doom'.   • Over-reliance on tests with poor sensitivity,  such as ECG, or on the initial values of cardiac  biomarkers will miss many patients with MI   • In a patient with chest pain, the clinical  response to GI cocktail (a mixture of liquid  antacid, viscous lidocaine, and an  anticholinergic), or sublingual nitroglycerin  (NTG), cannot reliably identify the source of  pain. Failure to respond to NTG should not  be used to exclude the possibility of CAD 7,1/   • A history of a psychiatric diagnosis or  overwhelming anxiety in a patient with    acute chest pain does not preclude the  possibility of an acute coronary event.   Cardiac syndrome X (CSX) § — It is a condition  defined by the presence of angina-like chest pain  with angiographically normal coronary arteries  which is observed in approximately 20-30% of  angina patients undergoing coronary arterio-  graphy. To establish the diagnosis, patients  must have evidence of stress-induced myo-  cardial ischemia by exercise ECG, stress  scintigraphy, or stress echocardiography, in  conjunction with anginal chest discomfort.  Coronary angiography reveals normal or near  normal epicardial coronary arteries. Patients  with CSX are usually younger (mean age 49  years) than patients with atherosclerotic CAD;  more common in women (most of whom are  perimenopausal) than men. Pain, which usually  occurs at rest, may have atypical features. The  exact pathophysiologic factors and mechanisms  of pain in these patients are unclear. However,  patients with chest pain and normal coronary  arteries have abnormal vasodilatory coronary  blood flow responses and an increased  sensitivity of the coronary microcirculation to  vasoconstrictor stimuli (microvascular angina).  Microvascular endothelial dysfunction appears  to be responsible for these coronary micro-  circulation abnormalities. Risk factors such as  hypertension, hypercholesterolemia, increased  plasma homocysteine levels, diabetes mellitus,  abnormal blood rheology, H. pylori infection,  and smoking can contribute to its development.  Most patients with CSX are postmenopausal  women and estrogen deficiency has been    ®CSX must be distinguished from metabolic syndrome x  of insulin resistance (glucose intolerance), hypertension,  hyperlipidemia, elevated BMI, and frequently associated  with abnormal coronary angiography.    therefore proposed as a pathogenic factor in  female patients. Recently, techniques such as  functional angiography, SPECT, and stress MRI  have been used to diagnose CSX. However, the  diagnosis remains one of exclusion. CSX has a  low mortality rate and an excellent prognosis  despite variable symptomatic improvement.    1. Dumville JC, et al. Non-cardiac chest pain: A  retrospective cohort study of patients who  attended a Rapid Access Chest Pain Clinic Family  Practice Advance Access published on April 1,  2007; DOI 10.1093/fampra/cmm002. Fam. Pract.  24: 152-7.   2. Sheps DS, et al. Chest pain in patients with  cardiac and noncardiac disease. Psychosom  Med 2004;66(6):861-7. [PMID: 15564350: Free  full text].   3. Kachintorn U. How do we define non-cardiac  chest pain? J Gastroenterol Hepatol 2005;20  Suppl:S2-5. [PMID: 16359344: Abstract],   4. Eslick GD. Noncardiac chest pain: Epidemiology,  natural history, health care seeking, and quality  of life. Gastroenterol Clin North Am 2004;  33(l):l-23. [PMID: 15062433: Abstract],   5. Nora Goldschlager. Chest pain: Avoiding com-  mon pitfalls. Internal Medicine World Report: Aug  2007.   6. Wilhelmsen L, et al. "Nonspecific" chest pain  associated with high long-term mortality: Results  from the primary prevention study in Goteborg,  Sweden. Clin Cadiol 1998;(7):477-82. [PMID:  9669056: Abstract],   7. Amany H Ahmed, et al. Silent myocardial ische-  mia: Current perspectives and future directions.  Exp Clin Cardiol 2007;12(4):189-96. [PMID:  18651003: Free full text],   8. Arslanian-Engoren C, et al. Symptoms of men  and women presenting with acute coronary  syndromes. Am J Cardiol 2006;98(9):1177-  81.Epub2006Sep7. [PMID: 17056322: Abstract].   9. Wilhelmsen L, et al. "Nonspecific" chest pain  associated with high long-term mortality: Results  from the primary prevention study in Goteborg,  Sweden. Clin Cardiol 1998;21(7):477-82. [PMID:  9669056: Abstract],   1 0 . Autore C, et al. Role of echocardiography in acute  chest pain syndrome. Am J Cardiol 2000;  86(4A):41G-42G. [PMID: 10997353: Abstract],   11. Nissen SE, et al. Intravascular ultrasound: Novel  pathophysiological Insights and current clinical  applications. Circulation 103:604-16.    12. DeFevter PJ, et al. Spiral multislice computed  tomography coronary angiography: A current  status report. Clin Cardiol 2007;30(9):437-42.  [PMID: 17803209: Abstract],   1 3 . Fruergaard P, et al. The diagnosis of patients admit-  ted with acute chest pain but without myocardial  infarction. Eur Heart J 1996;17(7):1028-34. [PMID:  8809520: Free full text],   14. Body R, et al. Do risk factors for chronic coronary  heart disease help diagnose acute myocardial  infarction in the emergency department? Resus-  citation. 2008 Aug6 [Epub ahead of print. PMID:  18691797: Abstract],    1 5 . Swap CJ, et al. Value and limitations of chest pain  history in the evaluation of patients with Suspected  acute coronary syndromes. JAMA 2005;294:2623-  29.   16. Berger JP, et al. Right arm and plain extension can  help to differentiate coronary diseases from chest  pain of other origin: A prospective emergency  ward study of 278 consecutive patients admitted  for chest pain. J Inter Med 1990;227(3):165-72.  [PMID: 2313224: Abstract],   17. Gibbons RJ. Nitroglycerin: Should We Still Ask?  Ann Intern Med 2003;1036-37.   The definition of constipation varies substantially  among patients, physicians, and researchers; and  includes expressions such as infrequent bowel  movements (too infrequent), incomplete eva-  cuation with small feces (too little), difficult bowel  movement, inability to evacuate at will, straining  at stooling, or a need for digital manipulation to  enable defecation (too hard). 1 ' 2   The frequency, consistency, and quantity of  stools also vary depending on an individual's  diet, fluid intake, physical activity, lifestyle, and  social factors. ’ In many patients the complaint  of constipation reflects a mistaken perception  of what constitutes normal bowel habits*. 4  Because of the subjective nature of the condition,  no consensus exists on the definition of  constipation.   However, a working definition of consti-  pation may be described as decreased stool  frequency from the patient's usual pattern, with  or without difficult passage of small, hard stools,  provided it does not represent a recent change in    * A common saying is," One man's constipation is another  man's diarrhea."    bowel frequency, and is not associated with  symptoms such as pain on defecation or  distension.   In clinical practice, constipation is generally  defined as fewer than three bowel movements per  week. An alternative (Rome III) definition for  functional chronic constipation in adults is two or more  of the following criteria 1 for at least 12 weeks, not  necessarily consecutive, in the preceding 12 months  (without use of laxative):   • Sensation of incomplete evacuation after at  least 25% of bowel movements   • Passage of hard or pallet-like stools in at least  25% of bowel movements   • Manual maneuvers (e.g. digital evacuation)  to facilitate more than 25% of bowel move-  ments.   The information acquired from the history  and examination largely determines the investi-  gations required. 3 Majority of chronic consti-  pation patients can be managed depending on    clinical assessment; however, the recently pub-  lished evidence-based recommendations by the  American College of Gastroenterology Task  Force on Chronic Constipation serve as a useful  guide in patients with sinister features at the  outset. 6   • Medication (Opioids, antacids, iron supple-  ments, calcium channel blockers, anticholi-  nergics, antiparkinsonian drugs, antide-  pressants, antipsychotics).   • Intestinal obstruction (volvulus, strangu-  lated hernia, intussusception, or extrinsic  compression by any growth)   • Neurologic disease (stroke syndromes,  dementia, spinal cord disease— paraplegia,  cauda equina lesion, tumors)   • Low Hb level due to occult blood loss in  colonic malignancy.   • In chronically constipated middle-aged or  elderly adults, and in at-risk individuals  (family history of colonic cancer, change in  stooling pattern, weight loss, blood in stools,  abdominal mass), FOBT may be useful to  assess an obstructing neoplasm of the colon.  Perianal lesions can give false-positive results.   • For presence of internal hemorrhoids, fissure,  ulcer, growth, polyp, or stricture; biopsy (Bx)  can be obtained to confirm the diagnosis.    • High blood glucose in uncontrolled chronic  diabetes mellitus complicating autonomic  neuropathy.   • Dilated bowel loops with multiple fluid  levels in intestinal obstruction.   • May provide evidence for an excessive  amount of stool in the colon.   • To assess extrinsic abdominal or pelvic  compression (e.g. pregnancy, fibroid, tumor).   • Preferred procedure in patients at risk (i.e.  with warning signs) for colon cancer or IBD.   • Enables biopsy (Bx) of suspicious lesion, and  remove any high impaction.   • May be appropriate in younger patients  who are not at risk for colon cancer. Polyps,  diverticula, strictures, and luminal wall  lesions can be demonstrated.   • In patients with chronic constipation with  no identifiable cause following initial  evaluation, and in whom initial treatment  has failed, or in those patients wherein  subtypes of constipation are suspected, such  as colonic motility dysfunction, or pelvic  floor dysfunction, following studies may be  helpful: 7   > Anorectal manometry — Mainly to exclude  adult-onset or short segment Hirschsprung  disease.   > Barium defecography— To evaluate eva or-  atory disorders such as rectal prolapse,  enterocele, and rectocele.   > Colonic transit studies (using radiopaque  marker) — To study colonic motility dis-  orders. In normal persons, most of the  markers should pass by day 5; in a patient  with slow colonic transit, the markers will  be scattered throughout the colon. If the  patient has pelvic outlet obstruction, more  than 20% of the markers will be held up in  the rectum.   • Helpful to diagnose Hirschsprung's disease,  ulcerative colitis, Crohn's disease, and infil-  trative diseases such as scleroderma, and  amyloidosis.   • The initial step is to define the nature of the  patient's bowel habit, and how the current  problem differs from the normal pattern.  History should include:    > Amount of time spent on the toilet while  waiting to defecate   > Whether the patient is c/o decreased  frequency of stools, or painful/incom-  plete evacuation   > What maneuvers (pharmacological or  physical) are used to facilitate this  process   > Any other symptoms (pain, protruding  mass, bleeding) the patient may be  experiencing   • Is the constipation acute or chronic— Consti-  pation is generally considered to be acute or  occasional if it's less than three months, and  chronic if it lasts thee months or more   • In acute constipation there is abdominal pain  and vomiting, suggesting the possibility of  intestinal obstruction. The most common  cause of acute constipation in the elderly is  fecal impaction. The diagnosis is made by  DRE by the presence of firm, clay-like mass  indicating impaction   • The most common cause of chronic habitual  constipation is usually a combination of poor  diet low in fiber (fast foods/eat on the run),  decreased fluid intake, physical inactivity,  and failure to acknowledge "call to toilets" 1 * *'   • Diet — Inquiry about a typical day's diet  should include the type and quantities of  fiber, fluid, fruits, vegetables, as well as any  recent change in diet   *'Dyschezia' or lazy bowel is the term used to describe a  rectum that has become unresponsive to fecal content  and this usually follows repeated ignoring of calls to  defecate.    weight loss, change in bowel habits (Table  9.2), nausea, vomiting, abdominal pain,  distension, presence of blood in the stools,  family history of colon cancer is important.    • Depression— Constipation can be a significant  symptom in all types of depressive illness  and may be aggravated by treatment with  depression   • IBS— With IBS the patient may c/o consti-  pation or diarrhea or both alternating. Asso-  ciated somatic and psychological complaints  such as anxiety, depression, chest pain,  headache, fatigue, myalgias, and gynecologic  symptoms strongly favor the diagnosis of  IBS   • Systemic disease— Diabetic neuropathy may  result in constipation due to chronic dys-  motility, and slow transit time. Symptoms    such as cold intolerance, hair and skin changes  suggest myxoedema. Any cause of  hypercalcemia, e.g. hyperparathyroidism,  and malignancy may cause constipation. The  patient may also c/o abdominal pain,  vomiting, nocturia, and mental symptoms  associated with this condition. A neurolo-  gical examination may detect signs of CVA,  dementia, Parkinson's disease, spinal cord  disease, or multiple sclerosis   • Past history — A long history of bowel  obsession®, abdominal surgery, radiation  therapy, may suggest the cause of constipation.   • Physical examination— For weight, nutritio-  nal status, thyroid, and abdomen (tender-  ness, mass, distended bowel loops)   • PR— It is an important procedure because  about one-forth of cancers are within reach  of the examining finger. Lesions such as  hemorrhoids, fissure, ulcer, impaction,  growth, fecal occult blood are obvious   • Anal wink— Sensation of the perianal area  and the 'anal wink' (a reflex constriction  upon pinprick sensation of the perianal area;  mediated by S2, S3, S4) reflex should be tested  in spinal cord disease or lumbosacral roots   • Constipation from infancy may be due to  Hirschsprung's disease. Occasionally symp-  toms may present for the first time in adult  life   • Lifelong constipation (severe refractory  constipation) is sometimes due to megacolon.    ®The older generation considers defecation every day a  sign of good health.   • Intermittent colicky abdominal pain with  distension and progressive constipation or  obstipation is an urgent indication to  evaluate the cause of intestinal obstruction   • Sexual abuse is a known cause of chronic  constipation and needs to be excluded in  patients especially with psychosexual  problems.   Hirschsprung's disease (Congenital Mega-  colon)— Abnormally large or dilated colon due  to congenital absence of myenteric ganglion cells  in a distal segment of the large bowel, and  resultant loss of motor function in this segment  causes massive hypertrophic dilatation of the  normal proximal colon, appears soon after birth,  is called "Hirschsprung's disease". Signs and  symptoms (abdominal distension, vomiting,  constipation, etc.), may vary with the severity  of the condition. Sometimes they appear  after birth; other times they may not be  apparent until the child becomes a teenager or  adult.   Pelvic floor dysfunction (PFD) —The pelvic floor  muscles support the pelvic organs, bladder and  rectum, and their function is critical to activities  such as urinating, having bowel movements,  and sexual intercourse. PFD has traditionally  been described as resulting from laxity or poor  tone of the pelvic floor musculature and/or  ligaments. Damage of this nature usually results  from aging, straining, or trauma, resulting in  complaints such as poor urine stream, consti-  pation, low back pain, pain with ejaculation or    vaginal penetration, pelvic pain or pressure, or  urinary frequency and urgency.    1 . Camilleri M, et at. Clinical management of intrac-  table constipation. Ann Intern Med 1994;  121(7):520-8. Full Text [PMID: 8067650: Abstract],   2. Herz MJ, et al. Constipation: A different entity for  patients and doctors. Fam Pract. 1996;13(2):156-  9. [PMID: 8732327: Free full text],   3. Chang L, et al. Gender, age, society, culture, and  the patient's perspective in the functional gastro-  intestinal disorders. Gastroenterology. 2006;  130(5):1435-46. [PMID: 16678557: Abstract],    4. Ashraf W, et al. An examination of the reliability  of reported stool frequency in the diagnosis of  idiopathic constipation. Am J Gastroenterol 1996;  91(l):26-32. [PMID: 8561138: Abstract],   far should evaluation and treatment go? Postgrad  Med 1990;88(3):49-51, 54,57-9,63. [PMID:   6. Locke GR, et al. American Gastroenterological  Association Medical Position Statement: Guide-  lines on constipation. Gastroenterology 2000;  119(6): 1761-6 [PMID: 11113098: Abstract],   7. Rantis PC Jr, et al. Chronic constipation— is the  work-up worth the cost? Dis Colon Rectum. 1997;  40(3):280-6. [PMID: 9118741: Abstract],   A convulsion is a violent spasm, or a series of  involuntary contractions of the voluntary muscles,  especially those affecting the face, trunk, or  extremities. During convulsions, the person may  cry out, fall to the floor unconscious, his or her body  shaking rapidly and uncontrollably, drool, or even  loose bladder control. Within minutes the attack is  over, and the person regains consciousness, but is  dazed, confused, and incoherent, or may be  exhausted and asleep. This is the image most people  have when they describe the symptoms of  convulsions to physicians which is typical of tonic-  clonic grand mal seizure (Table 10.1).    The term 'convulsion'* * is often used  interchangeably with seizure , + although there are  many types of seizures. Seizures are attacks of  cerebral origin consisting of sudden and  transitory abnormal phenomena of a motor  (convulsive jerking), sensory (light flashes,  buzzing), autonomic (sweating, enuresis),  automatic (abnormal behavior, memory lapse),  or psychic nature (hallucinations), resulting  from transient abnormal neuronal discharge of  the brain, with or without loss of consciousness.  Thus, paroxysmal changes in consciousness,  sensation, emotion, or thought processes may  all be the manifestations of a seizure disorder  without its motor component of convulsions,  which are termed as nonepileptic seizures (i.e. NES:  Table 10.2), especially those subclassified as  psychogenic origin, i.e. psychogenic nonepileptic  seizure (PNES). 1    The special problems posed by children with convulsions  are not addressed.   ^Seizure' is a sudden act, action, or attack of seizing  something (as of disease), especially the physical mani-  festations as convulsions; and the clinician should certainly  refrain from diagnosing a first seizure as epilepsy.   Two major types of NES are recognized; their differen-  tiating features being as follows:   • Psychogenic NESs are symptoms of an underlying  psychiatric disorder, without a physiologic basis,  e.g. conversion disorder, anxiety disorder, PTSD,  psy-chotic disorder, factitious disorder.   • Physiologic NESs are caused by physiologic dys-  function, such as cardiac arrhythmias, hypotensive  episodes, cerebrovascular disease, complicated mig-  raine, parasomnias, tics, and spasms. Such conditions  may result in loss of consciousness, with or without  associated motor manifestations. A detailed history  and appropriate investigations (e.g. Holter moni-  toring, noninvasive carotid artery studies, or tilt-table  testing) will usually reveal the true diagnosis.   Note: Most of the discussion in this article pertains to  psychogenic NESs, i.e. PNES.   Epilepsy * is a symptom complex in which  there is a tendency to have repeated (two or  more), unprovoked seizures, requiring definitive  diagnosis and treatment. Not everyone who has  seizures has epilepsy, but everyone who has  epilepsy has seizures.   Neither convulsions, seizures, nor epilepsy  are a final diagnosis, but are symptom complexes  requiring a search for underlying etiologic  factors. Further, it is extremely important to  differentiate epileptic seizures, including various  simple partial seizures, complex partial seizures,  typical and atypical absence seizures from NES,  because misdiagnosis leads to inappropriate  treatment with antiepileptic drugs, leading to  toxic side effects, causing additional disability  and frustration.   *The word 'epilepsy' is derived from the Greek word for  'attack', (presently meaning seizure). People once thought  that those with epilepsy were being 'attacked' by demons  or Gods. However, in 400 BC Hippocrates suggested  that epilepsy was a disorder of brain.   • Metabolic (electrolyte imbalance, hypo-  calcemic, DKA, uremia, hepatic encephalo-  pathy, cardiac arrest)   • Drug toxicity (aminophylline, theophylline,  ephedrine, terbutaline, bupropion, penicillin,  insulin, metronidazole, pentazocine, lidocaine)   • Hyponatremia, hypokalemia, hypomagne-  semia, hypoglycemia, and hypocalcemia can  precipitate seizures.   • To identify cardiac rhythm, detect possible  cardiac ischemia, and measure QT-interval.  Prolonged QT syndrome often presents with  simple or convulsive syncope.   • CT head is indicated in an emergency, e.g.  when seizures are due to head trauma,  decreased level of consciousness, or a new  neurologic deficit is evident. Otherwise,  waiting for a more definitive imaging with  MRI (for mass lesion, vascular malformation,  stroke, cysticercosis, and multiple sclerosis)  should be considered.   • CSF evaluation in febrile and immunocom-  promised patients suspected with bacterial,  viral, and fungal infection.   • In patients with systemic malignancy, CSF  cytology can identify meningeal carcinoma.   • Can help to establish the presence and type  of seizure. Both interictal (between seizures)  and ictal findings (during a seizure) are used  in evaluating seizure and epilepsy disorders.   • A normal EEG, however, does not exclude the  possibility of epilepsy or seizures. Often    abnormalities are seen after several EEGs  have been obtained. The yield of the test is  enhanced by using sleep deprivation  activating procedures (e.g. hyperventilation,  photic stimulation), increasing the recording  time, and capturing sleep during testing.   • In selected cases with recurrent events, and  nondiagnostic EEG findings, or lack of  response to treatment.   • Also useful in separating true seizure from  pseudoseizure, or other paroxysmal abnormal  behavior, especially when the two coexist.   • May be essential in difficult cases to  distinguish between epileptic and NES.  Video-EEG recordings of the actual event  provide a correlation of clinical and EEG  findings, and a means to assess their  evolution and resolution.   • For drugs and alcohol, especially if an  adequate history cannot be obtained.   • Although in the majority of the patients with  convulsions attending their physicians are  known to be suffering from some kind of  seizure disorder, in others the physician  usually does not witness the seizures, and  must rely on information provided by the  patient, an outside observer, or both. However,  every patient must be assessed in detail, for if  they are not, the systemic disorder that may  have triggered the attack will be missed   • Listen to the patient— Not all jerks, shakes,  tics, tremors, spasms, and dystonia are  convulsions. Therefore, the initial task, when  a patient presents with convulsions, is to  determine whether the attack in question  had indeed features of true seizure    Listen to the eyewitness — An accurate record  from an observer is invaluable, particularly  if there is evidence that his/her attack was  the first one. This record should include:   > Details of the circumstances of the attack  (anxiety, panic, pain, prolonged standing,  physiological acts, e.g. micturition).   > Details of the sequence of events of the attack  itself (e.g. a rhythmic flexion-extension  movement of the extremities, loss of  consciousness, incontinence, tongue biting).   > The aftermath - whether the episode was  followed by period of (postictal) con-fusion.   These observations, especially presence or  absence of aura, and postictal confusion are  critical and help to differentiate seizures  from syncopal and other common physiologic  NES, such as postural hypotension, TIA,  complicated migraine, sleep disorders, and  psychogenic NES (Table 10.3)   What is the cause of seizure? Knowledge of  patient's medical history, including family  history, aids in the understanding the cause of  convulsion or seizure. A history of head trauma,  fever, infection, alcoholism, and systemic disease  such as diabetes mellitus, hypertension,  cerebrovascular disease, and metabolic  disturbances suggest the cause of seizure  Medications and substance abuse— A review  of patient's medications is important. Bron-  chodilators (aminophylline, theophylline,  terbutaline, ephedrine); antidepressants  (bupropion, amitriptyline, imipramine);  antipsychotics (thioridazine, clozapine,  haloperidol); opioids (tramadol); anes-  thetics (lidocaine, pentazocine, fentanyl);  antimicrobials (penicillin, metronidazole,  isoniazid); antineoplastics (vincristine,  methotrexate), 'ecstasy', etc. are known to  provoke seizure.    possibility of pseudoseizure should be care-  fully considered as prompt recognition can  prevent subsequent intervention.   • Physical examination— A focused exami-  nation should be done soon after a paroxys-  mal event and should include:   > Heart rate, rhythm, BP, ECG (hypertensive  encephalopathy), and orthostatic changes  (syncope, arrhythmias).   Patient may fall, may  be injured, or tongue  bruising, incontinence  of urine and faces    > Carotid auscultation for bruits / murmur  (sources of embolic stroke).   > Fundoscopy — For evidence of papilledema,  indicating ICP caused by an intracerebral  hemorrhage, or space occupying lesion.   > Neurologic deficit — Dysarthria, facial  asymmetry, or right or left hemiparesis.  Pupillary asymmetry may indicate  brainstem herniation.   • If the patient is drowsy, the Glasgow Coma  Scale should be used to provide an objective  measure to any subsequent change in the  level of consciousness.   • Psychologic testing — Psychologic testing  may help distinguish patients with NES  from those with epileptic seizures. The  Minnesota Multiphasic Personality Inven-  tory 4 and other inventories, such as the  Washington Psychosocial Seizure Inventory  can have a role in this regard . 0   • New onset of seizures in the elderly may  indicate serious disorder such as CVA, tumor,  including alcoholism, and drug abuse; detail  investigations are indicated 6, 7   • In obscure cases, consider unusual presen-  tation of systemic disorder, e.g. sarcoidosis,  porphyria 1 2 3 4 5 6 7 8   • Discovery of papilledema should lead to  urgent investigations and treatment   • Consider inadvertent or unrecognized drug  or alcohol withdrawal or illicit drug use.  Obtain urine toxicology. An amphetamine  derivative. Ecstasy, (Methylenedioxy-metha-  mphetamine — MDMA) often cannot be  detected by standard toxicology screens;  these substances can present a vexing pro-  blem for clinicians faced with symptoms  from a totally unknown cause . 9    1 . Epilepsy Foundation. Non-epileptic seizure. Web  site:http://www.epilepsyfoundati on.org/answer  place/Life/adults/women/Professional/non-  epilep. Accessed on 22-11-08.   2. Ozkara C, et al. Differential diagnosis in pseu-  doepileptic seizures. Epilepsia. 1993;34(2):294-  8[PMID: 8453940: Abstract],   3. Bode NM, et al. Psychogenic non-epileptic  seizures-Diagnostic issues: A critical review.Clin  Neurol Neurosurg 2008. [Epub ahead of print]  [PMID: 19019531: Abstract],   5. Mimics Z, et al. Adjustment and coping in  epilepsy. Seizure. 2001;10(3):181-7.[PMID:  11437616: Abstract],   6. De Toledo JC. Changing presentation of seizures  with aging: Clinical and etiological factors. Geron-  tology. 1999;45(6): 329-35. [PMID: 10559651:  Abstract].   7. Collins NS, et al. Elders with epilepsy.Med Clin  North Am 2006;90(5):945-66. [PMID: 16962851:  Abstract].   8. Soundravally R, et al. Acute intermittent por-  phyria: Diagnosis per chance. Indian J Pathol  Microbiol 2008;51(4):551-2. [PMID: 19008594:  Abstract].   Cough may be defined as a sudden and variable  expiratory thrust of air from the lungs and  through the air passages, associated with  phonation, which momentarily interrupts the  physiological pattern of breathing.   The act of cough is an important physiologic  pulmonary defence mechanism which is beneficial  in most instances; it helps to keep the lower  respiratory passage clear, protects against entry of  foreign materials from outside, and prevents  stagnation of secretions within the air passages.  Nevertheless, in many patients cough may be  troublesome, sometimes distressing, due to  associated symptoms such as exhaustion, insomnia,  fever, hoarseness, body aches and pains, or its  complications such as rib fracture, urinary  incontinence and syncope, which can lead to  decrease in a patient's health-related quality of life.   Clinically, cough is generally divided into two  groups: productive cough that is accompanied  by sputum, and nonproductive cough, which is  dry and does not produce any sputum. Based on  its duration, cough is said to be acute— less  than some arbitrary duration of 3 weeks, and    chronic/persistent— when more than 3 weeks.  Acute cough, in the great majority of healthy  adults, is minor and self-limiting, although the  possibility of serious cause such as acute  pulmonary edema, asthma exacerbation,  pulmonary embolus, and pneumonia should  always be kept in mind. It is the chronic/  persistent variety that usually prompts patients  to seek medical care. In many patients, chronic  cough is either pathologic by itself, e.g. bronchial  asthma, TB, malignancy, or a manifestation of  systemic disease, e.g. mitral stenosis, GERD, and  LVF that requires attention. In some instances,  chronic cough may manifest as an acute event,  such as an acute exacerbation of chronic  bronchitis. In recent times, whooping cough  (pertussis), a preventable infectious disease in  pediatric age group, is being documented  frequently in adults too as the cause of chronic  cough (Table 11.1 ). lr 2 However, it is observed that,  in patients with uncontrolled and unexplained  persistent cough, with expensive work-up and  medications, and frequent visits to the physician,  as well as the patient's and family's distress and  concern about an underlying disease, may cause  significant psychological stress, including    anxiety, frustration, anger, and irritability.  Therefore, it is suggested that, in the diagnosis  and management of chronic cough, along with  clinical efficacy and cost-effective considerations,  psychological issues related to patients  satisfaction should also be taken into account in  formulating guidelines . 3 " 5   • Failure of children to receive full immunization  schedule as recommended; i.e. five shots by age 7.   • Failure of full protection in spite of completing  recommended immunization schedule.   • Protection from vaccines given in early childhood  diminishes over time, offering little or no protection  five to 10 years after the final injection, so that  pertussis can occur in such subset of older  vaccinated individuals, who may then infect  susceptible infants and individuals.   • Atypical presentation of pertussis in adolescents  and adults; symptoms may be indistinguishable from  those of other upper respiratory infections.   • Physicians often do not include whooping cough  in the differential diagnosis of a persistent cough.   • Ear wax, hair, foreign body in ear canal  (Arnold's reflex)   • Gram stain, acid fast stain and culture for  specific organisms    • Sputum eosinophilia in asthma and non-  asthmatic eosinophilic bronchitis (NAEB)^   > TB (upper lobe infiltrates, hilar lympha-  denopathy, cavitary lesions, pleural  effusion)   > CHF (pulmonary edema, vascular conges  tion, Kerley B lines, peripheral infiltrates,  pleural effusion, cardiomegaly)   • A normal CXR in an immunocompetent patient  with chronic cough usually excludes tuber-  culosis, bronchiectasis, persistent pneumonia,  bronchogenic carcinoma, and sarcoidosis.  However, chronic cough can be a cause of many  disorders in spite of a normal CXR; a few of such  conditions are given in Table 11.2.   • Serial measurements of peak flow rates on  waking, i.e. early morning, during day, and  before bed, demonstrating wide variations  in airflow limitation is seen in asthma, and  facilitates monitoring its treatment.   • Can differentiate obstructive, e.g. asthma,  COPD, from restrictive disease, e.g. sarcoidosis,  pneumoconiosis.   "^"NAEB — a recently defined clinical entity with high  eosinophilic count in induced sputum, that manifests similarly  to, but is distinct from asthma in that there is neither reversible  airway obstruction nor airway hypersensitivity as defined by  a positive methacholine challenge.   • To monitor arterial O n saturation in patients  with asthma or COPD.   • Ambulatory 24-hour esophageal pH monitoring  is the most reliable but invasive test for GERD.  It should, therefore, be performed only after  failure of empiric GERD treatment, and a  negative evaluation for asthma and sinusitis.   • More sensitive for evaluating patients with  equivocal or negative CXR findings.   • Assists in evaluating for mass lesions of  neoplasms, sarcoid, ILDs, and bronchiectasis.   • To evaluate GEDR or its complications such  as esophagitis, ulceration, stricture, Barrett's  esophagus, and adenocarcinoma.   > Chronic, persistent cough with negative  clinical and lab work out   • Performed in patients with high risk of  pulmonary TB. Results are read within 48  - 72 hours of placement. Test is considered  positive if skin erythema measures > 5  mm for HIV-infected and other  immunocom-promised individuals; > 10  mm for those at high risk; and > 15 for all  others.   • In a HIV positive patient CD4+ lymphocyte  count should be obtained; if it's below 200 /  mm 3 , a more intensive evaluation for  opportunistic infection, such as PCP, TB is  indicated.    * PCR confirmation is not recommended as there is no  universally accepted, validated technique for routine  clinical testing.   • Important historical features to be elicited  are: normal (as a part of local irritation due  to viral URTI) versus pathological cough;  acute versus chronic cough that persists for  3 weeks or longer; and respiratory versus  nonrespiratory causes   • Generally, in patients with chronic cough,  neither the patient's description of his or her  cough in terms of its character or timing, nor  the presence or absence of sputum production,  is helpful to rule in or rule out a diagnosis or to  determine the clinical approach   • Does the patient smoke - its frequency and  duration; are there any occupational and  environmental exposures? Is there any clear  triggering or reliving factor?   • Associated red flag symptoms, including  hemoptysis, weight loss, night sweats and  fever, and concomitant risk factors for  malignancy, HIV, and drug abuse (cocaine  lung) are very significant in the evaluation  of chronic cough   • Some physical signs which may provide  etiological clues are: sinus tenderness  (sinusitis); conjunctival injection, rhinitis  (URTIs); consolidation (pneumonia); fine  crackles (pulmonary edema); localized wheeze  (obstructive lesion - tumor, foreign body);  cardiac - (murmur in valvular disease, S 3 in  CHF); ear canal - wax, hair (Arnold's reflex)   • Ask specifically about UACS, i.e. postnasal  drip, as patients often do not volunteer this  information   • Although some evidence suggests that UACS  is a common cause of chronic cough, it is an  entity without a clear definition and no  pathognomonic findings. It is usually  diagnosed in the presence of suggestive  symptoms such as rhinorrhea, nasal  congestion, a sensation of drainage or tickle  in the oropharynx, and throat clearing, with  or without mucoid secretions visualized in    the posterior pharynx. Its role in chronic  cough, though controversial, is supported  by response to therapy — usually an  antihistamine-decongestant combination  drug or nasal corticosteroid spray 1 2 3 4 5 6 7 8   • Cough due to ACE inhibitors is a class effect  and has been documented with all ACE  inhibitors in use; changing to another agent  will not ameliorate the symptoms   • A past history of recurrent lung infections  from childhood is suggestive of cystic fibrosis  and bronchiectasis; a history of hay fever and  eczema suggests asthma; while tuberculosis,  emphysema (alphal-antitrypsin deficiency)  asthma, cystic fibrosis have a familial  predisposition   • In a healthy individual, cough, following  URTI and persisting for at least 3 weeks, but  no more than 8 weeks, consider the diagnosis  of postinfectious cough. In some patients,  transient bronchial hyperreactivity may be  demonstrated   • In all patients with chronic cough, even in  the absence of clinical signs or symptoms,  consider UACS, asthma, and GERD, as they  may present only as cough, and no other  associated clinical findings, i.e. 'silent' UACS,  cough-variant-asthma, and 'silent' GERD  respectively   • In a nonsmoking patient with a clear chest  radiograph who does not use ACE inhibitors,  one or more of the following four causes of  chronic cough account for the overwhelming  majority of cases; namely, UACS, asthma,  NAEB, or GERD.   • A normal lung examination does not exclude  asthma, bronchitis, COPD, GERD or lung  malignancy   • Failure to improve with appropriate manage  ment over 4 weeks signals a need for detail  work up to exclude TB, cough variant asthma,  resistant pulmonary infections, malignancy,  and immunosuppression    • In a patient with chronic bronchitis, any  change in the character of the cough or  sputum may be the presenting feature of a  superimposed bronchogenic carcinoma   • Smoker's cough should not be neglected; it may  be an early symptom of bronchogenic  carcinoma. Conversely, bronchogenic  carcinoma is known to occur in nonsmokers  or in patients with other pulmonary  conditions, such as chronic bronchitis   • When a patient has a cough lasting for >2  weeks without another apparent cause and  it is accompanied by paroxysms of coughing,  posttussive vomiting, and/or an inspiratory  whooping sound, the diagnosis of a B.  pertussis infection should be made unless  another diagnosis is proven   • In patients with unexplained cough, evaluate  the possibility of drug-induced cough.    1. Senzilet LD. Pertussis is a frequent cause of  prolonged cough illness in adults and adolescents.  Clin Infect Dis. 2001;32(12):1691-7. Epub 2001  May 21. [PMID: 11360208: Abstract],   2. Birkebaek NH. Bordetella pertussis in the  aetiology of chronic cough in adults. Diagnostic  methods and clinic. Dan Med Bull 2001;48(2):77-  80. [PMID: 11414122: Abstract],   3. Tomasz J, et al. Chronic Cough From the Patient's  Perspective. Mayo Clin Proc 2007;82:56-60.   chronic cough: Comparison of specific vs generic  quality-of-life questionnaires.Ann Allergy Asthma  Immuno 2005;94(5):581-5.[PMID: 15945562:   5. Brignall K, et al. Quality of life and psychosocial  aspects of cough. Lung. 2008; 186 Suppl 1:S55-  8. Epub 2007. [PMID: 17939003: Abstract],   6 . Braman SS. Postinfectious cough: ACCP evidence-  based clinical practice guidelines. Chest. 2006;  129(1 Suppl):138S-146S. [PMID: 16428703: Free  full text],   7. Pratter MR, et al. Chronic upper airway cough  syndrome secondary to rhinosinus diseases  (previously referred to as postnasal drip  syndrome): ACCP evidence-based clinical practice  guidelines. Chest. 2006;129(1 Suppl):63S-71S.  [PMID: 16428694: Abstract],   8. O'Hara J, et al. "Postnasal drip syndrome": Most  patients with purulent nasal secretions do not  complain of chronic cough. Rhinology. 2006;  44(4):270-3. [PMID: 17216744: Abstract],   Dementia is an acquired neurological syndrome,  common in the elderly, characterized by decline in  memory and cognitive impairment, occurring in a  state of clear consciousness (i.e. the patient is alert).   Although memory is the most common  cognitive ability lost with dementia* *, other  common findings include (Table 12. 1): 1   > Aphasia (i.e. difficulty with language,  speech, comprehension, naming, reading,  and writing);   > Apraxia (i.e. difficulty with motor actions,  inability to perform previously learned  tasks such as combing hair, dressing);   > Agnosia (i.e. difficulty with reorganization  or comprehension of specific auditory,  visual, and tactile stimulus); and   > Personality (e.g. social inhibition, disinterest,  explosive spells, mistrust of others, low  moral character);   * Three types of memory loss may exist in demented  individuals, either individually or in combination; namely:  immediate memory, i.e. difficulty in learning new information;  recent memory, i.e. recalling recent events; and remote memory,  i.e. remembering past personal information.   > Apraxia (impaired ability to perform motor  activities despite intact motor function)   > Agnosia (failure to recognize or identify objects  despite intact sensory function)   Cognitive deficits significantly interfere with work  or social activities and represent major decline from  previous level of functioning.   > Other CNS conditions that cause progressive  deficits in memory and cognition (e.g. cerebro-  vascular disease, Parkinson's disease, Huntington  disease, subdural hematoma, normal-pressure  hydrocephalus, brain tumor)   > Systemic conditions known to cause dementia  (e.g. hypothyroidism, vitamin B [2 and folic acid  deficiency, niacin deficiency, hypercalcemia,  neurosyphilis, HIV infection)   > Disturbance cannot be accounted for by any  nonorganic mental disorder (e.g. major depressive  disorder, schizophrenia)   > Behavior (e.g. repetitive actions, or  questioning; purposeless hyperactivity;  wandering, agitation).   These clusters of symptoms and disabilities  compromise the successful performance of activities  of daily living in a demented individual (e.g.  neglecting household chorus, neglecting self-care,  mistakes at routine work, difficulty handling money,  trouble with shopping, and difficulty in driving).   Dementia does not occur de novo, but probably  represents the end of a spectrum from normal aging  through an intermediate state called mild cognitive  impairment (MCI - vide infra -li). Early identification of  MCI is important because some of the disorders  that cause dementia might be treatable, reversible,  and preventable (Table 12.2). On the other hand,  dementia tends to be progressive, cognitive  functions tend to decline steadily, vegetative  symptoms such as change in appetite, weight,  sleep, and fatigue are often absent, and there is little  or no response to medications. The typical  differentiating features between MCI and  dementia + are given in Table 12.3.   The task of a physician caring for a demented  patient, therefore, is twofold:   > Early identification of those dementias  that are treatable, especially because more  treatment options are now available, and   > Educate and support the family of the  patient with incurable dementia. Much  can be achieved by careful analysis of the  problems, defining what can be restored  and what cannot, even if the condition is  irreversible.    + There are a variety of 'dementias' which most frequently  are categorized as cortical or subcortical. AD is the most  well-known example of a cortical dementia. Subcortical  dementias include Parkinson's, Huntington's, and AIDS  dementia. The presentation of these two types of  dementias differs.   • Endocrine: Thyroid disease, hyperglycemia, hypo-  glycemia, insulinoma, adrenal disease, pituitary  disease, parathyroid disease   • Others: Blindness, chronic seizures, CHF, dialysis  encephalopathy, hearing loss, obstructive sleep  apnea, radiation-induced   • Impaired memory and one or more of the features  of aphasia, apraxia, agnosia, and impaired executive  functioning   • Deficit cannot be explained exclusively by delirium,  CNS disorders, or major psychiatric illness   • Degenerative disorders (e.g. Alzheimer's  disease, i.e. AD; Parkinson's disease, i.e. PD)   • Vascular dementia (i.e. VaD; e.g. multi-infarct  dementia; single strategic infarct, lacunar state.   • Mixed dementia* (i.e. AD with VaD ) 2 " 4   • Infection (viral encephalitis, HIV-associated  dementia complex/ AIDS dementia complex,  meningitis — TB)   • Drug toxicity /polypharmacy/interactions  (e.g. anticonvulsants, anticholinergics,  antihistamines, antiparkinsonian, narcotics,  psychotropics) 5 ' 6   • Metabolic disorders (chronic electrolyte  imbalance— hypocalcemia, hypercalcemia,  hyponatremia, hypernatremia, hypokalemia,  hepatic encephalopathy, uremia).   • Degenerative disease (e.g. dementia with Lewy  bodies®, i.e. DLB; Frontotemporal dementia**,  i.e. FTD; Pick's disease; Huntington disease).    * Mixed dementia is diagnosed when patients have evidence  of AD and cerebrovascular disease, either clinically or  based on neuroimaging evidence of ischemic lesions.  Growing evidence indicates that vascular dementia and  AD often coexist, especially in older patients with  dementia.   ®A Lewy body, described by Fredrick H Lewy, is an  intracytoplasmic concentrically laminated round to  elongated eosinophilic inclusion which often has a dense  central core surrounded by a paler peripheral rim.   ’"The term FTD covers both the temporal and frontal  presentations of this condition: the frontal variant presents  with insidious changes in personality and behavior, with  neuropsychological evidence of disproportionate frontal  dysfunction.   • Nutritional deficiency (e.g. thiamine, Bj-  Wernicke's encephalopathy; B ]2 , folate-  pernicious anemia; nicotinic acid-pellagra)   • To exclude anemia, including macrocytic  anemia with B p deficiency and infection.   • May be useful to monitor serum sodium and  potassium in patients with dementia due to  metabolic disorders.   • An elevated TSH level with a low free T , level  is characteristic of primary hypothyroidism.   • A decreased TSH level with a high free T 4  level is characteristic of primary hyperthy-  roidism.   • As a general rule, imaging should be  performed in most patients with dementia.  However, it may not be warranted in  patients in whom the medical history  reveals no significant findings, the results of  physical and neurologic examination are  normal, and the onset and progression of  cognitive decline are consistent with AD.   • The choice of imaging method is determined  by either the patient's condition and  suspected pathologic cause at presentation  or the brain region to be examined.   • CT is useful for excluding large strokes,  subdural hematomas, tumor, and  hydrocephalus.   • MRI is particularly recommended in  patients with an atypical presentation,  rapid deterioration, incontinence, focal  neurologic signs, past history of head injury,  or systemic diseases that prominently affect  the brain (e.g. HIV infection, MS, SLE).   • New techniques including diffusion and perfusion  magnetic resonance imaging are helpful for the  differentiation between vascular dementia  and degenerative disorders. Magnetic Resonance  spectroscopy evolves as a tool for the diagnosis  of different forms of degenerative dementia.  Multimodal magnetic resonance holds promise to  diagnose AD at early clinical stages and to  monitor the progression of the disease. 7   • Blood and urine culture may be indicated in  immunocompromised patients with resistant  infection.   • Vitamin B J9 deficiency in megaloblastic  anemia, and not infrequently found with  subacute combined degeneration of the cord.   • Neurosyphilis — VDRL test produces false-  positive result; it must be followed with a  sensitive FTA-ABS test.   > Suspected CJD (detection of specific 14-3-  3 protein in CSF suggests CJD)   • To investigate possible cardiac and pulmo-  nary sources of cognitive dysfunction such  as silent MI; consolidation due to pneumonia,  SOL, or neoplasm.   • SPECT and PET techniques that visualize  cerebral functions as glucose metabolism and    blood flow, may provide positive evidence  supportive of the diagnosis of AD, and may  be helpful to differentiate AD, FTD, and CJD.   • MRA allows for examination of cerebral  arterial vasculature in patients with  suspected cerebrovascular disease, and   • Biopsy (Bx) sampling may be helpful in the  diagnostic approach to rare cases of  dementia for which a reliable diagnosis  cannot be established on the basis of clinical  symptoms, CSF parameters, EEG, and MRI  results, e.g. CJD, CNS vasculitis, and  potentially treatable neoplasms or sarcoid.   • The genetic test for apolipoprotein E4  (apoE4): In general apoE4 is associated with  increased risk of developing AD and other  neurodegenerative disorders.   • To diagnose early dementia and to rule out  pseudodementia n . Patients with pseudode-  mentia often have a pervious history of  depression or a family history of mood  disorder.    + Pseudodementia is a term used to describe the reversible  cognitive impairment associated with major depressive  disorder in older adults. Tire use of this term has been disputed  by some investigators who note that though severe  depression can cause real cognitive impairment, the  condition is treatable (unlike irreversible dementias such as  AD). When depression is treated, many experience  improvement in cognitive function, and some go on to  develop dementia within 2 years; therefore, there is nothing  pseudo about the disability resulting from severe depression.  (Ref. McAllister TW. Overview: pseudodementia. Am J  Psychiatry. 1983 May; 140(5):528-33. [ PMfD: 6342420]).   • Before confirming dementia, rule out benign  forgetfulness of the elderly, also known as age-  associated memory impairment, or MCI, i.e.  dementia not so progressive or serious that  it impairs reasonably successful and  productive daily functioning   • Dementia is diagnosed from the history and  basic examination, especially cognitive  testing (e.g. The Mini-Mental Scale Exami-  nation, 8 i.e. MMSE**; St. Louis University  Mental state examination, i.e. SLUMS) 9 and  confirmed by psychometric testing (e.g. the  Wechsler test and/or the Stanford-Binet  Intelligence Scales)   • The MMSE is commonly used as a screening  tool to detect dementia. However, it performs  poorly in identifying persons with mild  neurocognitive disorder. The SLUMS  examination is a 30-point screening questi-  onnaire that tests for orientation, memory,  attention, and executive functions, and is  possibly better at detecting mild neurocog-  nitive disorder, which the MMSE failed to  detect 10   • MMSE is also been found to be biased by age  and education level. Statistical data indicates  that its appropriate cut-off scores can  improve the sensitivity of culturally modified  versions of the MMSE. A 7 minute mental  screening (7MS) tool §§ , consisting of 4 brief tests  (enhanced cued recall, temporal orientation,  verbal fluency, and clock drawing) to  distinguish between patients with probable  AD and healthy control subjects appears    MMSE is only a formal screening procedure to quantify  cognitive impairment; it is not diagnostic, but can be used  over a period of time to follow progression of dysfunction.  Further cognitive assessment is indicated in specific  patients to confirm dementia.   Described by Solomon and colleagues, the 7 minutes  screening battery takes approximately 7 to 11 minutes.    highly sensitive to AD, and may be useful in  helping to make initial distinctions between  patients experiencing cognitive changes  related to the normal aging process, and those  experiencing cognitive deficits related to  dementing disorders such as AD. It has  reasonable inter-rater and test-retest  reliability, can be administered in a brief  period, and requires no clinical judgement  and minimal training. 11 " 13   • Unless the patient has obvious and profound  cognitive impairment, it is generally  advisable to first interview him or her alone,  followed by an interview with a close family  member or caregiver (Table 12.4). 14   • Have you noticed increased forgetfulness or anxiety  about forgetting tilings (such as using lists more, etc)?   • Have any activities been given up (hobbies and  interests, shopping, dealing with finances) and why?   • Have you noticed nocturnal confusion or muddling  when out of usual routine or environment, or  unusual avoidance of new circumstances?   • Have you noticed surprising failure to recognize  people (such as more distant relatives)?   • Have changes been gradual or has there been  sudden worsening?   • In an elderly with suspected dementia,  cognitive testing should be ideally performed  after assessing their visual and hearing status.  Their visual and hearing deficit may add to  confusion and misinterpretation of end result,  leading falsely being classified them as  demented. Patients with early or doubtful  dementia should be screened periodically up to  six months and possibly at intervals thereafter   • Ten early warning signs — Due to time constraint,  it is difficult to perform screening test on all elderly  patients coming to the office. Therefore, particular  attention to the presence of warning signs  suggestive of cognitive impairment is a useful  adjunct to maximize the gain:    1. Memory loss that is getting worse, e.g.  cannot remember recent information,  forget names and appointments;   2. Difficulties with familiar activities, e.g.  housewife to prepare a meal;   3 . Language problems, e.g. has trouble expressing  thoughts, difficulty finding right words;   4. Problems with spatial and temporal  orientation, e.g. get lost at familiar place;   8. Mood swings and behavioral changes,  e.g. sudden mood swing without  discernible cause, explosive outbursts;   9. Personality change, e.g. a friendly person  becomes unexpectedly angry, jealous; and   1 0 . Loss of initiative, e.g. lose interest in hobbies,  excessive procrastination, failure to thrive.  Some of the potentially reversible causes of  dementia should be considered before a  diagnosis of AD is made (Table 12.2).  History should include drug list, head  trauma, alcoholism, gastric surgery, risk  factors for HIV, functional disabilities, degree  of social support, and familial disorders.  Family history— As many as 40-50% of patients  with FTD have an affected family member.  Drug therapy of dementia— Although some  drugs have shown low risk for causing  cognition disorders in research studies, risk  may be increased in frail older adults taking  several medications, and each case should  be reviewed carefully. 15  As cognitive decline is a feature of number of  medical conditions, the physical and systemic  review must be thorough and detailed. Special  attention must be paid for signs of common  problems at the patient's age, including:   > Issues of poor balance when standing up  or walking or gait   > Depression in the elderly may mimic  dementia, and may even coexist in a  significant number of individuals ( vide  supra: pseudodementia).   > Patients with mild HIV dementia  commonly present with psychiatric  symptoms of depression and anxiety.  Therefore, screening all patients with HIV  infection who present with depression  for early HIV dementia is imperative.   • Among a long list of the differential diagnosis  of dementia, four common diseases — AD,  VaD, (Table 12.5), DLB, and FTD - should be  considered, based on history, physical  examination, and simple neuropsychological  evaluation. Although depression, delirium,  psychosis, aphasia, and mild cognitive  impairment share some features with  dementia, each is a distinct syndrome with  its own differential diagnosis. It is important  to consider all of these syndromes when  evaluating a patient with suspected dementia.   > AD— Memory decline is the hallmark of  cognitive change in AD. In the early stage,  memory impairment for recent events is  common whereas long-term memory  remains intact. As the disease progresses,  individuals with AD are increasingly  unable to recall more distant memories.    mellitus, hypertension, coronary heart  disease, and peripheral artery disease).  The onset of cognitive decline is either  subtle or abrupt, and there is psycho-  motor slowing, executive dysfunction,  focal cognitive deficits and motor signs.   > DLB— Clinical features are fluctuating  cognitive impairment over weeks or months  affecting memory and higher cortical  functions (language, visuospatial ability  such as clock drawing or copying of a complex  figure, or reasoning); mild spontaneous  extrapyramidal symptoms; recurrent visual  hallucinations, and parkinsonism, with  intervening episodic lucid interval. In terms  of making a diagnosis, the two most  confusing diseases are DLB and Parkinson's  disease with dementia (PDD) because the  clinical features are similar.   > FTD — Personality and behavioral  changes (apathy, withdrawal, mutism)  are predominant with less prominent  memory loss early in the course;  frequently FTD is misdiagnosed as  personality disorders or late-onset  psychiatric disorders.   • Aging affects the clinical presentation of both  hypothyroidism and hyperthyroidism. Some  of the classic clinical features seen in younger    patients (e.g. cold intolerance, weight gain in  hypothyroidism; and tremor, nervousness,  polyphagia, increased sweating in hyperthy-  roidism) are absent in elderly patients. Also,  apathetic hyperthyroidism (i.e. paradoxical  presentation of hyperthyroidism with fatigue,  psychomotor slowing, depression, and weight  gain) may also occur in this population.  Moreover, the common clinical features of  hypothyroidism (e.g. fatigue, constipation,  cognitive loss) are often attributed to normal  aging. These factors, along with the fact that  hypothyroidism has an insidious onset and  affects multiple organ systems, may cause  considerable delay and difficulty in diagnosis.  Therefore, it is important to have a high index  of suspicion and a low threshold for screening  for thyroid dysfunction in elderly patients who  present with vague, nonspecific symptoms  associated with MCI.   • Dementia and delirium can appear in the  same patient; however, it is important to  distinguish dementia from delirium (acute  metabolically induced state of fluctuating  consciousness). Table 12.6 compares the  features of delirium with those of dementia   • When dementia and delirium coexist,  making it difficult to separate them  clinically, it is not appropriate to give a  patient a new diagnosis of dementia during  a state of delirium. With serial observations  as the delirium resolves, it becomes possible  to differentiate them   • HIV dementia may manifest with acute-  onset psychotic symptoms including  delusions and hallucinations, and these  patients are at a higher risk for suicidal and  homicidal ideation. The initial interview  should include screening for possible suicidal  and homicidal ideation   Profound confusion, clouding  of or impaired consciousness,  drowsy, anxiety, agitation,  bewilderment   Global impairment of cerebral  functions (e.g. recent memory,  intellectual impairment, personality,  and behavior abnormalities)  Progressive course    • "Despite the reemergence of syphilis with  the AIDS epidemic, neurosyphilis is often  neglected in the differential diagnosis of  patients with aseptic meningitis and mental  status changes who are negative for the HIV.  The high mortality rate associated with  delay in recognition, diagnosis, and  treatment of neurosyphilis obligates its  inclusion in the differential of young  patients with cognitive decline." 19   • The mere presence of cerebral atrophy on a  scan should not be taken as evidence of  dementing process. Atrophy can occur in  individuals with no cognitive impairment.   describes hydrocephalus in the absence of  papilledema and with normal CSF opening  pressure on lumbar puncture. The clinical  symptom complex is characterized by  abnormal gait, urinary incontinence, and  dementia. It is an important clinical diagnosis  because it is a potentially reversible cause of  dementia. The features of raised intracranial  pressure are generally absent. The syndrome  mainly occurs in the seventh or eighth decades  of life. Possible etiologic factors include head    injury, subarachnoid hemorrhage, meningitis,  and CNS tumor. The most reliable marker of NPH  is the characteristic magnetic gait in which patient  has great difficulty in lifting feet off the ground  while upright. This gait disorder looks like a very  severe shuffling gait of PD with marked difficulty  taking the first step (start hesitation) or turning.  However, rigidity, tremor, and slowing of rapid,  alternating movements that are common with  PD are less commonly observed in NPH.  Incontinence is usually urinary but may be fecal.  In earlier stages, patients may complain of  urgency and frequency rather than true  incontinence. Dementia is characterized by  prominent memory loss and bradyphrenia, i.e.  slowness of thought processes. MRI assessment  of CSF flow is found to be a promising technique  for evaluation of patients with suspected NPH.   syndrome defined as cognitive decline greater  than expected for an individual's age (generally  older than 65 years) and education level, but  that does not interfere notably with activities  of daily life. Several terms have been suggested  to identify cognitive disorders without  dementia. Benign senescent forgetfulness, age-  associated. memory impairment and aging-associated  cognitive decline are considered to fall within the  limits of normal aging. A recently proposed  term, MCI, as opposed to the terms mentioned  above, identifies a transitional state between  normal aging and dementia. Some people with  mild cognitive impairment seem to remain  stable or return to normal over time, but more  than half progress to dementia within 5 years.  Mild cognitive impairment can thus be  regarded as a risk state for dementia, and its  identification could lead to secondary  prevention by controlling risk factors such as  alcoholism, smoking, obesity, systolic  hypertension, etc. Recently, it has been  proposed to classify mild cognitive impairment    according to memory and nonmemory  involvement as amnestic, multiple domain and  nonmemory single domain clinical subtypes.  However, further studies are suggested to  arrive at a consensus on the diagnostic criteria  for MCI, determining the subgroups and its  treatment modalities.   2. Rockwood K, et al. The diagnosis of "mixed"  dementia in the Consortium for the Investigation of  Vascular Impairment of Cognition (CIVIC). Arm N  Y Acad Sci 2000;903:522-8. [PMID: 10818547],   3. Kenneth M, et al. Mixed dementia: Emerging  concepts and therapeutic implications. JAMA  2004;292(23):2901-08 [PMID: 15598922],   4. Schreiter Gasser U, et al. Alzheimer disease  versus mixed dementias: An EEG perspective.  Clin Neurophysiol 2008 Sep l.[PMID: 18768349],   5. Moor AR, et al. Drug-induced cognitive  impairment in the elderly. Drugs Aging 1999;  15(l):15-28. [PMID: 10459729],   6. Gray SL, et al. Drug-induced cognition disorders  in the elderly: Incidence, prevention and  management. Drug Saf 1999 Aug; 21(2):101-22.  [PMID: 10456379],   7. Felber SR. Magnetic resonance in the differential  diagnosis of dementia. J Neural Transm 2002;  109(7-8):1 045-51 [PMID: 12111442],   10. Tariq SH, et al. Comparison of the Saint Louis  University mental status examination and the mini-  mental state examination for detecting dementia  and mild neurocognitive disorder— a pilot study.  Am J Geriatr Psychiatry 2006;14(11):900-10.  [PMID: 17068312],   1 1 . Paul R. Solomon, et al. A 7 Minute Neurocognitive  Screening Battery Highly Sensitive to Alzheimer's  Disease. Arch Neurol 1998;55(3):349-55.   12. de Jager CA, et al. Utility of the Malayalam  translation of the 7- minute screen for Alzheimer's  disease risk in an Indian community. Neurol India  [serial online] 2008 [cited 2008 Oct 11]; 56:161-  6. Available from:    13. Mathew R, et al. Issues in evaluation of cognition  in the elderly in developing countries. Ann Indian  Acad Neurol [serial online] 2008 [cited 2008 Oct  ll];ll:82-88.   14. Macdonald AJD. ABC of mental health: Mental  health in old age. BMJ 1997;315:413-7.   15. Lenzer J. FDA warns about using antipsychotic  drugs for dementia. BMJ 2005;330:922, doi:  10.1136/bmj.330.7497.922-c   16. Ho RC, et al. Metabolic syndrome and cognitive  decline in Chinese older adults: Results from the  Singapore longitudinal ageing studies. Am J  Geriatr Psychiatry. 2008;16(6):519-22. [PMID:  18515697],   17. Yaffe K, et al. Metabolic syndrome and cognitive  decline in elderly Latinos: Findings from the    Sacramento Area Latino Study of Aging study. J  Am Geriatr Soc 2007;55(5):758-62. [PMID:  1749319],   1 8 . Moretti R, et al. Risk factors for vascular dementia:  Hypotension as a key point. Vase Health Risk  Manag 2008;4(2):395-402. [PMID: 18561514],   19. Schiff E, et al. Neurosyphilis. South Med J 2002  Sep;95(9):1083-7. [PMID: 12356119],   2 0 . Gauthier S, et al. Mild cognitive impairment. Lancet  2006 Apr 15;367(95 18): 1262-70. [PMID:  16631882],   21. Gimzal A, et al. Mild cognitive impairment. Turk  Psikiyatri Derg 2004 Winter;15(4):309-16. [PMID:  15622511],   22. Portet F, et al. What is a mild cognitive  impairment? Rev Prat 2005;55(17):1891-4. [PMID:  16396229],   The definition of diarrhea is somewhat contro-  versial. It depends on the patient's as well as the  physician's perspective. Scientifically, diarrhea  exists if more than 200 g stool is passed daily,  which is best determined by a 72-hour stool  collection. 1   Patients usually consider diarrhea as being  an increase in the daily frequency, liquidity, or  volume of the stool. Clinically, it may be defined  as more than 3 bowel movements in a day.  However, there may be some exceptions to this  definition. Stool weight depends on dietary intake  (e.g. Indian diet has high fiber content, and hence  they have increased stool weight >200 g/day);  therefore, stool weight by itself is an imperfect  criterion to define diarrhea. Moreover, patient's  understanding of 'diarrhea' varies considerably—  many complain of diarrhea when their stool is  loose in consistency, while others complain only  when their stool frequency increases. 2 Therefore,  a more practical definition of diarrhea may be  taken as, ' too frequent passage of too fluid stools',  as compared to patient's baseline pattern.   Diarrhea that lasts less than 14 days is  referred to as acute, while chronic diarrhea is    defined as diarrhea that lasts for more than 4  weeks, and that often persists unless therapy is  instituted (unlike acute diarrhea, which is  usually self-limited). Diarrhea that lasts 14 days  and resolves within a month is generally  referred to as persistent acute diarrhea. Diarrhea is  also classified into groupings such as osmotic  versus secretory, infectious versus noninfec-  tious, and inflammatory versus noninflamma-  tory. Although each of these etiological factors  is helpful for understanding the pathophysio-  logy of individual diarrheal disease, most  diarrheas are complex, and are produced by a  combination of mechanisms.   Acute diarrhea is usually associated with  abdominal colicky pain, urgency, tenesmus,  nausea and vomiting, watery stools, with or  without blood or mucus. Systemic symptoms  such as fever and myalgia may be present. In  severe cases of diarrhea, urgency of defecation  and fecal incontinence is a common event.   In chronic diarrhea, the history is often  nonspecific and physical findings are lacking.  Many patients do not seek medical attention  unless their diarrhea is associated with other  symptoms, such as weight loss, fecal inconti-  nence, rectal bleeding, or abdominal pain.    The majority of cases of acute diarrhea are  benign and self-limiting; but in selected clinical  settings such as elderly, dehydrated, immuno-  compromised, or patients on immunosuppressive  therapy, this aliment can be life-threatening.  Further, the diagnosis of functional disease in  patients with chronic watery diarrhea should be  performed with caution, since in most cases there  is an organic cause that justifies diarrhea. J ' 4   The goal of the initial evaluation of an adult  with diarrhea, therefore, is to differentiate benign  patients from more serious or chronic disorders  needing thorough investigations because of the  possibility of more serious underlying disease.  Although the evaluation can be taxing, making  an accurate diagnosis is rewarding, because  effective therapy is available for many of the  conditions that cause chronic diarrhea. 5   > Bacterial ( Salmonella , Shigella, S. aureus,  Campylobacter, traveler's diarrhea)   • Anemia may suggest blood loss, malabsorp-  tion, infection, or malignancy.   • Megaloblastic anemia suggests malabsorp-  tion of B J2 or folic acid.   • The presence of fecal leukocytes > 10/ (or  lactoferrin) in stool suggests an inflamma-  tory diarrheal disease and may support  obtaining stool culture.   • Useful only if the patient has persistent fever,  bloody diarrhea, immunocompromised, or  occasionally in traveler's diarrhea. Routine  cultures will detect Shigella, Salmonella, and  Campylobacter species. Special media and  conditions are required for pathogens such  as E. coli-057: H, Vibrio cholerae, yersinia, etc.   • Positive fecal occult blood may indicate  inflammatory, neoplastic disease, or ischemic  colitis.   • Fecal ELISA test for giardia-specific antigen,  cysts of E. histolytica, and strongyloides may  be helpful.   • Helpful if the patient is taking or has received  antibiotics within the past one month and  PMC is strongly suspected.   • Stool volume, pH, osmolality, and electro-  lytes estimation is useful in evaluating  obscure cases of chronic diarrhea of secretory  and osmotic etiology. Osmotic gap < 50 mOsm  is suggestive of secretory diarrhea, and >125  mOsm is suggestive of osmotic diarrhea.   • If a patient is ingesting fat (>80 g per day),  Sudan Test is excellent for proving clinical    suspicion of fat malabsorption (part one of the  test - stool fat greater than 5 to 7 g. / 24 hr.), and  it has the added advantage of being able to  suggest maldigestion of dietary triglyceride  (part two of the test). If both part two and part  one of the Sudan Test is positive, it indicates  maldigestion of dietary triglyceride (pan-  creatic insufficiency, small bowel resection). A  negative part two of the Sudan Test does not  exclude pancreatic insufficiency. Mineral oil,  and the unabsorbable fat substitute, sucrose,  polyester could cause false-positive Sudan  Tests (parts one and two).   • Raised alkaline phosphatase in metastasis;  higher values of y-glutamyl transferase  (yGT) in chronic alcoholics.   • Flexible sigmoidoscopy may be useful in  patients with signs and symptoms of  proctitis (tenesmus, rectal pain, and rectal  discharge) or C. difficile colitis, or for  identifying noninfectious causes of bloody  diarrhea such as IBD or ischemic colitis.   • Colonoscopy is more sensitive than barium  enema in detecting PMC, ischemic colitis,  diverticular disease, and tumors and allows  procurement of mucosal biopsies. The  terminal ilium may also be inspected in most  patients.   • For evidence of organomegaly, metastasis, or to  know the site and extent of carcinoid syndrome.   • Stool water that turns red after alkanization  confirms the presence of phenolphthalein, a  stimulant laxative. Urine tests are available  to demonstrate the presence of aloes, senna  alkaloids, and bisacodyl. Sigmoidoscopy  shows Melanosis coli (graphically reminiscent  of tiger, crocodile, or toad skin: vide infrall), i.e.  brown discoloration to the colonic mucosa.   • Two common conditions, usually associated  with the passage of stool totaling < 200 g/d, must  be distinguished from true diarrhea. Pseudo  diarrhea, or the frequent passage of small volumes  of stool with rectal urgency, and accompanies  irritable bowel syndrome or anorectal  disorders like proctitis. Fecal incontinence is the  involuntary discharge of rectal contents and  most often caused by neuromuscular disorders  or structural anorectal problems. Diarrhea and  urgency, especially if severe, may aggravate or  cause incontinence. Many patients are hesitant  to discuss it because of embarrassment.  However, it is important to ask about fecal  incontinence because the condition requires    further evaluation. A careful history and  physical examination generally allow these  conditions to be discriminated from true  diarrhea   • The duration of symptoms is important in  the assessment of diarrhea. While infection  is the leading cause of acute diarrhea (viral  or bacterial), most cases of chronic diarrhea  are noninfectious — IBS being the leading  cause of chronic diarrhea   • History should include recent consumption  of unsanitary food or water (raw or poorly  cooked foods such as eggs, meat, shellfish,  dairy products, fruits and vegetables, or foods  that may have been improperly handled or  stored). Patients should be asked specifically  about the use of public swimming pools,  recent travel (ETEC infection), antibiotic use  within two months (PMC), domestic animal  exposure (Campylobacter infection), previous  surgery (cholecystec-tomy, intestinal  resection and surgery for peptic ulcer  disease), or radiation exposure   • A careful medication history should  specifically screen for antibiotic use causing  PMC, illicit drugs, alcohol, antacids, and  laxative abuse. In chronic diarrhea, associated  medical disorders such as diabetes mellitus,  dysmotility diarrhea, arthropathies in IBD  are helpful in the diagnosis   • Sexual history is important, particularly if  there has been oral-genital or oral-anal  contact. Homosexuals (gay bowel syndrome)  and HIV individuals are at a higher risk for  exposure to infectious agents, and diarrhea  may be the initial presenting manifestation   • Past medical history should focus on any  prior history of diarrheal illness, and  significant underlying medical problems (e.g.  AIDS, diabetes, cirrhosis, sickle cell disease,  cancer, endocrine - thyroid, Z-E syndrome,  or autoimmune disease), prior radiotherapy,  and immunological status.    • Important features in the history which help  guiding the evaluation and management of  patients with acute diarrhea are:   > Stool characteristics-frequency, consis-  tency, quantity, bloody, mucus-filled,  purulent, or greasy;   > Symptoms of dehydration — thirst,  lethargy, postural giddiness, decreased  urination; and   > Presence of associated symptoms —  nausea, vomiting, abdominal cramps,  and significant upper or lower gastro-  intestinal bleeding (coffee ground emesis,  hematemesis, melena, hematochezia).   • Some typical features of diarrhea and stools  associated with common diseases are:   > Diarrhea alternating with constipation -  TB abdomen, laxative abuse, diverticu-  losis, carcinoma of colon;   > Chronic bloody or melanotic stools with  weight loss - IBD, colonic malignancy;   > Pale, bulky, greasy, frothy, foul-smelling  stools, which float in toilet, and associated  with nutritional deficiency, weight loss -  malabsorption syndrome; and   • The Manning criteria (Table 13.1) are helpful to  differentiate IBS from organic causes of diarrhea   • Table 13.2 illustrates common findings on  physical examination and their significance  in patients with diarrhea.   • Infection with E. coli 0157: H7 presents with  many clinical manifestations and should be  included in the differential diagnosis for any    Table 13.1: The Manning criteria to distinguish IBS from  organic disease   5. Subjective sensation of incomplete evacuation  more than 25% of the time    patient with new-onset bloody diarrhea.  Development of the hemolytic uremic  syndrome (HUS) or thrombotic thrombocy-  topenic purpura (TTP) should raise strong  suspicion of E. coli 0157:H7 infection and  should lead to prompt evaluation   • Nocturnal diarrhea, unless occurring in a  known diabetic patient, usually points to an  organic cause   • Abdominal TB (intestinal or peritoneal) can  mimic IBS and must be considered in chronic  diarrheal disease, especially due to rising  HIV incidence   > Symptoms of dehydration: Particularly  postural giddiness, diminished urine  output, and excessive thirst;   Hemorrhagic colitis (E. coli 0157:H7)— Entero-  hemorrhagic E. coli (EHEC) strain designated E.  coli 0157:H7 serotype, causing Hemorrhagic  colitis, is a gram-negative rod-shaped bacterium,  capable of producing potent toxins [verotoxic  (VT), shiga-like toxin] that cause severe damage  to the lining of the intestine. Undercooked or raw  hamburger (ground beef) has been implicated in  many of the documented outbreaks, however, E.  coli 0157:H7 outbreaks have implicated alfalfa  sprouts, unpasteurized fruit juices, milk, dry-  cured salami, lettuce, game meat, and cheese  curds. The illness is characte-rized by severe  cramping abdominal pain, and diarrhea which  is initially watery but becomes grossly bloody.  Occasionally vomiting occurs. Fever is either  low-grade or absent. The illness is usually self-  limited and lasts for an average of 8 days. The  majority of infections resolve completely; some  victims, particularly the very young, have  developed HUS, characterized by renal failure  and hemolytic anemia. In the elderly, it may be  complicated by TTP with high mortality rate.  Because person-to-person transmission of E. coli  0157:H7 is not uncommon, and infection with  this organism may cause severe disease, stool  specimens from all patients with a history of  acute bloody diarrhea should be cultured for  E. coli 0157:H7.    Melanosis coli — It is a pigmentation of the  rectal and colonic mucosa due to use (or abuse)  of anthraquinone type laxatives, and occurs  because of the deposition of a brown black  pigment called lipofuscin in the lamina propria  of the colon. The initial event is mucosal cell  death or apoptosis resulting from anthraqui-  none laxative abuse. These cells are then  phagocytosed by macrophages in lamina  propria producing lipofuscin, which gives a  dark color to the colonic mucosa. Its incidence is  understandably higher in older population and  people who suffer from conditions like IBS and  chronic constipation, and is rising because of  the popularity of the herbal remedies containing  anthraquinone. Melanosis coli is a benign  reversible condition with no malignant  potential. The main importance of diagnosing  Melanosis coli correctly lies in the fact that if it's  extensive, there may be difficulty in differentiating  it from ischemic colitis. Withdrawal of the  offending laxative, which nearly always can be  substituted with a bulk laxative, is sufficient  treatment.   Peutz-Jeghers Syndrome ( Pronunciation : putz  ja'gerz)— It is a hereditary disease caused by  autosomal dominant mutations involving  Chromosome 19. It is characterized by the  presence of intestinal polyps, consistently in the  jejunum, and mucocutaneous pigmentation  with melanin spots (small, flat, brown or dark  blue spots with an appearance of freckles) of the  lips, buccal mucosa, and digits. Isolated  melanotic mucocutaneous pigmentation  without gastrointestinal polyps has also been  described because of the genetic variability of  the syndrome. History includes:   • Repeated bouts of abdominal pain in patients  younger than 25 years   • Menstrual irregularities in females (due to  hyperestrogenism from sex cord tumors  with annular tubules)   • Gynecomastia in males (possible due to the  production of estrogens from Sertoli cell  testicular tumors)   The risk of cancer remains elevated with  disregard to the presence or the absence, as well  as the number, of gastrointestinal polyps.   Pseudomembranous colitis — PMC is a descriptive  term for colitides associated with pseudo-  membrane formation (or plaques) on the colonic or  small intestinal mucosa. Although small intestine  can be involved in PMC, most cases encountered in  the modem era involve only the colon. Clostridium  difficile infection is responsible for virtually all cases  of PMC; the basic mechanism in its pathogenesis  being overgrowth of C. difficile and toxin production  (toxin A is an enterotoxin, while toxin B is a  cytotoxin) by the organism that causes a wide  spectrum of illnesses, ranging from mild diarrhea  to life-threatening PMC. The anaerobes that are  normally present in the colon control colonization  by C. difficile ; therefore, antibiotics that are most  active against anaerobic organisms are more  commonly associated with PMC. Although  clindamycin and lincomycin classically have been  linked to PMC, virtually all antibiotics can cause  PMC; its onset being within days after initiation of    antibiotic therapy, or can occur up to 6 weeks after  discontinuation. Other causative factors for PMC  are abdominal surgery, colonic obstruction,  uremia, and prolonged hypotension causing  hypoperfusion of the bowel. PMC also has been  described with lymphoma, leukemias, and  advanced HIV infection. Diagnosis is primarily by  the detection of C. difficile, or its toxins in stool by  ELISA techniques, or direct culture of C. difficile from  the stool. CT scanning of the abdomen can be helpful  by revealing the presence of bowel wall edema (>4  mm) and inflammation, particularly in cases  involving the right colon. Although these findings  are nonspecific, imaging studies are helpful in  patients with severe disease in detecting  complications (e.g. toxic dilation, perforation).    1 . Achkar E. What is a practical approach to outpatient  evaluation of diarrhea in a previously healthy,  middle-age patient? Cleve Clin J Med 2001;68:104.   2 . Talley NJ, et al. Self-reported diarrhea: What does it  mean?Am J Gastroenterol 1994;89(8):1160-4.  [PMID: 8053428: Abstract],   3. Fernandez-Banares F, et al. Systematic evaluation  of the causes of chronic watery diarrhea with  functional characteristics. Am J Gastroenterol 2007  Nov; 102(ll):2520-8. Epub 2006. [PMID:  17680846 : Abstract],   4. Bertomeu A, et al. Chronic diarrhea with normal  stool and colonic examinations: organic or  functional? J Clin Gastroenterol. 1991;13(5):531-  6. [PMID: 1744388: Abstract],   5. Fine KD, et al. AGA Technical Review on the  Evaluation and Management of Chronic Diarrhea.  Gastroenterology 1999;116:1464-86.   Dyspepsia has been said to be ill-defined, poorly  defined, defying definition, and vague and  misunderstood. 1,2 The Rome III committee  recommends the following pragmatic definition  of dyspepsia: "dyspepsia is defined as the  presence of one or more dyspepsia symptoms  that is considered to originate from the  gastroduodenal region, in the absence of any  organic, systemic, or metabolic disease that is  likely to explain the symptoms". 3,4   It further states that the term functional dyspepsia  should preferably be replaced by more distinctively  defined disorders: (1) meal-induced dyspeptic  symptoms (postprandial distress syndrome), and  (2) epigastric pain syndrome. However, the  committee recommends this definition particularly  for research purposes. 3 ' 6   A working definition of dyspepsia may be  considered as episodic or persistent upper  abdominal symptoms believed to arise from the  upper digestive tract (i.e. epigastrium; pain in  the right or left hypochondrium is not  considered to constitute dyspepsia), which may  or may not be related to eating, and may include  epigastric pain, bloating, fullness, belching.    nausea or early satiety. Patients use this term  variously to express a feeling of bloating,  burping, heartburn (pyrosis), regurgitation,  early satiety, acidity, and indigestion or 'upset  stomach'. It is often accompanied by anorexia,  nausea, vomiting, or flatulence. Although these  symptoms are imprecise and nonspecific, care  in taking the clinical history will often facilitate  making a tentative diagnosis and limit  unnecessary investigations. 7   The main concern of the physician is to allay  patient's fear of organic GI disease by standard  work up, and emphasize 'patient empowerment',  i.e. discuss and agree with the patient how best  he/she can control their symptoms with  treatments available, and advise when symptoms  need further investigations to rule out a more  serious underlying cause.   * A rare cause of indiscriminate eating (hyperoral) behavior  is frontotemporal dementia - vide infra li.    • Functional dyspepsia (Nonulcer dyspepsia,  i.e. NUD + , aerophagy, IBS)   • Peptic ulcer disease (PUD* * e.g. duodenal  ulcer, gastric ulcer, stress ulcer)   • Medications (NSAIDs, iron supplements,  oral antibiotics, corticosteroids, theo-  phylline, digitalis, potassium chloride,  bisphosphonates, metformin, acarbose, OTC  agents/herbal-garlic, gingko. Saw palmetto)   + The older synonym nonulcer dyspepsia, though still widely  used, is not recommended because some ot the patients  have symptoms typical of ulcer disease while others have  symptoms not at all like an ulcer. Furthermore, peptic  ulcer is not the only organic disease to be excluded before  the diagnosis of functional dyspepsia is appropriate. (Ref.  - Dyspepsia-A National Clinical Guidelines, Scottish  Intercollegiate Guidelines Network; March 2003).   • PUD includes ulcer in the stomach, pylorus, duodenum,  or a Meckel's diverticulum, as well as ulcers at sites of GI  anastomosis (stomal ulcer) and at the gastroesophageal  junction.   • To screen for GI carcinoma, adenoma,  intestinal ischemia, and IBD   > In younger patients with positive HP  serology, or urea breath test (UBT);   > Presence of any 'alarm ' features (see 'red  flags' below);   > To obtain biopsy (Bx) specimens, particu-  larly of gastric ulcer.   • These can be either noninvasive (serology,  UBT, or stool antigen test), or invasive  (histology, and rapid urease test)   • IgG serology is easy and most suitable for  initial diagnosis of HP infection because of  its easy availability and low cost; but a  positive test only indicates an ongoing or  previous exposure to HP, and not active  infection. Therefore, this test is not useful for  confirming eradication of the organism, and  documenting successful treatment   • With the UBT, if HP is present, the urease  produced by the organism breaks down  ingested carbon 14 labelled ( 14 C) urea into  ammonia and labeled carbon dioxide, which  can be detected in the patient's breath. UBTs  are useful both for diagnosing active infection  and confirming eradication following  treatment with antibiotics, because once HP  is eradicated, urease is no longer produced.  The UBT is more sensitive and specific than  serology testing, but its disadvantage is that  it requires 14 C (or 13 C) detection equipment  and tends to be more expensive   • Stool antigen test (PCR for HP), like UBT, is  useful both for diagnosing active infection    and confirming eradication following  therapy. It is inexpensive and the test of  choice, especially in children   • Histology: Mucosal biopsies (four — two  antral, and two corpus) obtained during  endoscopy can be stained (H&E, Giemsa, or  Genta stains) to identify HP   • In rapid urease test, the tissue specimen (obtained  at the time of endoscopy) is placed in urea  rich agar medium with a pH sensitive dye. A  color change represents a positive test   • Culture of HP is not often considered as  diagnostic tool due to the difficulty in  culturing this fastidious organism; it is  mostly confined to research laboratories   • Urine and saliva tests for HP have not yet  been completely validated.   • Used as indicated to identify lesions that may  be responsible for dyspeptic symptoms.   • Indicated if endoscopy is difficult or impossible  as in patients with altered esophagogastric  anatomy. A good barium meal study will  identify motility disorders of the esophagus,  (esophageal dilatation, loss of esophageal  peristalsis, poor esophageal emptying, and  'birds beak' tapering of the distal esophagus),  which may be missed endoscopically.   • Not routinely used for mild to moderate  symptoms because findings seldom influence  further medical management; may be  essential for patients who are undergoing  surgery for GERD.   • Performed in patients who have unex-  plained chest pain that does not respond to  medications.   • In patients with gastrin secreting multiple  neuroendocrine tumors (MNE: vide inf rail)  such as Zollinger-Ellison syndrome.   • Dyspepsia for which an underlying disease  process is thought to be responsible for the  symptoms is described as organic dyspepsia, e.g.  PUD, esophagitis; when symptoms persist for  more than 12 weeks, and for which no cause  (structural or biochemical) can be found after  investigation, is usually termed as functional  dyspepsia — this entity is synonymously  termed as NUD. The Rome III criteria for  functional dyspepsia are stated in Table 14.1.  However, according to the Rome III criteria,  frequent clinical overlap of functional  dyspepsia with IBS and GERD is very  common; but this overlap does not exclude a  diagnosis of functional dyspepsia. 8 " 11   with onset at least 6 months previously, of 1 or more of   • No evidence of structural disease (including at upper  endoscopy) that is likely to explain the symptoms.   • The investigation of choice to make the  diagnosis of NUD (functional) is endoscopy  of the upper GI tract. As such NUD can be  referred to as investigated dyspepsia, which  should be distinguished from uninvestigated  dyspepsia. 1    Categorizing NUD in the diagnostic  subgroups such as ulcer-like, reflux-like,  dysmotility-like, and nonspecific dyspepsia  have not shown to be helpful in predicting  diagnosis or response to treatment. This is  mainly due to large amount of overlap  between types of dyspeptic symptoms for  patients with underlying gastric ulcer,  duodenal ulcer, GERD, or NUD, which makes  the clinical history of little use in directing  therapy toward a specific disease state. 13,14  However, careful history is important to:   > Elicit classical symptoms of specific  disorders, e.g. PUD, cholecystitis, GERD;   > Detect complicated ulcer disease, e.g. IDA  due to chronic GI blood loss, vomiting  due to gastric or duodenal outlet  obstruction, sudden, severe abdominal  pain due to peptic perforation;   > Elicit alarm symptoms (see below) that  suggest a high probability of organic  disease, and need further testing rather  than empiric therapy; and   > Detect atypical symptoms more sugges-  tive of other disorders, e.g. MI, IBS.   History should also include a complete review  of medications and OTC agents (see above);  dosage reduction or discontinuation of the  offending agent may relieve patient's symptoms  and avoid further expensive work-up  Patient's habits (alcohol, smoking), lifestyle, past  history of surgical procedures (appendicectomy,  gastrectomy), etc. may suggest potential  etiologies   Evaluation of psychosocial factors — The  contribution of psychosocial factors to the  illness, i.e. functional dyspepsia, and the  decision for psychological referral can be  evaluated through several questions during  the first visit. For example:   > What is the patient's understanding of the  illness? Simple questions such as, "what  do you think is causing your symptoms?".    or "is there anything that you are worried  about regarding these symptoms?", may  help elicit concerns, relieve worries, and  improve patient satisfaction.   > Does the patient accept stressful lifestyle  and/or stressful life events playing a  contributing role?   > Is there a concurrent psychiatric diag-  nosis such as anxiety, depression,  somatization, alcoholism, and drug  dependency?   > What is the family's involvement in  terms of emotional and moral support?  When healthy and supportive behaviors  are present, the family members can be  recruited to help the patient toward  recovery; or else counseling may be  indicated.   • Unless the clinical data (e.g. occult blood in  the stool, significant weight loss, or  abnormal physical findings) suggest the  possibility of other disorders, the diagnostic  studies ordered on the first visit should be  limited. The choice depends on the nature  and severity of symptoms and associated  clinical factors (see below - alarm signs and  symptoms). However, in the majority of  patients with functional dyspepsia,  wherein a variety of emerging therapies  are being developed, but unfortunately,  to date, all of these therapies have yielded  only marginal results. Therefore, the  physician's most effective approach is to  maximize the physician-patient  relationship to help them cope with their  symptoms. 15   • It is prudent to consider any dyspeptic  symptoms as IHD, especially under follo-  wing circumstances:   > History of IHD or cardiac risk factors  A Pulse and blood pressure abnormality.   • Alarm symptoms and signs suggestive of  organic cause in dyspeptic patients, and in  whom endoscopy is indicated, irrespective  of their age, include:   > Pain that radiates to the back (posteriorly  located ulcer, pancreatitis)   > Unresponsive to the sequential treat-  ments for H. pylori eradication   Frontotemporal dementia (FTD) — It is a group  of diseases in which parts of the brain (the  frontal and temporal lobes) shrink, or atrophy,  causing changes in personality and behavior.   • Hyperorality— Excessive eating, be obsessed  with repetitive routines or develop unusual food  obsessions, such as eating the same kind of food  or eating in the same restaurant repeatedly   • Speech output change — Reduction of speech,  stereotype of speech, and echolalia, difficulty  understanding words and naming objects.   The physical examination usually reveals  early prominent primitive or frontal reflexes. One-  half of patients have a family history of dementia  in a first-degree relative. There are three principal  varieties of FTD: frontal variant FTD, semantic  dementia, and progressive nonfluent aphasia.  Frequently, FTD is misdiagnosed as personality  disorders or late-onset psychiatric disorders.   syndromes are genetic neoplastic conditions in  which two or more endocrine glands develop  hyperplasia, adenoma, or carcinoma, concur-  rently or consecutively. Two of the types that  occur are well- documented: MEN 1 (Werner's  syndrome) involves hyperplasia and adenoma-  tosis of the pituitary and parathyroid glands,  islet cells of the pancreas and, rarely, the thyroid  and adrenal glands; MEN 2 (Sipple's syndrome)  which has three variants, classified as MEN2A,  MEN2B and involves medullary carcinoma of  the thyroid, with hyperplasia and adenoma-  tosis of the adrenal medulla (pheochromocy-  toma) and parathyroid glands. MEN I is the  most common form, characterized by the  combined occurrence of tumors in the  parathyroid glands, the pituitary gland, and the  pancreatic islets. The resulting clinical signs    include hyperparathyroidism, hypercalcemia,  hyperprolactinemia, Cushing's disease, gastri-  noma, and Zollinger-Ellison syndrome. This  disease is due to loss-of-function of the MEN1  gene, a tumor suppressor gene on chromosome  11 (Locus: llql3). Diagnosis of MEN 1 depends  on having a high level of suspicion in patients  who present with one of the features such as  recurrent ulcers at atypical sites (esophagus,  jejunum) with poor response to standard ulcer  therapy, hyperparathyroidism, or increased  gastric acid secretion, and serum hyper-  calcemia. Many people may also be diagnosed  because of a proband in the family.   Zollinger-Ellison syndrome — A syndrome that  is characterized pathophysiologically by a  significant hypergastrinemia derived from a  gastrin-secreting neuroendocrine tumor with  a primary location in the pancreas or  duodenum, but also found at other anatomic  sites, (e.g. heart, ovary, gallbladder, liver,  kidney), including stomach and small intestine  (gastrinoma), which sometimes occurs in  families with MEN-1. Chronic hypergastrinemia  triggers gastric acid hypersecretion yielding in  chronic or recurrent or refractory peptic ulcer  disease and/or chronic diarrhea. One half of  patients with ZES will have distant metastases  in the liver by the time the diagnosis is  established and one half of all patients with ZES  will experience chronic diarrhea as chief  complaint rather than peptic ulcer-related  symptoms and signs. Therefore, a high index of  clinical awareness is needed to make a diagnosis  of ZES. The combination of diarrhea and  abdominal pain is present in more than half the  patients, usually > 40 years age. Heartburn is  the third most common symptom, and this  symptom mimics GERD. The other factors that  alert one to the presence of underlying  gastrinomas are the following: 16   > Duodenal ulcer that is not related to  Helicobacter pylori infection or nonsteroidal  anti-inflammatory drug use.   A family history of nephrolithiasis, hyper-  parathyroidism, and gastrinoma also may be  present. Fasting serum gastrin (serial measure-  ments on different days) is the best single  screening test. To localize the gastrin-secreting  tumor, computer-assisted tomography, endos-  copic ultrasound, and somatostatin receptor  scintigraphy provide useful help; but most  recently endoscopic ultrasound with high  resolution transducers appear to improve  preoperative site localization.   1 . Bytzer P, et al. Dyspepsia. Ann Intern Med 2001;  815-22.   2. Heading RC. Definitions of dyspepsia. Scand J  Gastroenterol Suppl. 1991;182:1-6. [PMID:  1896823: Abstract],   3. Drossman DA, moderator. AGA Clinical  Symposium — Rome III: New Criteria for the  Functional GI Disorders. Program and abstracts  of Digestive Disease Week; May 20-25,2006; Los  Angeles, California. [Sp461-469]. In: From Rome  to Los Angeles - The Rome III Criteria for the  Functional GI disorders. Lin Chang. Web site:  http://www.medscape.com/viewarticle/533460.  Accessed on 13-11-08.   4. Tack J, et al. Functional gastroduodenal disorders.  Gastroenterology. 2006;130:1466-79. [PMID:  16678560: Abstract],    5. Tally NJ, et al. The Rome III Classification of  dyspepsia: Will it help research? Dig Dis 2008;  26(3):203-9. Epub 2008. [PMID: 18463436:  Abstract],   6. Suzuki H, et al. Therapeutic strategies for  functional dyspepsia and the introduction of the  Rome III classification. J Gastroenterol 2006;  41(6):513-23. [PMID: 16868798: Abstract],   7. Malfertheiner P. Current concepts in dyspepsia:  A world perspective. Eur J Gastroenterol Hepatol  1999; 11 Suppl l:S25-9. [PMID: 10443909:  Abstract],   8. Wang A, et al. The clinical overlap between  functional dyspepsia and irritable bowel  syndrome based on Rome III criteria. BMC  Gastroenterol 2008;8:43.[PMID: 18808723 : Free  full text],   9. Geeraerts B, et al. Functional dyspepsia: Past,  present, and future. J Gastroenterol  2008;43(4):251-5. Epub 2008 May 6. [PMID:  18458839: Abstract],   10. Van kerkhoven LA, et al. Functional dyspepsia:  Not All Roads Seem to Lead to Rome. J Clin  Gastroenterol 2008. [PMID: 18719513: Abstract],   11. Lundquist P, et al. Symptom criteria do not  distinguish between functional and organic  dyspepsia. Eur J Surg 1998;164(5):345-52. [PMID:  9667468: Abstract],   1 2 . Sander JO Veldhuyzen van Zanten. Treating non-  ulcer dyspepsia and H. pylori. BMJ 2000;321:648-  9, doi: 10.1136/bmj. 321. 7262. 648.   13. Hansen JM, et al. Management of dyspeptic  patients in primary care. Value of the unaided  clinical diagnosis and of dyspepsia subgrouping.  Scand J Gastroenterol 1998;33(8):799-805.  [PMID: 9754725: Abstract],   14. Tally NJ, et al. Lack of discriminant value of  dyspepsia subgroups in patients referred for upper  endoscopy. Gastroenterology. 1993;105(5):1378-  86. [PMID: 8224642: Abstract],   15. Saad RJ, et al. Review article: Current and  emerging therapies for functional dyspepsia.  Aliment Pharmacol Ther 2006;24(3):475-92.  [PMID: 16886913: Abstract],   16. Jennifer Lynn Bonheur. Gastrinoma. Web site -  http://www.emedicine.com/med/ TOPIC2678.  HTM. Accessed on 15-11-08.   Dysphagia is defined as the nonpainful  subjective sensation of having difficulty in  swallowing, involving any structures of the  upper gastrointestinal tract— from the lips to  the lower esophageal sphincter (LES). The term  is used to describe disorders associated with  voluntary swallowing mechanism, and also the  sensation that swallowed bolus is delayed or  completely obstructed in its passage to the  stomach. Some of the ways patients commonly  describe these feelings are— food being stuck in  the throat, or retrosternally, and sometimes  difficulty initiating a swallow itself. Associated  symptoms such as difficult mastication, lump,  fullness, or pressure in the throat or neck  (globus), drooling, coughing while eating, change  in the voice, heartburn (pyrosis), and weight  loss may be present.   Dysphagia is usually divided into oropharyn-  geal and esophageal causes (Table 15.1). Dysphagia  of oropharyngeal disease occurs in disorders  proximal to the esophagus, most often of  neurological or muscular origin. The patient finds  difficulty in preparing and swallowing food bolus  from the mouth to the proximal esophagus ( transfer    dysphagia). There may be instant regurgitation of  food through the nose, chocking, repetitive  swallowing, or cough due to tracheal aspiration.  There may also be dysphonia, dysarthria, or other  neurological symptoms.   Esophageal dysphagia is difficulty in  transporting food bolus down the esophagus ( transit  dysphagia), usually as a result of obstructive or  motility disorders. Patients complain of food  sticking at some point in esophagus, usually lower  sternum or epigastrium. Patients find that they  must chew their food thoroughly and that fluids  may be required to 'wash the food down'. The time  taken to eat is frequently prolonged. Occasionally  the patient may notice regurgitation of undigested  food occurring minutes to hours after a meal.   Dysphagia should be distinguished from  odynophagia, i.e. painful swallowing; however, it  may be associated with dysphagia per se. In  addition, dysphagia should not be confused  with globus*, 1 i.e. constant or intermittent  sensation of a lump in the throat, although no  organic defect is apparent.   Complaints of dysphagia are common,  especially in aging persons, but many do not  necessarily disclose this symptom to their  physician, and for other patients swallowing  impairment does not seem to be a worry . 2 However,  in such patients with dysphagia, additional testing  may be indicated to diagnose the problem and  prevent complications. Therefore, although  patients' concern and experience of frequency,  duration, and life interference are critical variables  in consulting their physician for complaints of  swallowing impairment, it is prudent for the  physicians to remain alert to the presence of  dysphagia in their patients.   These may be grouped into the two broad  categories as stated above:   * Originally called 'globus hystericus'; however, the term  'globus' is preferred since there is no evidence to support  the occurrence of 'hysteria' with this condition.   • Oral ulcers (aphthous ulcer; viral ulcers, e.g.  HSV, CMV, HIV)   • Oral inflammatory lesions (glossitis,  stomatitis, tonsillitis, 'kissing' tonsils,  peritonsillar abscess, i.e. Quincy, epiglottitis,  pharyngitis, retropharyngeal abscess,  Vincent's infection, thrush)   • Stroke (hemispheric stroke, brainstem  stroke, Wallenberg syndrome, i.e. lateral  medullary syndrome: vide infra 44 )   • Advanced age-related oral disorders f (loose,  unhygienic, or structurally defective  dentures*, denture-induced stomatitis)   • Degenerative motor neuron disease (bulbar  palsy, pseudobulbar palsy, ALS, i.e amyo-  trophic lateral sclerosis: vide infra 4 - 4 )   • Autoimmune and rheumatologic disorders  (RA, scleroderma, SS, i.e. Sjogren's syndrome:  vide infra 44 , myopathies)    + Dysphagia as a result of healthy ageing is termed primary  presbyphagia   t Portcullis signs, i.e. the top denture falling on to the bottom  one when the mouth is opened.   • Pill-induced esophagitis (NSAIDs, iron  supplements, alendronate, potassium  chloride, doxycycline, zidovudine)   • Functional GI disorders (FGIDs — associated  with IBS, anorexia nervosa).   • Esophageal motility disorders, i.e. EMDs  (achalasia cardia, diffuse esophageal spasm,  i.e. DES, LES dysfunction, 'Nutcracker* **  esophagus, i.e. NE)    §In tetanus, rabies, and pharyngeal paralysis there is morbid  fear of swallowing, and refusal to swallow due to fear of  aspiration; this is known as Phagophobia.   **The term "nutcracker esophagus" comes from the finding  of increased pressures during contractions (when  pressures exceed 180 mmHg) in the lower esophagus; a  force so strong that some observers have described them  to a mechanical device called nutcracker — a tool powerful  enough to crack open a walnut or similar hard substances.    • Extrinsic compression (mediastinal mass,  pericardial effusion, enlarged left atrium,  thyromegaly, aortic aneurysm, dysphagia  lusoria vide infra 11)   • Reduced Hb with chronic infections, and  malignancy. Anemia may be associated with  P-V syndrome.   • For evidence of aspiration pneumonia, hilar  lymphadenopathy, growth, aortic aneu-  rysm, cardiomegaly (enlarged left atrium,  pericardial effusion), and for locating  swallowed radiopaque foreign body.   • For evidence of cervical osteophytes or any  soft tissue lesion of retropharyngeal or  postcricoid space (e.g. bacterial/tubercular  abscess, metastatic lymphadenopathy)  causing dysphagia.   • The initial investigation of choice in patients  especially with disorders of motor or  'transfer' dysphagia. Diagnostic features are  seen in patients with esophageal webs and  rings; pharyngeal pouch or diverticulum;    strictures — benign (smooth) or malignant  (irregular and tortuous 'rat- tail' deformity);  esophageal dysmotility or spasm ('corkscrew'  deformity); achalasia cardia ('bird's beak'  deformity with dilated proximal esophagus,  and air-fluid level); hiatus hernia; and  dysphagia due to external compression such  as mediastinal growth or aortic aneurysm. It  also reduces the risk of endoscopic perforation  in these disorders, especially in those having  pouch or diverticulum. Different consistencies  of barium (solid, semisolid, or liquid; barium  pill, or a standard marshmallow) further assess  swallowing disorders, as delays in transport  may not be apparent with simple liquid barium.  If the patient has noted a problem with a specific  solid food, a mixture barium paste plus the  offending food may provide definitive  information. 5 The disadvantage of barium X-  rays is that they are relatively insensitive in  detecting mucosal disease, even if air contrast  technique is added. Fluoroscopy can detect  GERD.   • Fiberoptic endoscopy directly visualizes the  esophageal mucosa as well as other areas of  the upper GI tract. Its direct view is superior  to barium X-rays for assessing mucosal  disease of the esophagus, and the esophago-  scope permits assessment of structural  lesions that are identified. Furthermore,  punch biopsies and/or brush cytology of  specific lesions are easily obtained through  the endoscope. Microscopic evidence of  esophagitis may be found even when the  mucosa looks grossly normal   • Endoscopy is the single most useful test in  the evaluation of patients with reflux  symptoms, as it permits one to establish the  presence or absence of esophagitis or  Barrett's esophagus. Endoscopy gives little  reliable information regarding esophageal    function. However, patients with mass lesion  or other lesions identified by barium  swallow should undergo EGD with cytology  and biopsy(Bx) to confirm the diagnosis   > To destroy a lesion by laser, cautery, or  photodynamic therapy, and   > To assist placing of implants or stents for  advanced esophageal malignancy.   • Indicated to assess EMDs, especially if no  obstructing lesion is identified by EGD or  barium swallow. Esophageal peristaltic  contractions — their amplitude, duration,  velocity, and coordination, as well as upper  and lower end sphincter pressure studies,  and their temporal correlations between  symptoms and reflux can be evaluated. On  some patients esophageal manometry is used  in combination with 24 hours pH monitoring  to evaluate uncommon causes of dysphagia,  e.g. DES, NE, achalasia, unexplained chest  pain, and scleroderma.   • Accepted as the most accurate method for  diagnosing reflux. It is, however, uncomfor-  table and expensive investigation. Therefore,  indicated especially:    tt This technique has been revolutionized by a catheter-  less, wireless pH system.    > In the evaluation of patients with chest  pain of undetermined origin.   • An abnormal result is indicated by a pH of  <4 for more than 3% of the time when the  patients are supine, and for > 8% of the time  when they are erect.   • The VSFS— performed jointly by a physician  (typically a radiologist) and a speech-  language pathologist— is the gold standard  for evaluating the mechanism of swallo-  wing. For this study, the patient is seated  comfortably and given foods mixed with  barium to make them radiopaque. The  patient eats and drinks these foods while  radiographic images are observed on a video  monitor and recorded on videotape.   • VSFS permits close observation of all structures  involved in swallowing process, i.e. lips,  tongue, palate, pharynx, larynx, and proximal  esophagus; indicated especially in patients at  risk for silent aspiration, e.g. patients with  stroke, or neurologic impairment such as  cerebral palsy, MS, PD, MG, motor neuron  disease, systemic sclerosis, and connective  tissue disorders such as SLE, and RA.   • VSFS not only allows estimation of risks of  aspiration and respiratory complications,  but also helps in determining dietary  modifications and training in swallowing  techniques and maneuvers.   • These assess gastroesophageal reflux, esophageal  motility disorders, or to identify silent aspiration.  In GERD, reflux is present if the isotope is seen to  travel back up into the esophagus. In esophageal  motility disorders, computer programs measure   ** The VSFS is similar to the MBS, except that the protocol  for the MBS specifies quite small bolus volumes and does  not include drinking from a cup. In practice, the terms  "VSFS" and "MBS" are often used interchangeably.    transit time in the upper, middle and lower thirds  of the esophagus. Scintigraphy also can be  combined with 24-hour pH manometry to  check the cause of chest pain between  esophageal and possible cardiac factors.   • In suspected structural CNS abnormalities, e.g.  primary or secondary tumors, MS; or, aortic  vascular lesions, e.g. aneurysm, lusorian artery.   • Elevated serum CK may be observed in  motor neuron diseases, e.g. polymyositis,  dermatomyositis.   • To detect hypothyroid or hyperthyroid  disorders causing dysphagia, e.g. Graves'  disease or thyroid carcinoma.   • Antiacetylcholine receptor antibody activity  may be elevated in patients suspected with  MG, and polymyositis.   • For example, in familial forms of ALS, or  muscular dystrophy.   • It is important to ascertain that the patient  truly has dysphagia, because some may  misinterpret Tump in the throat' (globus) as  dysphagia   • The clinical features of 'globus' sensation may  occur with organic disease in the neck, pharynx,  or cervical esophagus; hence this diagnosis  should only be made after a complete evaluation    • By asking following specific questions, the  cause of dysphagia can usually be identified:   > Are there any associated problems, e.g. stress,  cough, chest pain, dysphonia, collagen  disease, immunosuppression, weight loss?   • Generally, dysphagia at the very beginning  of swallowing characterizes oropharyngeal  dysphagia; whereas dysphagia a few seconds  after starting to swallow indicates an esopha-  geal cause   • Onset— Acute dysphagia is commonly due  to oropharyngeal causes such as infection,  inflammation, food bolus impaction, or  stroke (see above). Intermittent dysphagia  suggests esophageal dysmotility syndrome,  webs, or rings. Progressive dysphagia  indicates an organic cause such as achalasia,  carcinoma, mediastinal expanding lesion, or  other systemic disorder, e.g. PD, scleroderma   • The type of bolus that elicits symptoms of  dysphagia may indicate its cause (Table 15.2)   • Odynophagia often accompanies dysphagia in  esophagitis, pharyngitis, opportunistic  infections, pill esophagitis, diffuse esopha-  geal spasm, rheumatoid arthritis (inflam-  mation of cricoarytenoid joint), or malignant  process involving the mucosa   • Associated signs and symptoms as impor-  tant clues for possible cause of dysphagia  are given in Table 15.3    Muscular or neural control  disorders of swallowing  (bulbar, pseudobulbar palsy);  motility disorders  Esophageal obstructive  lesions (rings, webs,stricture)  Benign obstructive lesions  (rings, webs, stricture);  esophageal spasm   Obstructive inflammatory  stricture; achalasia;  malignancy (carcinoma  esophagus); scleroderma  Esophageal dysmotility,  especially spasm    Obstructive dysphagia,  esophagitis, brainstem  stroke, acute thyroiditis.  Rings and webs, DES, NE  Obstructive lesions,  carcinoma, scleroderma  Difficulty initiating swallow Oropharyngeal dysphagia  Food 'sticks' after swallow Esophageal dysphagia   Ulcers on the tongue;  tonsillar infection/abscess;  retropharyngeal abscess  Tongue fasciculations  Pallor, koilonychia,  hypochromic microcytic    Mask-like facies, saliva Parkinson's disease  drooling from the mouth,  tremors, cog-wheel rigidity    Drooping of eyelids,  diplopia, swallowing  becomes more difficult  as meal progresses,  extreme weakness  Palpable mass medial to  sternomastoid  Hoarseness of voice,  visible neck, goiter,  tracheal compression  Puckered and narrow  mouth, inability to open  mouth, thickened-hard-and  tight skin, Raynaud's  Phenomenon    • The swallow test 8 — The patient is observed  during the act of swallowing liquids (a few  ounces of water) and solids. Normally a person  can drink/chew, mix, and propel a food bolus  to the posterior pharynx without chocking or  coughing, and no significant amount of  material is retained after a swallow. Drooling,  delayed swallow initiation, coughing, throat  clearing, or a change in voice may indicate a  disorder. After the swallow, the patient is  observed for a minute or more to see if there is  delayed cough response indicating aspiration   • Oropharyngeal examination for ulcers, tonsillar  infection, patch on mucosa, movements of the  tongue, epiglottis, and soft-pallet, as well as  examination of neck for masses, thyromegaly,  and lymphadenopathy is important. Tongue  fasciculahons suggest ALS   • Pharynx and Gag reflex — Does the uvula elevate  symmetrically when the patient says, "Aah"?  Does the patient gag when the posterior  pharynx is brushed? Unilateral movement of  uvula or total absence of its upward movement,  or gagging indicates palatal muscle paresis due  to IX and X cranial nerve or brainstem lesion.  Noting the patient's speech and voice often  confirm the oropharyngeal causes of  dysphagia. The gag reflex needs to be tested  only in patients with suspected brainstem  pathology, impaired consciousness, or  impaired swallowing   • A decreased gag reflex, though commonly  associated with an increased risk of  aspiration, absence of a gag reflex does not  necessarily indicate that a patient is unable  to swallow safely   • Laryngoscopy — Indirect laryngoscopy helps to  confirm the diagnosis of lesions of  oropharynx, larynx, and hypopharynx.  Direct laryngoscopy may be indicated to  evaluate obstructive or neuromuscular  causes of oropharyngeal dysphagia. Changes  in speech, hoarseness, or a weak cough may  represent vocal cord paralysis. Slurred speech  may indicate weakness or incoordination of    muscles involved in articulation and  swallowing. Dysarthria, nasal speech, or  regurgitation of food into the nose may  represent weakness of the soft palate or  pharyngeal constrictors. The combination of  hoarseness, dysphonia (difficulty or pain in  speaking), and nasal speech accompanying  dysphagia is associated with the muscular  dystrophies. Direct laryngoscopy also  helps to differentiate dysphagia due to  laryngopharyngeal reflux disorder (LPRD) §§ ,  and GERD (Table 15.4). Laryngopharyngeal  reflux (LPR) and GERD are different disorders.  The term LPR is used to describe the acid in  the stomach that comes up into the throat at  the level of the laryngopharynx. LPR causes  irritation and changes in the larynx. GERD is  caused by the backflow of gastric contents  into the esophagus, which leads to tissue  damage or esophagitis and heartburn.   Heartburn and/or  regurgitation unusual  Hoarseness, cough,  dysphagia, globus  not usually present    • Neurologic examination includes testing of all  cranial nerves, especially those involved in  swallowing (sensory components of cranial  nerves V, IX and X, and motor components of  cranial nerves V, VII, X, XI and XII)   • Associated central nervous system deficits may  suggest neuromuscular diagnosis, e.g. evidence  of cogwheeling suggests Parkinson's disease;  impaired memory indicates Alzheimer's  disease or other dementia; ataxia, dementia or  dysarthria suggests central nervous system  disease.   • Esophageal dysphagia, e.g. spasm, reflux  esophagitis, may mimic angina pectoris in  every respect, including site (retrosternal);  radiation (neck, jaw, shoulder, thoracic spine,  arm, epigastrium); nature (crushing or  burning); vasovagal symptoms (pallor,  sweating, tachycardia); and promptly relieved  by nitroglycerine, or sublingual nifedipine, as  in angina pectoris. The crucial historical  differentiating points are— esophageal pain is  generally much longer in duration (15-30  minutes), has no relation to exertion, and ECG  or cardiac enzymes are normal   • In complicated cases, both esophageal and  CAD may coexist; hence it is prudent to  exclude CAD by more definitive tests such as  barium esophagography, esophageal pH  monitoring, Holter ECG monitoring, or stress  thallium myocardial perfusion scintigraphy   • Consider esophageal disease as a possible  cause in a patient with recurrent pneumonia;  symptoms are often nocturnal due to  tracheal aspiration or regurgitation of  esophageal contents   • A new onset dysphagia may indicate  esophageal cancer, especially in the elderly   • Dysphagia due to recurrent oral/pharyn-  geal ulcers or thrush may indicate an   • Although patients with dysphagia usually  present with a variety of signs and symptoms,  these can be quite subtle or even absent, e.g. in  those with silent aspiration.   Amyotrophic lateral sclerosis (ALS) — This is the  most common variety of degenerative motor  neuron disease, with a combination of UMN and  LMN signs, although one type may predominate.  Virtually all patients with ALS have dysphagia  - the initial complaint is food sticking at the level  of the cervical esophagus. Bulbar involvement  leads lip and tongue weakness, followed by jaw  and suprahyoid weakness. This, in turn, leads  to labial spillage, poor bolus propulsion, poor  laryngeal elevation, depressed gag reflex, and  poor airway protection. This disorder is  sometimes associated with dementia or  Parkinsonism.   Barrett's esophagus — BE is a condition in which  columnar cells replace the usual squamous cell  in the mucosa of the esophagus. The condition  is recognized as a complication of GERD or  inflammatory disorders of the esophagus. It  occurs more often in men than in women (3:1  ratio); with the average age at diagnosis being  55 years. Barrett's esophagus does not produce  symptoms distinct from GERD or esophageal  inflammation. Most patients complain of  heartburn pain, indigestion, blood in vomit or  stool, difficulty in swallowing solid foods, or  nocturnal regurgitation. Its importance lies in  its predisposition to evolve into adenocar-  cinoma in the esophagus. EGD is the procedure  of choice for the diagnosis of BE. The diagnosis  requires biopsy confirmation (from 4 quadrants  at standard intervals within the esophagus).  Chromoendoscopy, i.e. vital staining with  Lugol's solution performed at the time of upper    endoscopy to aid in cancer detection to identify  abnormal mucosa, may be used as a means of  esophageal cancer screening. In patients who  are at increased risk for squamous cell  carcinoma, the dye stains the glycogen in  normal squamous epithelium a dark brown  color. Areas that are unstained, particularly  those that are larger than 5 mm in size, are  likely to be dysplastic or malignant, and can be  readily targeted for endoscopic biopsy.   Dysphagia lusoria — This is caused by a rare  anomaly of the subclavian artery. This artery  arises from the aortic arch distal of the left  subclavian artery, crossing the midline, behind  the esophagus. This abnormality is generally  silent and often an incidental X-ray finding, but  can result in dysphagia, which generally  appears after the age of 40 years. The diagnosis  can be overlooked at endoscopy, but barium  contrast examination of the esophagus shows a  characteristic diagonal impression at the level  of the fourth thoracic vertebra. CT with contrast  study or MR angiography confirm the diagnosis  and exclude aneurysms.   Eosinophilic esophagitis — This is an emerging  cause of dysphagia, typically seen in young  adults. Often, the history of dysphagia dates to  adolescence. In children it is responsible for  feeding disorders, vomiting, reflux symptoms  and abdominal pain, and in adults it causes  intermittent solid food dysphagia or food  impaction. The natural history of this disorder  has not been well-characterized, but appears  to be marked by periods of spontaneous  remission and exacerbations that are not linked  to specific factors, although food allergies and  exposure have been implicated. Some have a  history of atopy. Endoscopy may reveal a  number of subtle features that include a  'corrugated' esophagus with fine rings; a  diffusely narrowed esophagus that may have  proximal strictures; the presence of linear    furrows, adherent white plaques, or a friable  (crepe paper) mucosa, prone to tearing with  minimal contact; or even normal looking  esophagus. Frank esophagitis is not part of the  macroscopic endoscopic picture of eosinophilic  esophagitis. The most important element in the  diagnosis of eosinophilic esophagitis is to know  its macro- and micromorphological character-  istics. Biopsies from the proximal to the distal  esophagus demonstrating > 15-20 eosinophilic  granulocytes per high powered field favor the  diagnosis. With increasing recognition, this  entity is taking its place as an established cause  of solid food dysphagia.   Progressive systemic sclerosis — Patients with  progressive systemic sclerosis usually present  with heartburn, dysphagia, and regurgitation. The  oral, pharyngeal, and esophageal phages of  swallowing can all be affected. Progressive  atrophy and fibrosis of esophageal smooth muscle  is usually prominent. Gastroesophageal reflux is  frequent. Esophageal manometry typically shows  lower pressures and sometimes aperistalsis. Poor  peristalsis, decreased lower esophageal sphincter  pressures, and gastroesophageal reflux can result  in a transition from a patulous dilated esophagus  to one that is strictured and scarred. Barrett  esophagus may develop. The presence of  oropharyngeal disease is usually accompanied by  pulmonary disease. Patients with progressive  systemic sclerosis may also have xerostomia  (which is frequently due to medications), dental  problems (due to fibrosis of the ligamentous tooth  attachments), trigeminal nerve involvement  (decreased bolus sensation), and lingual atrophy  that can also contribute to dysphagia.   Schwartz ring (pronounced - shats-ke or schatz-ki's  ring) —This is narrowing in the lower part of the  esophagus, consisting of a membrane-like  structure, lined by squamous epithelium on its  superior aspect and columnar epithelium  interiorly. Such a ring is quite common, being    detected in up to 10% of all upper GI barium X-  rays. Few produce sufficient luminal obstruction  to cause dysphagia. When the lumen is narrowed  to a diameter of 13 mm or less, the patient will  experience intermittent solid-food dysphagia or  even episodic food-bolus obstruction.   Sjogren's syndrome (pronounced — "SHOW-  grins")— SS is a chronic disease, probably due to  auto- immunologic factors with genetic predis-  position. Viral infections such as Epstein-Barr  virus (EBV), human T-lymphotrophic virus 1  (HTLV-1), human herpesvirus 6 (HHV-6), human  immunodeficiency virus 1 (HIV-1), hepatitis C  virus (HCV), and cytomegalovirus (CMV) could  be involved in the induction of SS. Women are  affected more often than men — the female-to-male  ratio is 9:1; usually occurring between 30-50 years.  The hallmark symptoms are the "sicca complex",  a combination of dry eyes (keratoconjunctivitis  sicca— KCS) and dry mouth (xerostomia). SS can  affect the oral phase of swallowing when the  salivary glands are involved. The oral dryness of  SS leads to difficulty swallowing dry food, unless  they are washed down with liquids. Patients  with xerostomia have a delayed swallow; some  patients will have dysphagia for solids and some  may take longer to complete a meal. Abnormal  esophageal motility consists of absent or  decreased contractility in the upper third of the  esophagus, while decreased esophageal  peristalsis can be seen in the distal esophagus.  SS occurs in a primary (glandular) form not  associated with other diseases (i.e. KCS and  xerostomia only) and in a secondary  (extraglandular) form (i.e. KCS, xerostomia, and  an autoimmune disease). Most commonly, this  autoimmune disease is RA. The disease is usually  benign; however, in a few with systemic  involvement, there is increased incidence of non-  Hodgkin's lymphoma.   Wallenberg or lateral medullary or posterior  inferior cerebellar artery (PICA) syndrome— It    stroke manifested by imbalance, vertigo,  difficulty swallowing, hoarseness of voice, and  sensory disturbance. Brainstem stroke is  associated with a higher frequency of dysphagia.  This is because the swallowing response control  center resides primarily in the medulla. These  patients often exhibit dysphagia at 1-2 weeks  after stroke, but can make improvements up to  week 3. Common problems include delayed or  absent swallow response, unilateral pharyngeal  paresis, and upper esophageal sphincter  dysfunction. VSFS demonstrates a lack of upper  esophageal sphincter (UES) opening during  swallow in patients with lateral medullary  syndrome, leading to varying degrees of  aspiration.   Zenker's diverticulum — It is also called a pharyn-  goesophageal diverticulum — an outpouching of  posterior hypopharyngeal wall at an area of  potential weakness in the inferior pharyngeal  constrictor muscle referred to as the Killian  dehiscence (usually at the C5/6 level), seen most  commonly in the elderly, in the seventh or eighth  decade of life. The most common presenting feature  is upper esophageal dysphagia; other common  symptoms include halitosis, regurgitation of  undigested food, noisy swallowing, and  aspiration. Hoarseness can be present when the  diverticulum is large enough to compress the  recurrent laryngeal nerve. Some patients also  report excessive salivation and the sensation of a  mass within the throat. A very large diverticulum  can produce an external neck mass, usually on  the left side. Weight loss and recurrent pulmonary  infections occur in approximately one-third of  patients. There is an association with hiatal  hernia, gastroduodenal ulcer, midesophageal  diverticulum, esophageal spasm, and achalasia.  Fluoroscopic barium esophagography is the  mainstay of diagnosis of Zenker diverticulum.  Care must be taken in performing endoscopy in  patients with known Zenker diverticulum, as  passage of the endoscope into the diverticulum  carries some risk of perforation.    1. Deary, et al. Convert psychiatric disturbances in  patients with globus pharyngis; Br J Med Psychol  1989;62 (Pt 4):381-9. [PMID: 2597654]   2. Wilkins, et al. The Prevalence of Dysphagia in  Primary Care Patients: A HamesNet Research  Network Study; J Am Board Fam Med 2007;20:  144-50. [PMID: 17341750],   3. Yan BM, et al. Eosinophilic esophagitis: A newly  established cause of dysphagia; World J of  Gastroenterology 2006;12(15):2328-34. [PMID:  16688820],   4. Farnoosh F, et al. Idiopathic (primary) achalasia.  Orphanet J Rare Dis 2007;2:38. [PMID:  17894899],    5. Boyce HW. Dysphagia and odynophagia. In:  Weinstein WM, Hawkey CJ, Bosch J. Editors.  Clinical Gastroenterology and Hepatology, Part  I, Chapter 3, p.12. Mosby Elsevier,2005.   6. Karthik Ravi, et al. New technologies to evaluate  esophageal function. Expert Review of Medical  Devices, Vol. 4, No.6, 2007;829-37(9).   7. Mariani G, et al. Radionuclide gastroesophageal  motor studies. J Nucl Med 2004;45(6):1004-  28. [PMID: 15181137],   8. Kaor N, et al. Identification of a simple  screening tool for dysphagia in patients with  stroke using factor analysis of multiple  dysphagia variables. J of Rehabilitation Med  Vol. 37, Issue 4 July 2005,247-51. [PMID:  16024482],   Literally the term dyspnea means difficult breathing.  Clinically, dyspnea is a term applied to sensations  experienced by individuals who complain of  unpleasant or uncomfortable respiratory sensations.  The sensation of dyspnea is subjective*, and  includes both the perception of labored breathing  by the patient and the reaction to that sensation , 1,2  which varies in quality and intensity. A recent  consensus statement from the American Thoracic  Society offered the following definition of dyspnea:  "Dyspnea is a term used to characterize a subjective  experience of breathing discomfort that is  comprised of qualitatively distinct sensations that  vary in intensity. The experience derives from  interactions among multiple physiological,  psychological, social and environmental factors,  and may induce secondary physiological and  behavioral responses/   A person with dyspnea may describe this  symptom in terms such as shortness of breath,  breathlessness, chocking sensation, or tightness  in the chest. Subjectively (i.e. from the patient's   *Like pain, dyspnea is a sensory experience that is  perceived, interpreted, and rated solely by the patient  himself.    point of view), patient with acute dyspnea  experiences abnormally uncomfortable aware-  ness of breathing, which is accompanied by  objective findings such as tachypnea, increased  respiratory effort, distress, and even altered  mental status. The patient in such an attack of  acute dyspnea is classified as belonging to class III  or class IV gradation based on New York Heart  Association classification; i.e. dyspnea on minimal  exertion or dyspnea at rest respectively.   Acute dyspnea 1 is a cardinal symptom affecting  the cardiopulmonary system, and can be a sign of  potentially fatal illness (e.g. MI and pulmonary  embolism); hence all reasonable methods should be  used to distinguish between cardiac and pulmonary  causes of dyspnea as rapidly as possible, so as to  improve outcomes and patient survival.   + Acute dyspnea may be considered as 'sudden', i.e.  within seconds to minutes, and 'acute', i.e. within hours  to days.    • Pneumonia (especially in immunocom-  promised or immunodeficiency patients  such as HIV disease and alcoholics)   • Acute LVF (due to MI, pericarditis, cardiac  tamponade, fulminant myocarditis)   • Reduced flow rate of < 150 1/mit (normal  value 400-600 1/mit) indicates obstructive  pulmonary disease that may require  hospitalization; its complete reversibility  is diagnostic of asthma.   • Although in most dyspneic patients the ECG  does not contribute much to diagnosis, it does  indicate whether heart disease of any  disorder is present, such as cardiac ischemia,  arrhythmia, chamber hypertrophy, and  heart block. These cardiac disorders can  contribute to acute dyspnea. Also, lung disease  eventually affects right side of the heart, and  may cause changes suggesting lung disease  such as right atrial or right ventricular  hypertrophy in pulmonary hypertension   • The complex of an S wave in lead I, a Q wave in  III, and an inverted T wave in lead III is specific  for pulmonary embolism, but rarely seen.   • Can demonstrate consolidation, infiltrate,  effusion, pneumothorax, bullae, pulmonary  edema, tumor, and cardiomegaly   • In pulmonary embolism, the CXR is usually  normal, but abnormalities include focal  oligemia (i.e. Westermark's sign); a peripheral  wedge shaped density (i.e. Hampton's hump);  pleural effusions; elevated hemidiaphragm;  or an enlarged right descending pulmonary  artery (i.e. Palla's sign).   • May be indicated in patients with stridor,  e.g. to exclude obstructive lesion or foreign  body aspiration.   • Used as a rapid method for assessment of  oxygenation; hypoxemia of <90% on pulse   • Cardiac troponin and CK-MB is elevated  with MI in the setting of acute LVF.   • They are of value when infective etiology such  as pneumonia, lung abscess is suspected. In an  acutely dyspneic patient the value of sputum  examination depends on the production of  uncontaminated sputum sample.   • Spirometry — With increasing airflow  limitation, FEV falls proportionately more than  the FVC, so that the FEV X / FVC ratio is reduced.   • Useful in assessing the type, degree of  respiratory failure, and measuring the  overall acid-base status   • An increased pH with decreased pC0 9  indicates acute respiratory alkalosis, whereas  both decreased pH and bicarbonates indicate  metabolic acidosis, such as due to DKA.  However, normal levels of oxygenation are  not useful to exclude respiratory or cardiac  diseases causing acute dyspnea.   • It should be performed if aspiration of  foreign body is suspected; the procedure can  be both diagnostic and therapeutic.   • It also allows collection of bronchial  secretions for bacteriological/cytological  examination.   • This is useful in determining risk for DVT or  PE.   • Spiral CT scanning of the chest with  iodinated contrast is gradually replacing  ventilation-perfusion lung scanning as the  screening procedure of choice for the  diagnosis of pulmonary embolic disease   • V/Q scans are recommended only if spiral  CT is not available   • MR angiograms are recommended as a first  line investigation only if spiral CT is  contraindicate d .   • V/Q scan should be used in cases where results  of HRCT are inconclusive, which may  necessitate the use of pulmonary angiography.   • This test is useful to evaluate for the presence  of CHF in patients with dyspnea. A low value  (<80 pg/ml) has a high (99%) negative  predictive value that helps to rule out CHF;  a high value (>100 pg/ml) is nonspecific, but  is about 90% sensitive for CHF.   • This procedure is indicated if CHF, valvular  heart disease, or pericardial effusion is  suspected. It also helps to identify an  embolus in suspected PE. Pulmonary artery  pressure can also be estimated to rule out  pulmonary hypertension causing dyspnea.   • Serum levels of salicylates and other drugs  (e.g. Amiodarone) suspected to be responsible.   • In an acutely dyspneic patient it is important  to ensure that the Airway, Breathing,  Circulation (ABC) are attended to before  continuing with the diagnostic process. Life-  threatening problems must be excluded during  initial examination (Table 16.1). The following  checklist of questions is useful in practice:   > Is the patient receiving drugs; if so what  is the response?   • Once an emergent situation has been excluded,  reassess the patient's airways, mental status,  ability to speak, and breathing effort, and  question the patient (or a family member)  about duration of the dyspnea, any underlying  cardiac or pulmonary disease, medication use,  cough, fever, chest pain, and trauma   • Dyspnea should be differentiated from  tachypnea and hyperventilation which refer  to respiratory variations regardless of the  patient's subjective sensations. Tachypnea is    the objective finding of a rapid respiratory  rate and may or may not be associated with  the feeling of not being able to breathe  properly; tachypnea may be necessary for a  sufficient gas-exchange of the body, for  example after exercise, in which case it is  not hyperventilation. Hyperventilation (or  overbreathing) is an increase in the  respiratory rate above normal — a state of  breathing faster and/or deeper than  necessary, thereby reducing the carbon  dioxide concentration of the blood below  normal. These conditions may not always  be associated with dyspnea. Orthopnea is the  sensation of breathlessness in the recumbent  position, relieved by sitting or standing. Two  uncommon types of breathlessness are  trepopnea and platypnea. Trepopnea is  dyspnea that occurs in one lateral decubitus  position as opposed to the other (e.g. in  patients with unilateral lobectomy,  pneumonectomy). Platypnea refers to  breathlessness that occurs in the upright  position and is relieved with recumbency  (e.g. hepatopulmonary syndrome, cardiac  shunt — Tetralogies of Fallot)   Although the diagnosis of hyperventilation  syndrome is suggested by associated  symptoms of panic and anxiety, or frequent  sighing, it is wise to exclude cardiopulmo-  nary diagnosis before arriving at this  diagnosis   Differentiation between bronchial asthma  and cardiac asthma is critical (Table 16.2).  However, both cardiac and pulmonary  disease and/or disorders of different systems  may coexist in the same patient; e.g. LVF and  COPD, pneumonitis and ARDS, respiratory  muscle paralysis and aspiration pneumonia    • Intensity of wheezing is unreliable. Some  patients with asthma do not wheeze and  some who wheeze do not have asthma   • The presence of orthopnea or paroxysmal  nocturnal dyspnea (PND) is more suggestive  of cardiac failure than of lung disease   • Deep 'sighing' respiration (Kussmaul  respiration, air hunger) of acidosis, usually  seen in diabetic and uremic patients, or  Cheyne-Stokes respiration (periodic  breathing), usually seen in cerebrovascular  disease, or poisoning, should not be  mistaken for acute dyspnea   • A review of medications may provide useful  clues to the possible cause of the dyspnea.    especially in the evaluation of a new patient.  For example, use of an inhaler would point  to a possible history of asthma or COPD. If  patient is taking furosemide he may have a  history of CHF   • Angioedema, characterized by facial,  extremity, and airway edema, may cause  difficulty breathing, and is a possible adverse  effect seen in patients who begin taking an  ACE inhibitor such as captopril   • Cardiac tamponade related to trauma or HIV  is more common in young adults, whereas  tamponade due to malignancy and/or renal  failure occurs more frequently in elderly  individuals   • A diagnostic strategy that combines a high  degree of clinical suspicion ; careful evaluation  of historical and clinical findings (e.g. dyspnea,  pleuritic chest pain, tachypnea, and  tachycardia); risk factors for venous  thromboembolism (e.g. recent surgery or  immobilization, stroke, CHF, cancer, fracture  of the pelvis, femur or tibia, obesity,  pregnancy or recent delivery; estrogen  therapy; inflammatory bowel disease, and  various genetic or acquired thrombophilia);  and corroborative findings from noninvasive  diagnostic techniques (e.g. D-dimer, HTCT of  lungs) can improve diagnostic accuracy of  PE. However, many cases of PE are indeed  clinically silent   • Respiratory rate over 30/mit, pulse rate over  120/mit, and pulsus paradoxus greater than  18 mm Hg indicate a dangerously severe  episode of dyspnea   • Dyspnea at rest, orthopnea, sweating, and  difficulty speaking in sentences, use of  accessory muscles of respiration, decreased    Table 16.3: Physical examination findings in the  diagnosis of acute dyspnea in adults and children   Edema, JVP, S 3 or S 4 gallop rhythm,  hepatojugular reflux, murmurs,  basal crepts, hypertension   Chest pain, localized crepts, friction  rub, edema feet, calf swelling,  recent child delivery    mental status or consciousness indicate a  life-threatening situation and constitute an  indication for urgent intubation   • In a case of asthma, absence of wheezing  (silent chest) or decreased wheezing can  indicate worsening obstruction   • No single noninvasive test or clinical  evaluation can definitively point to a  diagnosis of PE, and this frequently missed  diagnosis may have fatal consequences   • Cardiac tamponade is a medical emergency.  Early diagnosis and treatment are crucial to  reduce morbidity and mortality. Untreated,  it is rapidly and universally fatal.   1. Martinez-Moragon E, et al. Asthma patients'  perception of dyspnea during acute bronchocon-  striction. Aech Bronconeumol 2003;39(2):67-  73. [ PMID: 12586046: Abstract],   2. Bijl-Hofland ID, et al. Relation of the perception  of airway obstruction to the severity of asthma.  Thorax. 1999;54(1):15-19. [PMID: 10343625:  Abstract].   3. Dyspnea. Mechanisms, Assessment, and Manage-  ment: A Consensus statement. American Thoracic  Society. (1999). Am J Respir Crit Care Med; 159,  321-40. [PMID: 9872857: Free full text]   Breathlessness that persists for more than a  month may be termed as chronic dyspnea. This  symptom is present in many different illnesses.  Fortunately, only a few disorders are seen in  practice; therefore, a logical and time saving first  step is to do a rapid assessment of the patient's  general level of distress and vital signs to  exclude the causes for acute dyspnea.* The next  step is to evaluate the patient for the possible  causes of chronic dyspnea.   A patient with chronic dyspnea may present  with any of the following four grades based on  New York Heart Association classification:   • Class I - Disease present but no dyspnea or  dyspnea only on heavy exertion   It is more useful, however, to determine the  amount of exertion that actually causes  dyspnea, i.e. the distance walked, or the number  of steps climbed to assess the functional    capacity. Although there are many tests or  protocols developed to assess individual's  functional capacity, they are prone for  subjective errors by either overestimating or  underesti-mating their true functional  capacity. Therefore the American Thoracic  Society (ATS) has issued standardized  guidelines for the 6-minute walk test (6MWT: vide  infra 44 ), which is safe, easier to administer,  better tolerated, and better reflects functional  cardiopulmonary status and activities of daily  living. 1 " 5   • Upper airway obstruction (foreign body,  tonsillar obstruction, vocal cord paralysis,  external compression, tracheal tumors)   • Neuromuscular diseases (Guillain-Barre  syndrome, myasthenia gravis, amyotrophic  lateral sclerosis, i.e. ALS).   • Erythrocytosis may be seen with any  chronic pulmonary or cardiac cause of  chronic dyspnea   • Gram stain for pneumococcal pneumonia;  ZN stain for mycobacteria; and Giemsa's   • This can demonstrate effusion, pneumothorax,  and cardiomegaly, signs of CHF, fibrosis,  tumor, or hilar lymphadenopathy   • In ILDs it may demonstrate a linear  fibronodular, or fibroreticular infiltrate   • In COPD such as chronic bronchitis and  emphysema, signs of hyperinflation of the  lungs, tapering vascular shadows, and  bullous changes may be seen.   • Useful method for rapid assessment of  oxygenation. In severe COPD, ILDs, desatu-  ration at rest with values of S p( p less than  90% is a sensitive indicator of gas exchange  abnormalities. If abnormal, consideration  should be given to obtaining arterial blood  gas measurements.   • In almost all forms of chronic pulmonary  disease, ECG may show right axis deviation,  right ventricular enlargement and strain,  right atrial enlargement, atrial arrhythmias.  RBBB may occur in long-standing lung  disease. Evidence of left ventricular disease  (ischemia, hypertrophy), pericardial disease  may be seen in chronic left sided heart  failure   • Changes in acid-base balance reflected by the  bicarbonate level in a metabolic panel may  provide a clue to dyspnea. In severe chronic lung  diseases such as COPD, asthma, ILDs,  neuromuscular disorders with hypoventilation,  the serum bicarbonate level may be increased   • Sr creatinine, and urea will often be found to  be high in patients with severe anemia; and  presence of albuminurea, especially when  associated with hypertension   • Formal spirometry differentiates restrictive  and obstructive lung disorders + (Table 17.1).  It can also provide information regarding  severity of the disease and response to  inhaled bronchodilators. Other measure-  ments and lung volumes, and diffusion  capacities such as forced vital capacity (FVC),  forced expiratory volume in 1 second (FEV1),  total lung capacity (TLC), residual volume  (RV), and diffusion capacity of lung for  carbon monoxide (DLCO) are useful in  differentiating various pulmonary and  cardiac causes of dyspnea. However, results  of spirometry need to be evaluated in relation  to reference values. 6 ' 7   • This test is used if the symptoms of dyspnea  are intermittent, or lung disease is suspected  and PFTs are normal.   • Indicated in patients with cardiac causes of  chronic dyspnea, especially if heart failure  is suspected. Other indications include  cardiac valvular dysfunction, pulmonary  hypertension, and pericardial disease.    + The two breathing patterns frequently are seen together  in one disease.    Table 17.1: Diseases commonly associated with  restrictive and obstructive lung diseases   • Plasma BNP, a neurohormone, its major  source is cardiac ventricles, suggesting that  BNP may be a more sensitive and specific  indicator of ventricular disorders than other  natriuretic peptides.lt is released in response  to pressure/volume overload, resulting in  increased wall tension. The magnitude of  elevation is proportional to the severity of  heart failure. BNP test may be helpful,  especially in patients who have coexisting  cardiac and pulmonary disease, and are  found to be very reliable in differentiating  CHF from pulmonary disease. 8 " 10   • HRCT is especially helpful in diagnosing  unsuspected ILD. It is the preferred test for  diagnosing bronchiectasis, and can identify  both acute and chronic PE, particularly in  larger vessels.   • Conventional pulmonary angiography is  currently replaced by HRCT angiography,  which has better sensitivity and specificity  in patients presenting with isolated or  chronic dyspnea. 11,12   • Unlike in acute massive PE wherein V/Q  scan usually shows major areas of decreased  perfusion diagnostic of PE, this investigation  in chronic PE may show no abnormality.  Most V/Q scans revert to normal after 24  hours of the episode.   • GERD may be clinically silent, except for the  symptoms of dyspnea and may require  ambulatory esophageal monitoring to confirm  the diagnosis. Studies have identified an  association between gastroesophageal reflux  and chronic dyspnea despite normal pulmo-  nary function tests. Reflux may stimulate vagal  reflexes that inhibit diaphragmatic function,  thereby causing breathlessness. This etiology  can be established by performing a 24-hour pH  monitoring.   • These tests are useful for confirming and  differentiating neuromuscular disease such  as Guillain-Barre syndrome and myasthenia  gravis.   • In some patients with coronary artery disease,  dyspnea may represent an anginal equivalent.  Noninvasive cardiovascular testing (e.g. stress  thallium, stress echocardiography, cardiac  magnetic resonance imaging) and/or cardiac  catheterization should be considered for these  patients.   • This procedure helps quantify cardiac  function, pulmonary gas exchange, venti-  lation, and physical fitness. It is especially  useful in cases where no apparent cause for  dyspnea is found after a thorough evaluation  or in patients who have multiple potential  causes for dyspnea. Parameters that are  measured by computerized systems are  blood pressure, electrocardiography, heart  rate, ventilation, oxygen saturation, oxygen  uptake, and carbon dioxide output. In normal  individuals, pulmonary capacity is greater  than cardiac. By determining the function of  both the cardiac and pulmonary systems,  the relative degree of impairment can be used  to guide therapy.   • Lung biopsy may be indicated in cases of  ILD that are difficult to diagnose or when  malignancy is suspected.   • The first step in the evaluation of patients with  chronic dyspnea is to establish the primary  organ/system involved - pulmonary, cardiac,  both, or neither   • Specific questions regarding change in weight,  exercise habits, occupational exposures,  asthmatic triggers, cardiac risk factors  (diabetes, hyperlipidemia, hypertension, and  tobacco abuse) psychiatric history, sources  of stress and anxiety, or symptoms of GERD  should be asked   • History of connective tissue disorders such  as rheumatoid arthritis, polymyositis, and  scleroderma is suggestive of ILDs causing  chronic dyspnea   • History of endotracheal intubation, tracheo-  stomy is suggestive of upper airway obs-  truction causing dyspnea    • In a patient with history of chronic, episodic  dyspnea with superficial/hilar lymphade-  nopathy, arthralgia, cutaneous nodules, and  raised serum calcium is suggestive of sarcoidosis   • Progressive dyspnea may be the initial  manifestation of carcinoma of lung, breast,  stomach, prostate, or other organs   Orthopnea; PND; JVP;  pedal edema; S 3 ;  basilar crepts; hypertension;  CAD;DM   B-Blokers causing bronchospasm;  Amiodarone / nitrofurantoin  causing pneumonitis;  methotrexate causing lung fibrosis   • Dyspnea in older people may be associated  with disease in a single or more likely  multiple organs   • The common causes of dyspnea are frequently  over diagnosed when a less common cause of  dyspnea is actually present; e.g. dyspnea in  an elderly smoker is commonly diagnosed as  bronchitis (smoker's cough), which could  have been due to lung carcinoma    • Chronic cough/dyspnea are commonly  treated as 'allergic', which could have been  due to ILDs   • Chronic dyspnea may present as an acute  event; e.g. acute LVF in CHF; pneumothorax  in chronic asthmatic; pulmonary embolism  in valvular heart disease   • ILDs may present with minimal physical  signs or CXR findings, especially in early  stages, despite the presence of significant  dyspnea   • The presence of COPD doubles the risk of lung  cancer in smokers, independent of their  smoking history. lj ' 14   Six-minute walk test (6MWT) — The ability to  walk for a distance is an easy way to measure  exercise capacity in patients with cardiac and  pulmonary diseases. A variety of walk tests,  including self-paced walk tests, controlled-  pacing incremental walk tests, and time-paced  tests are considered to be objective measure-  ments of functional capacity. The 6MWT is an  objective, submaximal exercise test method,  used as a clinical indicator of the functional  capacity in patients with moderately severe  impaired cardiopulmonary diseases such as  COPD, ILD, pulmonary hypertension, heart  failure, and peripheral arterial diseases, and  ability to perform daily living activities. It is  also performed to monitor therapy, or assess  the prognosis in patients with cardiac and  pulmonary diseases. With 6MWT the instruc-  tions to the patient are to "walk as far as you  can during 6-minutes" on a level and straight  track; and not an oval or circular track. The new  ATS guidelines provide a standardized  approach for performing the test. In comparison  to traditional pulmonary exercise test, 6MWT  needs less technical support or equipment,  making it a simple and inexpensive method to    measure functional capacity. The six minute  walk distance (6MWD) can be correlated with  patient's height, BMI, Borg scale, spirometric  parameters and diffusion capacity. Absolute  contraindications to the test include an history  of unstable angina or MI during the previous  month; relative contraindications include  resting tachycardia (heart rate >120/mit),  uncontrolled hypertension, or arthritis and  other musculoskeletal disease.   2 . A1 Ameri HF. Six minutes walk test in respiratory  diseases: A university hospital experience. Ann  Thorac Med 2006;1:16-19.   3. Kervio G, et al. Intensity and daily reliability of  the six-minutes walk test in moderate chronic heart  failure patients. Arch Phys Med Rehabil 2004;  85(9):1513-8. [PMID: 15375827],   4. Pereira de Sousa LA, et al. Six-minute Walk Test  in Patients with Permanent Cardiac Pacemakers.  Cardiopulm Rehabil Prev 2008;28(4):253-7.  [PMID: 18628656: Abstract],   5. Roul G, et al. Does the 6-minute walk test predict  the prognosis in patients with NYHA class II or III  chronic heart failure? Am Heart J 1998;136(3):449-  57. [PMID: 9736136: Abstract],   6. Lung function testing: Selection of reference  values and interpretative strategies. American   7. Aggarwal AN, et al. Comparison of Indian  reference equations for spirometry interpret-  ation. Respirilogy 2007;12(5):763-8. [PMID:  17875069],   8. Yap LB, et al. Natriuretic peptides, respiratory  disease, and the right heart. Chest 2004;  126(4):1330-6. [PMID: 15486400: Free full text],   9 . Tsuchida K, et al. Plasma brain natriuretic peptide  concentrations and the risk of cardiovascular  events and death in general practice. J Cardiol  2008;52(3):212-23. Epub 2008 Aug 26. [PMID:  19027599: Abstract],   10. Sirithunyanont C, et al. Role of the plasma brain  natriuretic peptide in differentiating patients with  congestive heart failure from other diseases. J  Med Assoc Thai 2003;86 Suppl l:S87-95. [PMID:  12866774: Abstract],   11. Kontrus M, et al. Spiral-CT [corrected] in chronic  lung thromboembolism. Radiologe 1996 Jun;  36(6):496-502. Erratum in: Radiologe 1996;  36(8):645. [PMID: 8767120: Abstract],   12. Remy-Jardin M, Remy J. Spiral CT angiography  of the pulmonary circulation. Radiology 1999;  212(3):615-36. [PMID: 10478224: Abstract],   13. Singh RB, et al. Tobacco consumption in relation  to causes of death in an urban population of north  India. Int J Chron Obstruct Pulmon Dis 2007;  2(2):177-85. [PMID: 18044690: Abstract],   14. Woloshin S, et al. The risk of death by age, sex,  and smoking status in the United States: Putting  health risks in context. J Natl Cancer Inst 2008 Jun  18; 100(12):845-53. Epub 2008 Jun 10. Erratum in:  J Natl Cancer Inst 2008;100(16):1133. [PMID:  18544745: Abstract],   Careful studies have shown that mild to  moderate facial asymmetry is, in fact, the norm.  On average, both men and women have right  hemi-face dominance. This normal asymmetry  is usually not prominent on visual scrutiny.  Facial asymmetry is said to exist only when the  asymmetry exceeds the balance that we accept  as normal . 1,2   Symmetry of the face (i.e. facial configuration in  general) depends primarily on the functional  integrity of its muscles, and the movement of these  facial muscles of each side is controlled by the seventh  cranial nerve (CN VII). * If both (i.e. right and left)  facial tracts are intact from the cortex (center) to the  periphery, the muscles will move symmetrically.  Hence, any lesion in the course of its central and/or  peripheral pathway mainly manifests as weakness  or asymmetry of facial muscles . 1    * Most of the present discussion about facial asymmetry is  related to acquired disorders of CN VII palsy. For facial  asymmetry not due to facial nerve palsy, refer to Page no.  125, Table 18.5: Differential diagnosis of altered facial  counter.   + Taste sensation in the anterior part of the tongue may  also be affected.    From therapeutic and prognostic point of  view, it is critical to differentiate this peripheral  (i.e. nuclear) nerve palsy from the central (i.e.  supranuclear) lesions of the CN VII; the latter  manifests only in the lower divisions of the  seventh nerve because of the bilateral cortical  representation. Thus, a central CN VII (upper  motor neuron, i.e. UMN) lesion involves only  the lower face (i.e. upper half escapes), while the  usually benign and self-limited peripheral  (lower motor neuron, i.e. LMN) lesion affects the  entire half of the face on the affected side. Besides  the UMN and the LMN facial nerve palsy, facial  weakness and asymmetry is also seen in muscle  or neuromuscular junction disorders.   Patient with obvious facial asymmetry or  weakness, besides disfigurement, suffer from  impaired function such as difficulty with speech  and eating. A less obvious but often of grave  concern is the inability to express emotion on  the affected side. This loss of nonverbal emotional  communication (e.g. patient cannot register  pleasure, laughter, surprise, interest and worry;  the patient tends to sit with hand over the  affected side of face) can be extremely bothersome    and may even lead to social isolation. Therefore,  in order to minimize the potential for neurological  damage, its possible recurrence, and social  implications, it is imperative that the diagnosis  of the cause for facial asymmetry (Table 18.5)  and weakness be established quickly.   • Metastasis to temporal bone (from carci-  noma breast, bronchus, prostate)   • May be helpful to rule out lymphoproliferative  malignancies such as lymphocytic leukemia,  the initial manifestation of which may be  peripheral facial palsy.   • To exclude sarcoidosis or to rule out TB in  selected patients before treating with steroids.   • CT scan of the temporal bone for evidence of  temporal bone fracture.   • Associated anomalies of the external ear,  middle ear, inner ear, etc. can be assessed.   > Lesion suggesting a posterior fossa lesion  as the cause of CN VII palsy   • Indicated only in inflammation, granuloma,  or malignancy is a consideration.   • A mild pleocytosis of the CSL may be seen in  Bell's palsy.   • To predict recovery, but not needed for diagnosis;  most informative when at least three weeks  have elapsed after the onset of facial palsy.   • Lyme disease serology, i.e. enzyme immuno-  assay (EIA) or immunofluorescent assay  (IFA); ELISA for Lyme disease; especially in  endemic areas.   • If sarcoidosis is suspected; these levels are  high in sarcoidosis.   • Careful observation of the patient's face during  conversation and at rest almost always reveals  facial weakness. Additionally, the face may  'droop' on the side of lesion. Inspection of the  face can also include overall muscle function  during speech and expression. Occasionally  blepharospasm due to facial nerve misdirec-  tion (synkinesis), or hemifacial spasm due to  inflammatory lesions, or posterior fossa tumor  may be noted   • History is reviewed for mode of onset,  associated symptoms, ear infection, herpes  zoster, tick bite, facial trauma, relevant surgery,  and systemic diseases such as diabetes  mellitus, hypertension, and malignancy   • Pregnancy and facial palsy— Reports have  shown that during pregnancy the incidence  of Bell's palsy —including facial diplegia, and  recurrent LMN facial paralysis in successive  pregnancies — is increased significantly  compared to nonpregnant women; most  cases of Bell's palsy occur in the third  trimester or early puerperium; onset is acute  and painful 3 " 5    • When suspecting lyme disease in the absence of  skin lesions (erythema migrans), ask about travel  and residence history, and carefully review  other signs and symptoms (fever, arthralgia,  lymphadenopathy, neuropathy, etc.)   • Associated symptoms such as hyperacusis,  deafness, and abnormality of taste, salivation,  and facial pain, etc. point to different sites of  facial nerve lesions (Table 18.1)   • Onset— Acute onset is common with Bell's  palsy, diabetic neuropathy, TIA, CVA,  pregnancy, and trauma to facial nerve. CNS  infection, abscess, acoustic neuroma, and  brain tumor have subacute or gradual onset   • Is there associated hemiparesis or hemiplegia?  Presence of such associated neurological deficit  of acute onset favors CVA or subdural or  extradural hematoma. If hemiplegia or  hemiparesis of acute onset is present on the  contralateral side, then brainstem thrombosis  or hemorrhage must be considered. If the  deficit is gradual in onset, and on one side,  consider a brain tumor, abscess, or brain  degenerative disease   • Evaluation of facial muscle innervated by CN  VH such as — wrinkling of the forehead (frontalis),  closing the eyes tightly (orbicularis oculi), closing  the lips tightly/ whistling (orbicularis oris),  pulling back the comers of the mouth as in  smiling (buccinator), and wrinkling the skin of  the neck/frowning (platysma) - help to decide  whether UMN or LMN type of facial weakness  is present (Table 18.2)   • A careful neurological examination may detect  focal deficit such as taste sensation in the  anterior 2/3rd of the tongue (lost in LMN type),  comeal reflex, plantar response (lost in LMN  type), evidence of cerebellar signs and CN VIII  involvement (affected in acoustic neuroma)   • Unilateral or bilateral lesions can be tested by  having the patient retract one corner of the  mouth at a time, winking one eye at a time, and   to anterior 2/3rd of tongue due to  involvement of nervous intermedius;  impaired salivary and tear secretion,  hyperacusis (if CN VIII is not affected);  additional CNs may be involved: deafness,  tinnitus, vertigo (CN VII), sensory loss  over face and absence of corneal reflex  (CN V); ipsilateral ataxia (cerebellar  peduncle).   paralysis of stapedes muscle; loss of taste  from anterior 2/3rd of tongue.    I Millard gubler syndrome— due to occlusion of the penetrating branches of the basilar artery in the pons. Its features  are: lateral rectus palsy — cranial VI; ipsilateral facial paralysis — cranial VII; and contralateral hemiplegia; often  accompanied by contralateral sensory loss — light touch and proprioception - due to medial lemniscal damage.  However, this is not part of the defined syndrome.   II Foville's syndrome— due to occlusion of the perforating branches of the basilar artery in the region of the pons. Its  features are: unilateral facial palsy; paralysis of conjugate gaze towards the affected side; and contralateral hemiplegia.    elevating one eyebrow at a time. UMN lesion is  usually unilateral as in C VA and neoplasm and  rarely bilateral as in GBS and MS. LMN lesion  may be unilateral or bilateral (Table 18.3)   • Facial myokymia is a rare form of involuntary  movement affecting the facial muscles. It is  clinically defined as continuous twitching of  small bands or strips of muscles that give an  undulating or rippling appearance to overlying  skin, descriptively called as 'bag of worms'    appearance. It is an important physical sign, as  it is most often seen in cases of multiple sclerosis  and with neoplastic and inflammatory lesions  of the brainstem, and if noted makes brain  imaging (MRI) mandatory  • Mimic palsy, also known as emotional facial palsy  (EFP) refers to weakness or abolition of facial  movements during emotions like smiling or  weeping, while voluntary movements do not  show any deficit. EFP has been described in   Table 18.2: Difference between UMN and LMN type of CN VII palsy    • Upper face escapes; only lower face  affected, i.e. eyes can be closed,  forehead wrinkled but teeth cannot  be shown with weakness of lips  and buccinator muscles   In bilateral UMN lesions whole face  is paralyzed and emotional movements  are also affected   • Plantar response— extensor on the  paralysed side of the face   • Examples — CVA, CNS neoplasms, MS,  syringobulbia, motor neuron disease   • Hemiplegia— may be an isolated phenomenon; and  if associated with hemiplegia, it is always crossed   • Plantar response— flexor on the paralysed side of the face;  may be extensor on the opposite side    * Bell's phenomenon, i.e. if the patient tries to close his affected eye, the eyeball turns upwards and inwards.   Melkersson syndrome, i.e. recurrent facial palsy with  facial edema, unilateral or bilateral; and lingua plicata (scrotal  tongue)   Mobius syndrome, i.e. facial paresis with Ophthalmoplegia-  Myasthenia gravis (not due to facial palsy)    association with lesions of anterior part of  frontal lobe, lesions in the neighborhood of  optic thalamus, Parkinson's plus syndrome  and postencephalitic parkinsonism.   • A CN VII palsy (Bell's palsy) is the most common  cranial nerve lesion and is the most common  neurologic manifestation of sarcoidosis. 6   • With bilateral facial palsy, although very rare,  it's important to rule out all other possible  diagnoses for facial weakness, including  UMN and LMN disorders, with thorough  diagnostic tests (Table 18.4).   • Melkersson syndrome, i.e. recurrent facial palsy  with facial edema, unilateral or bilateral; and lingua  plicata (scrotal tongue)    • Bilateral facial palsy seen in pregnancy may be a  sign of serious underlying disease. Some  authors suggest that Bell's palsy increases the  risk of hypertension and toxemia of pregnancy,  whereas the pregnant state, in turn, may affect  the course and severity of disease. 7   • Peripheral facial palsy has been considered  as a possible neurological complication of the  early stages of HIV infection. In the early stage    of HIV, paralysis can be directly due to the  viral infection. In later stages paralysis is  more likely to be associated with the  opportunistic infections or tumors associated  with severe immune deficiency. 8  • Dissatisfaction with facial appearance seems  to be a factor in many suicides. In a patient  with facial asymmetry (Table 18.5), negative  coping strategies may include avoidance of  social contact, alcohol misuse, and  aggression. It is dangerous for the physician  to dismiss a complaint of this type or  labelling these patients as 'psychiatric'. 9   uncommon condition of unknown cause.  Several factors, such as infection, autoimmunity,  neurotropic factors, atopy, and hypersensitivity  to food additives have been implicated in the  pathogenesis, but none of them are proven. An  autosomal dominant inheritance with variable  expression has been proposed in some cases of  MRS.   Although early manifestations of the  syndrome can start at any age, MRS generally  develops at the end of the second decade of life.  The classical triad includes recurrent orofacial  edema involving predominantly the lips  (macrocheilitis), peripheral facial palsy and  scrotal tongue, although it is accepted that the  presence of two manifestations is sufficient to  make the diagnosis. Facial palsy can be  unilateral or bilateral; may tend to be recurrent  to such an extent that it's sometimes described  as intermittent. Recurrences don't follow any  pattern— each recurrence can be on the same  side, alternating side, or bilateral. Disturbances  of salivary, lacrimal and nasal secretion,  disorders of taste and vision, migraine, and  febrile symptoms occasionally accompany the  condition. MRS is an unusual cause of facial    swelling that can be confused with angioedema.  Diagnosis of this syndrome can easily be missed,  as the obvious symptoms may look like Bell's palsy.  However, unlike MRS, Bell's palsy recurrences tend  to be separated by wide time spans.    1. Leigh W, et al. Are human preferences for facial  symmetry focused on signals of developmental  instability? Behavioral Ecology Advance Access  published on September 1, 2004, DOI 10.1093/  beheco/arh099.Behav. Ecol. 15: 864-71. Web site:  http://beheco.oxfordjournals.org/cgi/reprint/15/  5/864. Accessed on 09-11-08.   2. Michael ER, et al. Detecting hemifacial asym-  metries in emotional expression with three-  dimensional computerized image analysis. Proc  Biol Sci 2004;271(1540): 663-8. Web site: http://  www.pubmedcentral.nih.gov/picrender.  fcgi?artid=1691649&blobtype=pdf. Accessed on  09-11-08.    3 . Cohen Y, et al. Bell palsy complicating pregnancy:  A review. Obstet Gynecol Suey 2000;55(3):184-  8. [PMID: 10713984: Abstract],   4. Mari I, et al. Facial diplegias during pregnancy.  Presse Med 2000;29(40):2213-5. [PMID:  11196051: Abstract],   5. Gbolade BA. Recurrent lower motor neurone  facial paralysis in four successive pregnancies. J  Laryngol Otol 1994;108(7):587-8. [PMID:  7930897: Abstract],   6. James DG. Differential diagnosis of facial nerve  palsy. Sarcoidosis Vase Diffuse Lung Dis 1997;  14(2):115-20 [PMID: 9306501: Abstract],   7. Mylonas I, et al. Idiopathic facial paralysis (Bell's  palsy) in the immediate puerperium in a patient  with mild preeclampsia: A case report. Arch  Gynecol Obstet 2005;272(3):241-3. Epub 2005  May 3. [PMID: 15868184: Abstract],   8. Abboud O, et al. Isolated bilateral facial paralysis  revealing AIDS: A unique presentation.  Laryngoscope. 2008;118(4):580-4. [PMID:  18197137: Abstract],   9. McGrouther DA. Facial disfigurement. BMJ  1997;314(7086):991. [PMID: 9112836: Free full  text].   Facial swelling, i.e. swelling of the central portion  of the face— known as facial edema — is a condition  wherein there is fluid and/or excess subcuta-  neous fat accumulation in the face.* It can be  localized or generalized, and may even  sometimes spread to the neck and upper arms.  Sometimes, it precedes onset of either peripheral  or generalized edema. If the facial swelling is  mild, it may be difficult to detect; occasionally  the patient, or usually someone who is familiar  with patient's appearance may report it before  it is noticed during assessment. Most of the time  facial swelling is not a cause for alarm, but when  the swollen area is inflamed, or there is  difficulty in breathing, or the swelling does not  decrease over time, it becomes a cause of concern.  Many causes are due to infection and allergy,  but it may be a sign of systemic disease.  However, the patient usually presents because  of the abnormal facial features, expressions, and  even disfigurement.    * Disorders of only facial subcutaneous and soft tissues  are considered; those related to other facial organs (eyes,  nose, jaws, vascular, neoplasms, etc.) are excluded.   • Systemic disorder (CHF, acute glomerulo-  nephritis, nephrotic syndrome, uremia,  hepatic failure)   • In hypoproteinemic edema, total plasma  protein level is less than 5 g/dl and the plasma  albumin content is below 1.5-2. 5 g/dl.   • In diabetic patients, especially in Type 1 DM,  insulin therapy may be associated with the  development of transient edema.   • Pulmonary opacity, hilar lymphadeno-  pathy, mediastinal tumor, aortic aneurysm,  etc. may be evident, causing superior vena  caval obstruction   • Bronchogenic carcinoma may lead to  'ectopic ACTH syndrome', causing non-  iatrogenic Cushing's syndrome.   • Opacity or a fluid level may be evident in  the involved sinus; bony erosion may  suggest malignancy.   • To detect any abnormality and obstruction  of the Stensen's duct.   • For evidence of cavernous venus thrombosis,  Cushing's syndrome (pituitary microadenoma  secreting ACTH tumor).   • In patients with CNC signs and symptoms  due to trichinellosis.   • For detailed evaluation of PNS; obscure  lesions such as polyps, tumors may be  evident causing recurrent sinusitis and facial  edema.   • Evaluation of facial swelling requires conside-  ration of onset, severity, location, duration,  aggravating and ameliorating factors   • Other causes of facial edema, such as edema  secondary to congestive heart failure, renal  insufficiency, hepatic insufficiency, or venous  stasis disease must be excluded   • Acute onset associated with pain and  tenderness is usual with infective and allergic  lesions, whereas gradual onset indicate renal,  endocrine, and autoimmune disorders   • Recurrent painful swelling of the affected  parotid gland at meals and regressing  afterwards is very characteristic of obstruction  to the duct of the gland by a stone   • In patients with salivary gland enlargement,  inquiry about symptoms of rheumatologic  disease or 'sicca syndrome' (dry eyes, dry  mouth) is important   • A unilaterally enlarged painless parotid gland  with a facial palsy suggests parotid tumor;  bilateral involvement may indicate lymphoma,  sarcoidosis, and Sjogren's syndrome   • Drugs — History of steroid therapy and  allergic reactions to NSAIDs, antibiotics,  blood products, and vaccines may result in  periorbital or facial edema.   • Any facial swelling involving deep facial  spaces, as evidenced by fever, trismus.   (i.e. neurological disorder characterized by facial  swelling, especially of the lips).    elevation of the tongue, or ophthalmoplegia  (e.g. facial cellulitis, angioedema, Ludwig's  angina) could be dangerous (causing  asphyxia); close monitoring/referral is  indicated   • Mediastinal lesion, e.g. bronchogenic  carcinoma may present as facial edema due  to compression/obstruction to the superior  vena cava   • In lupus erythematosus, dramatic peri-  orbital edema and erythema without any    evidence of other significant cutaneous or  systemic involvement, though unusual,  could be the sole manifestation of cutaneous  lupus erythematosus. Therefore, every  patient with persistent periorbital edema  should undergo histologic and immuno-  fluorescent evaluation, and lupus erythe-  matosus should be included in the  differential diagnosis. 1 2 3   • Unilateral facial swelling, involving orbital  region, may signal cavernous sinus throm-  bosis, especially in immunocompromised  and diabetic patients.   Morbihan's disease — It is a rare condition  characterized by chronic persistent erythema  and edema of the upper half of the face. Such  conditions have also been designated as chronic    lymphedema or solid persistent facial edema in  acne or rosacea. The chronic course, absence of  serological abnormalities and nonspecific  histopathological features, as well as resistance  to therapy is the most important diagnostic  criteria of this disease. Cases remain difficult to  treat and can challenge afflicted patients both  cosmetically and psychologically.    1 . Jansen T, et al. Persistent erythema and edema of  the face associated with rosacea and lymph vessel  dysplasia. Hautarzt 1998;49(12):932-5. [PMID:  9914893: Abstract],   2. Holzle E, et al. Morbihan disease— chronic persistent  erythema and edema of the face. Hautarzt 1995;  46(ll):796-8. [PMID: 8641887: Abstract],   3. Ghaninejad H, et al. Persistent periorbital edema  as a sole manifestation of cutaneous lupus  erythematosus: Report of two cases. Dermatology  Online Journal 2006 28;12(2):14.[PMID: 16638407:  Free article].   Fever or pyrexia is a common presentation in most  fields of medical practice. It is usually associated  with benign transitory infection. In most  patients, the epidemiological guidelines and  incidence greatly help in the evaluation of the  underlying cause, generally within a week, or  the patient recovers spontaneously. It is only  when fever prolongs, and the cause remains  unknown, that it causes a diagnostic challenge,  and fever of such cases is labeled as Fever of  Unknown Origin (FUO). However, modern  diagnostic and imaging techniques enable early  detection of a number of occult diseases such as  neoplasms, lymphomas, and connective tissue  disorders in patients previously thought to have  FUO. 1   Several authors have devised criteria for  defining a FUO. Petrsdorf and Beeson defined  FUO in adults as:   • Temperature higher than 38.3°C (> 101°F) on  several occasions (i.e. fever does not have to  be continuous or daily, but occurs in  majority of days of the illness)   * Petersdorf and Beeson (1964); Durrack and street (1991);  Lohr and Hendley (1977).   The criteria of three weeks were chosen  because it eliminates the prolonged but self-  limiting viral and bacterial diseases, and  allows sufficient time for appropriate initial  investigations to be completed. However, "over  the past 40 years, health care has shifted from  the inpatient to the ambulatory setting. As a  result, it has now become widely accepted that  the requirement for a one week evaluation in  hospital be modified so that evaluation may  now be completed in an outpatient setting". 2,3   In most cases the cause of fever becomes  evident within two weeks, thus underlying the  common axiom that FUO is more often an  unusual presentation of a common disease  rather than a common presentation of a rare  disease. Conversely, failure to utilize clinical  findings correctly, delay in ordering appropriate  tests, and misinterpretation of test results have  all contributed to missed diagnoses.   Some experts have argued for a more  comprehensive definition of FUO that takes into  account medical advances and changes in disease  states, such as the emergence of HIV infection and    an increasing number of patients with neutropenia  (neutrophil count < 500/microliter). Others contend  that altering the definition would not benefit the  evaluation and care of patients with FUO. 4 " 6   FUO demands great tenacity for constant  observation, frequent careful physical  examination for the evidence of newer signs,  avoidance of unnecessary investigations at early  stages, and above all an excellent rapport with  the patient. "It is in the diagnosis of a febrile illness  that the science and art of medicine come  together". 7 With such an approach, FUO will but  be a challenge in a minority of patients. However,  about one-third of patients have no diagnosis at  the end of the work up, and for them the prognose  is usually good. There is no algorithm to know  which tests to order. Focused history and detailed  physical status give important clues to decide  about additional laboratories testing. An empirical  treatment is justified only in case of vital risk.   • HIV infection (pyogenic; atypical myco-  bacterial; fungal: Pneumocystic carinii,  candidiasis; viral).   • Anemia will be revealed in a variety of  disorders such as malignancy, connective  tissue disorders; leukocytosis in many  infective, inflammatory diseases, and  leukemia; low platelets in leukemia; malarial  parasites; abnormal WBCs in leukemia; and  atypical lymphocytes in infectious mononu-  cleosis, HIV, viral hepatitis can occasionally  help in the diagnosis.   • A markedly raised ESR is common in TB,  malignancy, inflammatory and connective  tissue disorders.   • Blood (infective endocarditis), urine, and  abnormal fluid collection or secretion such as  from throat, urethra, cervix, abdominal,  pleural, and joint space for suspected infection.   • Microscopic examination of blood film, routine  blood chemistry (including lactic dehydrogenase,  bilirubin, and liver enzymes)   • Examination for specific endemic infectious disease  in returning travellers or persons living in such  geographic areas (e.g. systemic leishmaniasis in  India, Mediterranean area, etc.)   ** Source: Siegenthaler Walter. Siegen thaler's Differential  Diagnosis in Internal Medicine From Symptoms to  Diagnosis, Thieme, 1st English ed. Chapter-4-Fever of  Unknown Origin-Table 4.2 - Minimum Diagnostic work-  up to qualify as FUO, p. 114.   • WBCs in infection; granular or red cell casts in  renal inflammation; hematuria in infection,  endocarditis, hypernephroma, and blood  dyscrasias. Proteinuria suggests renal disease.   • Should be done in all cases of FUO. Negative  results are reported in miliary TB, sarcoidosis,  Hodgkin's disease, AIDS, or malnutrition.   • Usually detects infiltration, consolidation,  effusion, masses, and lymphadenopathy  even before they are clinically evident.   • TB — Parenchymal or miliary, primary and  metastatic malignancy, lymphoma, sarcoids.   • In osteomyelitis, periosteal reaction and  sequestration develop 10-15 days later; for  earlier diagnosis radionucleotide bone scan  is preferred.   • To rule out intra-abdominal masses or  abscesses of liver, spleen, kidney, and pelvic  organs.   • Hepatic involvement in FUO is common;  significant elevated values of transaminase  levels indicate hepatitis; elevated alkaline  phosphatase levels point to infiltration of the  liver.   • In suspected cases with pyogenic, tubercular  meningitis, and viral encephalitis.   • Recommended as one of the first  investigations in FUO in the majority of  patients with symptoms suggesting an  intraabdominal abscess and lymphoma; in  patients with suspected retroperitoneal  tumors or infections, or those with abnormal    LFTs. Even in asymptomatic patients with  FUO, a normal CT abdomen is very helpful  in ruling our serious intra-abdominal or  retroperitoneal pathology.   • Between Gallium (Ga) 67, Technetium (Tc)  99 m, or indium (In) 111, Tc 99 m is the tracer  of choice in localizing a potential infection  or inflammatory focus   • 18F-fluorodeoxy glucose positron emission  tomography, i.e. (18) F-FDG PET— Osteo-  myelitis can be diagnosed with a high degree  of certainty. Negative findings on (18) F-FDG  PET essentially rule out orthopedic  prosthetic infections. In patients with  noninfectious inflammatory diseases, (18) F-  FDG PET is of importance in the diagnosis of  large- vessel vasculitis and seems to be useful  in the visualization of other diseases, such  as inflammatory bowel disease, sarcoidosis,  and painless subacute thyroiditis. In  patients with tumor fever, diseases  commonly detected by (18) F-FDG PET  include FFodgkin's disease and aggressive  non-FFodgkin's lymphoma, and also  colorectal cancer and sarcoma. 12,13   • A temporal artery biopsy (Bx) should be  considered in elderly patients with FUO   • Color duplex ultrasonography of the temporal  arteries may be a helpful alternative to  temporal artery biopsy   • Lymph node biopsy will rule out  lymphomas, TB, metastatic carcinomas, and  mycotic infections   • Bone marrow biopsy can diagnose leukemia,  lymphomas, carcinoma, and granuloma.   • LD bodies may be noted in lymph node,  spleen, or bone marrow aspirate in patients  with kala-azar.   • Transthoracic echocardiography (TTE) — For  evidence of infective endocarditis, to detect  vegetations on the valve cusp, especially if  blood cultures are negative.   • Transesophageal echocardiography (TEE) —  Considered to investigate suspected  pacemaker lead infection in patients with  negative transthoracic echocardiography. 14   • May be helpful in disorders such as viral  hepatitis (anti-HAV IgM, HBsAg, anti-FFCV);  FFIV (ELISA, Western Blot); infectious  mononucleosis (heterophil test); antibodies  against CMV infection, amoebiasis, brucellosis,  toxoplasmosis; salmonella (Widal titer); and  collagen vascular diseases (ANA, RF,  Antineutrophil cytoplasmic antibody-  ANCA).   • Miliary TB, which can be missed on normal  CXR, is better defined by Lf RCl .   • Bronchoscopy, mediastinoscopy, EGD,  retrograde cholangiography, colonoscopy,  transrectal sonography, or laparoscopy may  help direct visualization, and biopsy  procedures when organ specific manifes-  tations are present.   • The first step should be to confirm the  history of fever, its documentation, and  exclusion of habitual, factitious, or drug-induced  fever (see text below)    sustained may prove to be helpful but rarely  diagnostic; it may aid in diagnosing cases of  tertian or quartan malaria, or Hodgkin's  disease (with Pel-Ebstein fever characterized  by 5-10 days of fever alternating with 5-10  days of afebrility)   • A single record of temperature in a febrile  patient gives very little information. In all  cases of fever, a serial record of temperature is  essential; four-hourly in acute cases and eight-  hourly in all other cases. A simultaneous  record of pulse rate and respiration gives  additional information that may be clinically  useful   • The duration of fever prior to seeking medical  help may give some clues. The longer the  duration of the fever, the less likely there is  an infectious etiology; if it is of month's  duration, then autoimmune or malignant  disorders are the possibilities; when it's more  than a year or so, then granulomatous  diseases are the probabilities   • Naproxen test 15 : The response to fever to  naproxen sodium may be helpful in that  fever due to solid tumors and many  rheumatologic diseases (most notably Still's  disease) usually subside promptly, while  fever due to other causes may persist   • History of recent travel (malaria, S ARS) ; pets,  animal and insect contacts (toxoplasmosis,  brucellosis, leptospirosis, Lyme disease);  occupation (brucellosis in abattoir workers,  anthrax in leather workers); and recent  contact with persons exhibiting similar  symptoms (viral hepatitis, TB) are important  aids in the diagnosis   • The family history should also be carefully  elicited for hereditary causes of fever, such  as familial Mediterranean fever. Diseases  such as rheumatic fever, tuberculosis,  lymphoma, etc. in other family members  must be enquired    antineoplastics, atropine and its compounds,  barbiturates, iodides, phenytoin, quinidine)  must be considered in patients who are taking  medications, including OTC drugs, because  elimination of the offending agent may solve  the problem and eliminate the need for  extensive investigations. If fever persists  beyond 72 hours of stopping all possible  offending drugs then the likelihood of fever  being drug-induced is markedly reduced   • History of high risk sexual activity and I V drug  abuse need screening for HIV, viral hepatitis,  and infective endocarditis. History of alcohol  abuse indicates cirrhosis, and hepatoma   • A past history of intermittent illness over a  period of years involving multiple organ  systems suggests the possibility of connective  tissue disease   • Fundoscopic examination may provide the  first clue to the diagnosis of tuberculosis if  choroid tubercles are demonstrable. Ocular  manifestations of systemic diseases such as  scleritis, uvulitis in connective tissue disorders  may provide clues to the diagnosis of obscure  fever. Hence, referral to an ophthalmologist in  the early stages of FUO is particularly useful   • Physical examination— Must be thorough  and often repeated. Symptoms and signs of  common diseases causing FUO are given in  Table 20.2   • Fever associated with rash may be a viral  exanthem (e.g. rubella, varicella) or a clue to  a serious disease (e.g. meningococcemia,  thrombocytopenia, erythema multiforme).   • Rule out habitual hyperthermia, i.e. exaggerated  circadian rhythm, characterized by  temperature between 100 and 100. 5°F in the  afternoon hours; other febrile symptoms  (chills, sweats, and tachycardia) are absent  and initial tests are normal    • Rule out factitious fever. Clues to the diagnosis  are a patient with medical knowledge or  training, inconsistent histories, excessively  high temperatures (105°-107°F, which are a  rare occurrence), normal pulse and respiratory  rates at the time of fever, and rapid  defervescence unaccompanied by diaphoresis   • A high index of suspicion of temporal (or  giant cell) arteritis, characterized by  headache, fever, jaw claudication, visual  symptoms, polymyalgia rheumatica, and  constitutional symptoms must be  maintained, since failure to do so, and to  institute appropriate treatment may lead  to permanent vision loss   • FUO should be presumed to be secondary to  an infection (bacterial, parasitic, fungal,  viral, rickettsial, and chlamydial) until  proven otherwise because infections cause  the majority of FUOs and can be life-  threatening   • The diagnosis of TB may be delayed despite  a high index of suspicion because of normal  CXR, negative skin and sputum test, and  inconclusive histopathologic examination.  Repeated examination and work-up is  indicated in patients with strong clinical  suspicion of TB   • A high index of suspicion and familiarity  with the rapidly changing epidemiology of  SARS is extremely useful in its early diagnosis  and minimizing transmission   • Patients who are elderly, immunocom-  promised, talking steroids or NSAIDs may  not show evidence of fever, even in the  presence of a severe infection   • Patients who present with rash associated  with FUO should have a skin biopsy (Bx)  unless the diagnosis is straightforward   • Patients who are immunosuppressed (on  corticosteroids, chemotherapy) or who have    altered immune response due to disease  (Hodgkin's, HIV), are likely to have fever due  to infection caused by atypical organisms.    1 . Knockaert DC, et al. Fever of unknown origin in  the 1980s. An update of the diagnostic spectrum.  Arch Intern Med 1992;152(l):51-5. [PMID:  1728929: Abstract],   2 . Ophry M, et al. A comprehensive evidence-based  approach to fever of unknown origin. Arch Intern  Med 2003;163:545-51.   3. Vanderschueren S, et al. From prolonged febrile  illness to fever of unknown origin: The challenge  continues. Arch Intern Med 2003;163(9):1033-41.   4. Cunha BA. Fever of unknown origin. Infect Dis  Clin North Am 1996;10:111-27.   5. Roth AR, et al. Approach to the adult with fever  of unknown origin. Am Fam Physician 2003;  68:2223-8.   6 . Barbado FJ, et al. Fever of unknown origin: Classic  and associated with human immunodeficiency  virus infection: A comparative study. J Med 2001;  32(3-4):152-62. [PMID: 11563813: Abstract],   7. Kasper DL, et al. Harrison's Principles of Internal  Medicine 16th ed. Vol.I:p.l06.    8. Shamsuzzaman SM, et al. Thoracic amebiasis.  Clin Chest Med 2002;23(2):479-92. [PMID:  12092041: Abstract],   9. Victor F, et al. Pacemaker lead infection:  Echocardiographic features, management, and  outcome. Heart 1999;81(l):82-7. [PMID:  10220550: Abstract],   10. Haaker R, et al. Osteomyelitis after endoprostheses.  Orthopade. 2004;33(4):431-8. [PMID: 15146838:  Abstract],   11. Sharif MA, et al. Prosthetic stent graft infection  after endovascular abdominal aortic aneurysm  repair. Vase Surg 2007;46(3):442-8. [PMID:  17826231: Abstract],   12. Meller J, et al. 18F-FDG PET and PET/CT in fever  of unknown origin. J Nucl Med 2007;48(1):35-  45. [PMID: 17204697: Free full text],   13. Keidar Z, et al. Fever of unknown origin: The  role of 18F-FDG PET/CT. J Nucl Med 2008;  49(12):1980-5. Epub 2008 Nov 7. [PMID:  18997040: Free full text],   14. Corrado G, et al. Pacemaker-induced infection:  Diagnosis by multi-plane transesophageal  echocardiography. Cardiologia 1997;42(10):  1083-6. [PMID: 9534285: Abstract],   15. Agarwal PK, et al. Fever of unknown origin. J of  Assoc Phy of India, (52),2004;317.   Gait normally means the rhythmic stepping  movements to advance in space, i.e. the  manner or posture of a person while walking.  When a normal person walks (i.e. locomotion),  he maintains an upright, erect posture;  balancing is easy, i.e. he is able to stand up  and remain upright against the force of  gravity (equilibrium); the arms swing at the  sides; turning is smoothly accomplished; and  cyclical stepping movements are well-  coordinated . The person is able to stand with  feet together without falling with eyes open  or closed.   The erect posture of the body is governed by  four primary antigravity muscle groups:  gastrocnemius/soleus group, the quadriceps  group, the glutei, and the erector spinae group.  These muscles act on the information from the  three major sensory systems in the body: the  proprioceptive, vestibular, and visual systems.    * Gait consists of two phases: stance and swing. In the stance  phase the foot is in contact with the floor, and one limb  bears all the body weight. In the swing phase the foot is  not touching the floor. This phase begins when the toe  comes off the floor and ends with the heel strike.    The feedback by these sensory systems is further  integrated and modified by brainstem, basal  ganglia, cerebellar, and cortical influences. The  spinal cord coordinates muscles of locomotion  in all the four limbs by its neural circuitery. The  cerebellum maintains proper position and  balance. The cortex and basal ganglia evoke  walking motion and can modify the slow walk  to quick pace.   • Lower level 1 ) i.e. motor system (muscles,  nerves), joint/skeletal system, proprio-  ception (sensory) system, visual/ vestibular  system, spinal cord   • High level, i.e. cortical frontal lobe system-  can lead to gait disorders.   Patients with abnormal gait commonly  complain of unsteadiness or imbalance,  staggering, unsteady, walking like a 'drunk sailor/  veering, or having a fear of falling, which is  generally an expression of difficulty in maintaining   + The anatomical structures that subserve the system of  balance and locomotion are divided into low, middle, and  high anatomical levels.    upright posture, either while standing (balancing)  or walking (gait). In addition, they may complain  of stiffness, cramping, numbness, easy fatigability,  muscle wasting, foot drag, frequent tripping, or  difficulty climbing stairs and rising from a seated  position.   Although the physical examination is the  key in evaluating balance and gait disorders,  history is also important, mainly to delineate  onset and temporal pattern and determine  whether symptoms are static, worsening, or  improving overtime. The work-up depends on  the presence or absence of other neurologic  signs.   • 'Fear-of-falling' gait 1 ( vide infra 4 - 4 -)   • Hemiplegic gait (i.e. circumducting, spastic  gait-due to unilateral UMN lesion, e.g.  stroke; mass lesion, e.g. tuberculoma, tumor;  MS; and Brown-Sequard syndrome: vide   • Antalgic gait (i.e. painful gait due to joint,  bone, or muscle lesion; e.g. trauma, previous  bone/joint surgery, malunion, septic arthritis,  osteomyelitis, OA, and RA)   • Cerebellar gait (i.e. ataxic or wide-based gait  due to drugs; e.g. phenytoin, alcohol,  cerebellar ischemia, hemorrhage, and  acoustic neuroma)   • Stepping gait (due to LMN lesion— unilateral  or bilateral, e.g. common peroneal nerve  palsy, foot drop)   • Festinating gait (due to basal ganglia,  extrapyramidal lesion; e.g. parkinsonism).   • Scissors gait (i.e. spastic or paraparetic due  to bilateral UMN lesion, e.g. cerebral palsy;  MS; cervical cord compression)   • Waddling gait (due to proximal muscle  weakness, myopathy, myasthenia, bilateral  congenital dislocation of the hip)   • Stomping gait (i.e. sensory gait due to dorsal  column disease, e.g. Vit B deficiency, tabes  dorsalis, HIV myelopathy)   • Leukocytosis in bone and joint infection, and  megaloblastic anemia in patients with dorsal  column disease.   • In hypokalemia, ECG may show sinus  bradycardia and evidence of hypokalemia  (flattening of T waves, U waves in leads II,  V2, V3, and V4, and ST segment depression).  In hyperkalemia, tall T waves may be seen.   • The most common initial imaging test is a  brain/spinal MRI scan. This test enables to   • Particularly useful to detect tumors of the  posterior fossa, brainstem, and MS. Also  helpful to exclude other causes of neurological  deficit, e.g. arteriovenous malformation,  including lesions causing compression of the  spinal cord.   • Leukocytosis in bacterial meningitis,  cerebral abscess; eosinophils in helminthic  (neurocysticercosis) infection; low glucose  in bacterial, TB infection; oligoclonal bands  of IgG in MS; and cytology to detect  malignant cells.   • In patients with hypokalemia, serum  potassium level decreases during attacks, but  not necessarily below normal   • In patients with hyperkalemia, serum  potassium level may increase to as high as 5-  6 mEq/1. Sometimes, it may be at the upper  limit of normal, and it seldom reaches  cardiotoxic levels.   • Increased levels of various muscle enzymes  such as CK, AST (e.g. muscular dystrophy,  polymyositis: vide infrai 4-); in the presence  of polymyositis, CK levels can be elevated as  much as 50 times the reference level.   • Proximal myopathy is known to occur in  hyperthyroidism, and cerebellar ataxia may  be seen in hypothyroidism.   • May be informative in inherited peripheral  neuropathy (Friedreich's ataxia : vide infra 44 -,  Charcot-Marie-Tooth disease) or myopathy.   • DNA testing for inherited neuropathies,  Friedreich's ataxia (FA), and muscular  dystrophy.   • Gait abnormality can indicate a serious  medical emergency, especially when the  problem is associated with any of these  additional symptoms:   A vascular or any lesion causing increased  ICP, such as an abscess or a tumor needs to    be urgently treated. It is therefore important  to note the mode of onset and progress   > Tinnitus, deafness, or vertigo suggests  Meniere's disease, labyrinthine disease, or  eighth nerve lesion;   > Headache, nystagmus, or papilledema  suggest a cerebellar tumor or acoustic  neuroma; and   > Glove and stocking anesthesia with  diminished reflexes suggest peripheral  neuropathy or tabes dorsalis.   • Acute onset hemiplegic gait with symptoms  of raised ICP is mostly due to contralateral  stroke or head injury. Acute ataxic gait with  cerebellar signs (hypotonia, slurred speech,  and nystagmus) may be due insufficiency/  thrombosis of to basilar artery/posterior  inferior cerebellar artery; drug toxicity;  alcohol abuse; or cerebellar hemorrhage   • Chronic gait disorders are usually due to  CNS/spinal mass lesion, infection, nutrit-  ional deficiency, substance abuse, or autoim-  mune disease such as MS   • Medications, e.g. diuretics, statins, steroids are  known to cause myopathies leading to  progressive weakness and wasting of skeletal  muscles, thus resulting in gait disorders.  Drugs such as antiepileptics (particularly  phenytoin and carbamazepine), antihista-  mines, benzodiazepines, sedatives-hypnotics,  antidepressants, neuroleptics, alcohol,  chemotherapy, heavy metal poisoning (e.g.  lead, mercury, and thallium), and bromide  intoxication are common and reversible causes  of gait disorders   • A careful family history should be obtained  to determine if an inheritance pattern can be  found. Many types of gait disorders are  hereditary, e.g. autosomal recessive ataxias    such as Friedreich ataxia, ataxia telangiec-  tasia; and autosomal dominant ataxias such  as spinocerebellar ataxia, episodic ataxia, etc.)  It is therefore important to look for subtle  symptoms in family members. Eliciting  information by asking questions such as —  are there relatives with clumsiness, frequent  falling, late walking, early speech therapy,  unusual eye movements, deafness, poor  handwriting, or other neurological problems,  tendency to diabetes mellitus or mali-  gnancies— are very helpful to trace the  hereditary etiology and genetic pattern  Observing the patient stand and walk across  the room and carefully observing his posture,  gait initiation, base width, step rhythmicity,  step length, and arm swing may indicate the  likely causative lesion (Table 21.1)   Tandem walk: Ask the patient to walk a straight  line in tandem, i.e. heel to toe. This may  reveal a gait abnormality not previously  obvious. It also exacerbates all existing gait  disorders, especially associated with  vestibular and cerebellar disease. Patients  with cerebellar disease (e.g. midline  cerebellar vermis lesion) will tend to fall  preferentially to the side of the lesion  Ask the patient to walk on his heels. This can  not be done by patients with distal muscle  weakness or foot drop (L4 or L5 lesion)   Ask the patient to walk on his toes. This can  not be done by patients with Parkinson's  disease, cerebellar disease, or marked soleus  or gastrocnemius muscles (SI lesion)   A thorough gait assessment should be  performed in all older people. An abnormal  gait may suggest a remediable risk factor for  falls, e.g. difficulty in getting out of a chair  without arm support and initiate movement  suggests Parkinson's disease or limb-girdle  dystrophy. The 'Timed Up and Go' (TUG) test.   Unsteady; careful; slow; short steps;  wide base; stooped posture; diminished  arm swing; no rigidity   Age-related without accompanying  neuropsychiatric abnormality; diffuse  cerebral cortex dysfunction; multi-  infract dementia   Extended leg; arms flexed; circum-  duction (i.e. round and forward  movement)of the affected leg   Limping; avoidance of bearing full  weight on the affected leg; limitation  of range of movement due to pain in  the extremity   OA of the hip or knee; herniated disk;  fracture of any of the bones of the limb;  sprained ankle   High stepping; wide-base; bangs feet  down (stamps) clumsily; tends to look  at them throughout the cycle (loss of  position sense); positive Romberg's sign   Peripheral neuropathy (diabetes  mellitus); posterior column lesions,  (B deficiency-subacute combined  degeneration of the spinal cord, HIV  myelopathy); tabes dorsalis   Foot drop; high lift to avoid tripping;  slaps on floor; unilateral or bilateral   Lateral popliteal nerve palsy; peroneal  muscular atrophy; cauda equina  tumor; Guillain-Barre syndrome;  poliomy-elitis; lead intoxication   Rigidity; shuffling (short accelerating  steps when walking); festination with  stopped posture   Wide-based; hips tilted alternately  (glutei weak); waddling or rolling from  side to side; toe-walk; lumbar lordosis;  symmetrical   Proximal myopathy (muscular dyst-  rophy, polymyositis, dermatomyo-  sitis); congenital dislocation of the  hips; old polio   Lack of motor coordination which  leaves the patient unable to stand or  walk unassisted but normal leg  movements can be done when in a  sitting or lying down position.   Conversion disorders; rarely in  children with posterior fossa tumor,  e.g. medulloblastoma    in which the patient is asked to stand up from  a sitting position without use of hands, walk  10 feet, turn around, walk back, and sit down,  is a valid procedure to readily assess gait  disorders. 2,3 Patients who take less than 10  seconds are usually normal, patients who    take longer than 30 seconds tend to need  assistance with many mobility tasks  Gait disorders worse in the dark are due to  lesions of the posterior column, e.g. Friedreich's  ataxia, pernicious anemia, MS, or tabes dorsalis  Romberg's test (eyes-open-eyes-closed): Cerebellar    ataxia can be differentiated from sensory  ataxia by Romberg's test, where removal of  the visual input dramatically reduces  compensatory ability in sensory ataxia.   > Ask the patient to stand in one place with  his feet together. If he is able to stand with  his eyes open as well as eyes closed, the  test is negative, i.e. normal.   > If he is able to stand with eyes open, but  tends to fall with eyes closed (i.e.  removing visual input), the test is  positive. The cause may be posterior  spinal column lesions due to tumor, vit  B 12 deficiency, cervical spondylosis, or  tabes dorsalis.   > If he is unable to stand with eyes open  and feet together, it indicates severe  unsteadiness, commonly involving the  peripheral and central vestibular system  and the cerebellum.   • Fukuda test: Marching in place for 50 steps;  abnormal if patient deviates close to 90° or  more, either to left or right. If abnormal, it  reflects vestibular disorder   • Hoover sign: It is a maneuver aimed to  separate organic from nonorganic lower limb  paralysis. The physician takes a position at  the foot of the supine patient and places one  hand under the heel of the patient's 'weak'  leg while pressing down with the other hand  on the good leg. Now the patient is asked to  attempt to raise the affected 'weak' leg. In  organic disease, the associated movement  causes the unaffected heel to press  downward; in hysteria, the associated  movement is absent   • The chair test to aid in the diagnosis of  psychogenic gait disorders: In this procedure  of 'chair testing' patient is asked to walk 20-  30 feet forward and backward toward the  examiner. The patient is then asked to sit in a  swivel chair with wheels and to propel the  chair forward and backward. Compared with    his walking, the psychogenic patient is found  to perform well on the chair test (sitting  versus standing), showing improved ability  to propel a chair forward than when seated.  By contrast, a normal person performs  equally when walking or propelling utilizing  the chair.   > Three "Ds" contribute to gait disorder;  viz. drugs, depression, and dementia;  these must be specifically looked for and  excluded before any other intervention.   > Acute onset gait disorder is likely to be  due to acute systemic decompensation,  such as MI, stroke, or sepsis; a careful  systematic evaluation is indicated to  exclude such catastrophic presentations.   > It is often not advisable to attribute gait  disorder to a single disease because many  different conditions (e.g. degenerative  joint disease, postural hypotension, and  stroke) can present in similar gait  abnormalities.   • In a patient with history suggestive of  secondary gain and normal neurological  examination, except bizarre gait, strongly  favors malingering.   Brown-Sequard syndrome— It is associated with  injury to the lateral half of the spinal cord  (involving interruption of the lateral corticospinal  tracts, posterior white column, and lateral  spinothalamic tracts), usually as a result of  penetrating trauma to the cervical or thoracic  spine. Multiple causes of Brown-Sequard  syndrome have been described in the literature.  The most common cause remains traumatic injury,  often a penetrating mechanism, such as a stab or  gunshot wound or a unilateral facet fracture and    dislocation due to a motor vehicle accident or fall.  The condition is characterized by the following  clinical features (which are found below the level  of the lesion): contralateral hemisensory  anesthesia to pain and temperature, ipsilateral  loss of proprioception, and ipsilateral motor  paralysis. Tactile sensation is generally spared.  The pure Brown-Sequard syndrome reflecting  hemisection of the cord is not often observed. A  clinical picture comprising fragments of the  syndrome or the hemisection syndrome plus  additional symptoms and signs, known as  'Brown-Sequard-plus syndrome', is more  common. 4 In the absence of trauma, this condition  needs to be differentiated from acute poliomyelitis,  Guillain-Barre syndrome, cervical disk disease,  vertebral artery dissection, infection and  inflammatory causes. MRI is helpful to define  the extent of spinal cord injury and is also helpful  when differentiating among nontraumatic  etiologies. CT myelography may be useful if MRI  is contraindicated or not available.   'Fear of falling' gait — It is largely a psychogenic  gait disorder of the elderly that is often  unrecognized. It usually begins after a fall and is  characterized by a shuffling or sliding stride and  an intense need to hold on for support. It appears  to be most common in elderly women, can be  reversed by education, suggestion, and physical  therapy, and is often mistaken for Parkinson  disease, or other gait disorders in the elderly.   Friedreich's ataxia — FA is the most common  autosomal recessive ataxia; the major  pathophysiologic finding in FA is a "dying back  phenomena" of axons, beginning in the periphery  with ultimate loss of neurons and a secondary  gliosis. Classic FA is the result of a gene mutation  at the centromeric region of chromosome 9 (9ql3-  21.1) at the site of the gene encoding for the 210-  aminoacid protein frataxin. Onset of FA is early,  with gait ataxia being the usual presenting  symptom. Gait ataxia manifests as progressively    slow and clumsy walking, which often begins  after normal walking has developed. Diagnostic  criteria of typical FA include: disease duration at  least 5 years, onset < 25 age, progressive ataxia of  gait and limbs, absent knee and ankle jerks, and  extensor plantar responses*. As the disease  progresses, ataxia affects the trunk, legs, and arms.  As the arms become grossly ataxic, both action  and intention tremors may develop. Eventually,  the patient is unable to walk because of the  progressive weakness and ataxia, becoming  wheelchair bound and ultimately bedridden.  With disease progression, dysarthria and  dysphagia appear, incapacitating the patient by  20, and death by 25 (40 in autosomal dominant  form), especially due to cardiac failure.   characterized by Adam's triad (impaired gait,  urinary incontinence and dementia) — and an  anatomic abnormality, i.e. enlargement of the  cerebral ventricles, which can be seen on CT or  MRI of brain. The gait is typically wide-based  with reduced step height, stride length, and  velocity, which gradually progresses to so-called  'magnetic' gait ('feet stuck to ground' - due to  simultaneous contraction of opposing muscles  while walking), it becomes almost impossible for  the patient to initiate gait. The urinary  incontinence is of 'urge' type. The precise  pathogenesis of NPFT is not known, but it is well-  known that despite the absence of increased  intracranial pressure, the drainage of CSF  regularly induces transient clinical improvement,  and ventriculosystemic shunting usually results  in prolonged remissions. Recently, another  anatomic abnormality was described in NPH —  a decrease in midbrain diameter on MRI that is  restored to normal by ventriculosystemic  shunting. The criteria to define cerebral   ^Only diseases with decreased deep tendon reflexes and  positive Babinski signs are Friedreich's ataxia, amyotrophic  lateral sclerosis, B 17 deficiency and syphilis.    ventriculomegaly precisely are vague and  difficult to establish, and enlarged ventricles are  surprisingly common. Other disorders of elderly  people such as Alzheimer's disease, Parkinson's  disease, and cerebral atrophy may show  enlarged ventricles, and demential disorders  may be difficult to differentiate from each other.   Polymyositis — It is an idiopathic inflammatory  myopathy with symmetric proximal muscle  weakness, characterized by subacute or slowly  progressing symmetrical weakness, primarily  affecting the proximal limb and trunk muscles.  The illness may occur at any age, but is most  frequent in the fourth to sixth decade of life,  women being more frequently affected than  men. Although the initial inciting agent remains  unknown, possibilities include virus-mediated  muscle injury, e.g. Coxsackie virus Bl, HIV,  Human T-lymphotropic virus 1 (HTLV-1)  Hepatitis B, influenza, echo virus, and adenovirus.  Many drugs are known to cause myopathy, e.g.  hydroxychloroquine, D-penicillamine, hyd-  ralazine, procainamide, phenytoin, ACE  inhibitors, and statins. Patients may report  muscle pain and tenderness, arthralgias or  arthritis that may be confused with polymyalgia    rheumatica. Later symmetric proximal muscle  weakness in the upper and lower extremities  develops. Weakness of pharyngeal and laryngeal  muscles, interstitial lung disease, and inflam-  mation of the myocardium may also occur. Serum  CK levels are usually elevated from 5-50 times  the normal value. Other muscle enzymes — lactic  dehydrogenase, aspartate aminotransferase,  alanine aminotransferase, and aldolase — may be  elevated. Muscle biopsy is crucial in helping  diagnose PM and in excluding other rare muscle  diseases. MRI can be used to guide the site of  biopsy.    1. KurlanR."Fear of falling" gait: A potentially  reversible psychogenic gait disorder. Cogn Behav  Neurol 2005;18(3):171-2. [PMID: 16175021:  Abstract],   2. Podsiadlo D, et al. The timed "Up & Go": A test of  basic functional mobility for frail elderly persons.  J Am Geriatr Soc 1991; 39(2):142-8. [PMID: 1991946:  Abstract],   3. Morris S, et al. Reliability of measurements  obtained with the Timed "Up & Go" test in people  with Parkinson disease. Phys Ther 2001;81(2):810-  8. [PMID: 11175678: Free full text],   4. Koehler PJ, et al.The Brown-Sequard syndrome.  True or false? Arch Neurol 1986;43(9):921-4. [PMID:  3741208: Abstract],   Gastrointestinal (GI) bleeding includes bleeding  from both upper and lower GI tract.   The upper GI (UGI) bleeding is defined as  bleeding from source above the ligament of  Treitz*, and includes the mouth, esophagus,  stomach, and small intestine up to the  duodenojejunal junction.   The lower GI (LGI) bleeding is usually defined  as bleeding originating from below the ligament  of Treitz, and includes the small intestine, colon,  and anal canal.   The UGI bleeding manifests clinically as  hematemesis and melena, and that of LGI  bleeding as hematochezia.   Hematemesis is vomiting of blood from the  UGI tract as defined above. Bright red or blood  streaked vomitus indicates fresh or recent  bleeding; dark red, brown, or black vomitus (the  color and consistency of coffee-grounds)  indicates that blood has been retained in the  stomach and partially digested.    * An important anatomical landmark of the duodenojejunal  junction which divides GI tract as UGI and LGI portion.    Melena is the passage of black, tarry stools  containing altered blood; its characteristic color  results from bacterial degradation, and  hydrochloric acid acting on the blood as it travels  through the GI tract. Thus, melena suggests that  the blood has had time to be processed by the  intestinal tract, implying slower bleeding that  originated in the UGI tract. About 100 to 200 ml  of blood in the GI tract is essential to produce  melena which may persist for several days after  the bleeding has ceased.   Hematochezia is passing bright red blood per  rectum (BRBPR), the source of bleeding is usually  from the LGI tract; however, approximately 10-  15% of patients presenting with acute severe  hematochezia have an UGI source of bleeding  identified on upper endoscopy.   Occult GI bleeding ( OGIB : Table 22.1) refers to  chronic or intermittent loss of minute amount of  blood of which the patient is unaware; i.e. there  is insufficient bleeding to cause obvious melena  or hematochezia. Chronic GI blood loss less than  100 ml per day may cause no apparent change in  stool appearance. Therefore, OGIB in an adult is  identified by positive/eca/ occult blood test (FOBT)  or as a manifestation of iron deficiency anemia.   , Cameron lesions are linear gastric ulcers or erosions  positioned on the crests of mucosal folds at the  diaphragmatic impression in patients with large hiatus  hernia.   >, Watermelon stomach is the popular name for Gastric  Antral Vascular Ectasia (GAVE) in which the lining of the  stomach bleeds, causing it to look like the characteristic  stripes of a watermelon when viewed by endoscopy; it  can occur in patients with diffuse systemic sclerosis.   Obscure GI bleeding (Table 22.2) refers to  bleeding that persists or recurs, and for which  there is no obvious source found after routine  endoscopic (upper and lower) evaluation.  Obscure GI bleeding, though uncommon, may  be clinically evident, manifesting as recurrent  melena, hematochezia, iron deficiency anemia,  or positive FOBT.   GI bleeding is most commonly a result of  benign pathology, which resolves spontaneously  and has favorable outcomes. 1 However, long-term    recurrence is a substantial problem, especially for  elderly patients with LGI bleeding. 2 Additionally,  the stability of the patient and the rate of bleeding  dictate the order in which various diagnostic  procedures should be conducted. Therefore, the  goal is to identify, and if necessary, treat the source  of bleeding, while maintaining hemodynamic  stability of such patient.   As noted above, the source of GI bleeding may  be categorized into two broad groups: viz. UGI  bleeding and LGI bleeding.   •• Iatrogenic bleeding (due to anticoagulant  usage, e.g. heparin, warfarin, or thrombo-  lytic therapy).   • Solitary rectal ulcer syndrome (SRUS: vide  infra 4-i) 3 ' 4   • HIV/AIDS colitis (Cytomegalovirus colitis,  colonic histoplasmosis, Kaposi's sarcoma of  the colon, and bacterial colitis)   • Colonic arteriovenous (AV) malformation  (i.e. vascular ectasias, angiomas, angiodys-  plasias, and Heyde's syndrome 4 )    + The Heyde's syndrome consists of the association of  gastrointestinal bleeding from angiodysplasia with aortic  valve stenosis.   • A low hematocrit and MCV in a stable patient  suggests intermittent, chronic bleeding.   • Serial estimation of hematocrit (i.e. PCV) can  be useful in assessing ongoing blood loss.   • PT, PPT and platelet count — to assess  bleeding diathesis, liver disease, and to  monitor anticoagulant therapy.   • Blood urea is elevated disproportionately to  creatinine in patients with GI bleeding (due  to reabsorption of blood from the bowel).   • AST, ALT, and Aik. Phosphatase — elevated  in hepatitis, cirrhosis, and neoplasm.   • To rule out cardiac ischemia due to  hypovolemia and related factors, especially  in the elderly.   • Diagnostic procedure of choice for acute UGI  bleeding; can demonstrate most lesions, e.g.  varices, esophagitis, PUD, gastric erosions,  MV tear, and carcinoma   • Screening procedure in patients with  cirrhosis and portal hypertension, but  without prior variceal hemorrhage   • Advantages of early EGD include: confirmation  of bleeding source in UGI tract; obtaining    biopsy (Bx), and providing therapeutic  measures which lessen transfusion require-  ments, need for surgery, and hospitalization.   • Useful primarily in patients < 40 years of age for  minor bleeding due to low-lying anal disease.   • First procedure of choice in LGI bleeding  diagnosis; may be performed urgently or  electively depending on patient's hemodyna-  mic status and risk-stratification criteria such  as positive FOBT in patient > 40 years of age   • Though colonoscopy is recommended for  patients with LGI bleeding, it may also be used  in combination with EGD (i.e. bidirectional  endoscopy) for patients with upper GI bleeding,  OGIB, or nondiagnostic EGD   • Advantages include: direct visualization; access  for tissue biopsy (Bx), and ability to treat  bleeding lesions primarily with heat probe,  laser therapy, band ligation, or hemoclipping.   • Used for active, heavy bleeding and/or if  colonoscopy is inconclusive   • The main advantage include: accurate  localization of bleeding sites that are not  identified by endoscopy   • It may also permit therapeutic interventions,  e.g. vasopressin infusion and embolization.  Complications such as renal failure,  rebleeding may occur.   • MDCT angiography is a promising first-line  modality for fast and accurate localization of  acute GI and intraperitoneal bleeding.   • Like angiography, it is only of value in  patients with active bleeding. The newer  techniques involving dynamic imaging  (more frequent acquisition of data), extra  large field-of-view gamma cameras, and cine  scintigraphy, or movie-mode displays have  proved to have an accuracy of nearly 90% in  the localization of the bleeding site   • May be indicated to diagnose associated  disorders such as pancreatitis, aortic  aneurysm, ascites, metastasis, and aortic graft  infection.   • May be an alternative in patients with  contraindications to colonoscopy.   • When endoscopy is undiagnostic, the small  bowel is evaluated. Common procedures  employed are contrast radiography, i.e. UGI  barium follow-through series, and push  enteroscopy, which is an extension of EGD that  allows visualization up to 160 cm. of small  bowel distal to ligament of Treitz; allows tissue  biopsy (Bx), and treatment of bleeding lesions  up to 160 cm. of the proximal small bowel.   • It is a noninvasive visual evaluation of the entire  small bowel and esophagus, indicated in:   > Suspected small intestinal bleeding in  persons with objective evidence of  recurrent, obscure gastrointestinal bleeding  (e.g. iron-deficiency anemia, positive fecal  occult blood test, or visible bleeding) who  have had EGD and colonoscopy within the  past 12 months that have failed to identify  a bleeding source.    > For initial diagnosis in persons with  suspected Crohn's disease without evidence  of disease on conventional diagnostic tests,  including small-bowel follow-through and  upper and lower endoscopy.   > For screening or surveillance of Barrett's  esophagus, and esophageal varices.   • There is a well-recognized association  between angiodysplasia and aortic stenosis  and replacement of the stenotic valve has  been reported to stop GI bleed in over 90%  of patients. Echocardiography should  therefore be a part of the investigations in  such cases. 12 " 14   • A last option in the diagnostic evaluation of  nonemergent cases.   • Confirm hematemesis; patients often confuse  vomiting up and coughing up blood. A history  of epistaxis, bleeding gum disorders, hemo-  ptysis indicate sources other than GI tract.  Ideally viewing the vomit is the best way to  confirm hematemesis   • Confirm melena; black stools may result from  ingestion of iron salts, charcoal, beets, etc.   • Patients with severe bleeding may present  with signs of shock (tachypnea, tachycardia,  hypotension; systolic blood pressure  <100 mm Fig usually indicates <30%  reduction in blood volume), which in  patients with co-morbid disease such as IF1D  may precipitate angina or MI because of  hypoperfusion. However, resuscitative  measures and appropriate level of patient  monitoring must be established before  diagnostic testing or specific therapeutic  interventions    • Nasogastric lavage should be performed in  patients with UGI bleeding. Nasogastric  lavage may be useful as a diagnostic  technique. A bloody lavage may be helpful  in predicting a high-risk lesion, particularly  in hemodynamically stable patients without  hematemesis; a clear lavage may be helpful  in predicting low-risk lesions. Nasogastric  lavage can also facilitate endoscopic  visualization by clearing blood and other  gastric contents. A negative lavage, however,  does not exclude upper GI bleeding; the  procedure carries a false-negative rate of 10%.  The bleeding in such cases may be  intermittent or located in the duodenum.  Aspiration of bilious, nonbloody material  strongly indicates that no active duodenal  bleeding is occurring 15 ' 16   • In UGI bleeding important historical  information should include the onset,  character, frequency, and quantity of  hematemesis. Peptic ulcer pain is epigastric,  gnawing, rhythmic, and dull. GI malignancy  is associated with vague epigastric pain,  dyspepsia, or weight loss. Coughing,  retching, or vomiting preceding hemate-  mesis suggest MW tears   • Although LGI bleeding is usually painless, a  history of abdominal pain, weight loss, fever,  diarrhea, vomiting, or partial small intestinal  or colonic obstruction are important findings  in the differential diagnosis of inflammatory,  infectious, or malignant lesions. Diverticular  disease presents as painless with high  volume bleeding. Cancer and angiodysplasia  present with symptoms of chronic blood loss  (anemia, fatigue, dyspnea on exertion)   • History of prior GI or vascular surgery, e.g.  aortic bypass, and history of any comorbid  disease such as pancreatitis, cirrhosis, renal  failure, cancer, etc. precipitates hematemesis    • A history of cutaneous bleeding (e.g.  purpura, ecchymosis) may indicate bleeding  diathesis (e.g. hemophilia, hepatic failure)   • Age is an important feature in discrimi-  nating the source of LGI bleeding. For  patients aged more than 50 years, ischemia,  colonic AV malformation, diverticulosis, and  malignancy are most common 17   • Colonic AV malformations are most  commonly found in the cecum, often  associated with several systemic diseases,  including atherosclerotic cardiovascular  disease, aortic stenosis (Heyde's syndrome),  chronic renal disease, collagen vascular  disease, von Willebrand disease, and  cirrhosis of the liver   • Medications — NSAIDs, steroids, and use of  recreational drugs, cigarettes, or alcohol  increase the incidence of erosive gastritis or  ulcer disease   • Because of increasing number of elective aortic  aneurysm repairs in the aging population, it  is likely that more patients with secondary  aortoenteric fistula will present with LGI  bleeding. Hence, a high index of suspicion is  necessary for prompt diagnosis and  management of this life-threatening event   • The clinical findings of initial physical  examination and their possible etiologies are  given in Table 22.3.   • It is crucial to remember that identification  of a benign anorectal lesion (hemorrhoids,  ulcer, etc.) does not eliminate the possibility  of a more proximal cause of hemorrhage. In  general, patients with hemorrhoids  identified by physical examination should  still undergo thorough endoscopic  evaluation of the colon to rule out other  pathological conditions (e.g. portal  hypertension, anorectal varices, etc.).   • Bright red or 'coffee-ground'  in UGI bleeding; positive for  blood    • Positive FOBT may be the first sign of colon  cancer or polyp, particularly in patients  above 45 years of age   • Solitary rectal ulcer syndrome should be  considered in all patients with malignant  looking rectal tumors   • Aortoenteric fistula must be suspected in any  patient presenting with UGI bleeding with  known aortic graft (e.g. prior aortic aneurysm  repair). Urgent diagnosis and surgery is  mandatory to prevent exsanguinating  hemorrhage   • Most commonly missed OGIB disorders  related to UGI segment are: erosions in large  hiatal hernias; AV malformations, and peptic  ulcer on the first endoscopic evaluation   • The LGI lesions most commonly missed on  initial endoscopy are: AV malformations and  neoplasms. Repeat upper, lower, or bidirec-    tional endoscopy may be essential depen-  ding on clinical suspicion, and to ascertain  that these lesions have not been overlooked.   Dieulafoy's lesion— It is an abnormally large  artery that penetrates the gut wall, mainly in the  proximal stomach, causing massive bleeding.  The lesion bleeds into the GI tract through a  minute defect in the mucosa, which is not a  primary ulcer of the mucosa, but erosion  probably caused on the submucosal surface by  the pulsatile arteriole protruding into the  mucosa. Dieulafoy's lesion is most commonly  located in the proximal stomach (75% of cases).  Lesion typically occurs within 6 to 10 cm of the  esophagogastric junction, generally along the  lesser curvature of the stomach. Detection and  identification of the Dieulafoy's lesion as the  source of bleeding can often be difficult,  especially because most present with massive  bleeding. Because of intermittent nature of  bleeding, initial endoscopy is diagnostic in 60%  of the cases, so repeated endoscopies are often  necessary. Similar lesions have been identified in  the duodenal bulb, jejunum, ileum, colorectum,  anal canal, and even in bronchus. With the  advances in endoscopy and awareness of  Dieulafoy's lesion as the cause of massive  bleeding that can cause a high fatality rate if the  condition remains unrecognized, it has gained  the reputation of an unusual but important cause  of bleeding, especially LGI hemorrhage.   hereditary disease of vascular malformation  transmitted as an autosomal dominant trait  affecting men and women, characterized by the  presence of multiple arteriovenous malformations  ( AVMs) that lack intervening capillaries and result  in direct connections between arteries and veins.  Small AVMs (or telangiectases) close to the    surface of skin and to mucous membranes often  rupture and bleed after slight trauma. The most  common clinical manifestation is spontaneous and  recurrent epistaxis beginning at approximately 12  years of age. About 25% of individuals with HHT  have GI bleeding, which most commonly begins  after age 40 years. Large AVMs often cause  symptoms when they occur in the brain, lungs,  or gastrointestinal tract, causing complications  from bleeding or shunting, which may be  sudden and catastrophic. The diagnosis of HHT  is based on family history and the presence of  cutaneous or mucocutaneous telangiectases or  large visceral AVMs. HHT is caused by a  mutation in ENG, the gene encoding endoglin  or ACVRL1 (ALK1), the gene encoding the activin  receptor. Molecular genetic testing of these genes  detects mutation in 60-80% of individuals with  HHT and is available on a clinical basis.   Mallory- Weiss syndrome —It is characterized by  UGI bleeding secondary to longitudinal mucosal  lacerations at the gastroesophageal junction or  gastric cardia; may occur after any event that  provokes a sudden rise in intragastric pressure  or gastric prolapse into the esophagus secondary  to precipitating factors such as retching or  vomiting. The classic presentation consists of an  episode of hematemesis following a bout of  retching or vomiting. Hematemesis is present  in 85% of patients. Less common presenting  symptoms include melena, hematochezia,  syncope, and abdominal pain. Excessive alcohol  use has been reported in 40-75% of patients, and  aspirin use in up to 30%.   Peutz-Jeghers syndrome — It appears to be a  germline mutation of the STK11 gene, located on  band 19pl3.3. ; characterized by the combination  of pigmented lesions in the buccal mucosa and  gastrointestinal polyps. Mucocutaneous pigmen-  tation and melanin spots are typical, and are  present in more than 95% of cases. They appear  as small, flat, brown, or dark blue spots with an    appearance of freckles, most commonly in the  peribuccal area. The number, as well as the size  and the location of polyps may vary from patient  to patient. Isolated melanotic mucocutaneous  pigmentation without gastrointestinal polyps  has also been described because of the genetic  variability of the syndrome. Presentation may  include — repeated bouts of abdominal pain in  patients younger than 25 years, unexplained  intestinal bleeding in a young patient, and  menstrual irregularities in females. Family  history of Peutz-Jeghers syndrome may be  present. Many of the gastrointestinal lesions  will start developing early in life even if the  syndrome is clinically apparent in the second  and third decades of life. (Pigmented lesions  are present in the first years of life and may fade  at puberty, except for those on the buccal  mucosa, making diagnosis possible in pediatric  patients with a high level of suspicion). Genetic  counselling and proper screening for both  intestinal cancers and extraintestinal cancers  should be implemented.   rare debilitating disorder of the rectum,  characterized by perianal chronic pain with  passage of blood and mucus. The macroscopic  appearance varies from single to multiple ulcers  or even circumferential lesions. The pathogenesis  remains uncertain; however, trauma to the anterior  or circular rectal wall caused by straining due to  functional disorders of defecation, and pelvic floor  disorders are the main hypothesis. The diagnosis  includes clinical symptoms associated with  endoscopic lesion (erythema, ulcer or polypoid  lesion). Defecography, transrectal ultrasonography,  anorectal manometry, dynamic MRI, etc. are  suitable procedures that may be used to detect  the causative disorder. Histopathological  features of SRUS are characteristic and  pathognomonic; nevertheless the endoscopic    and clinical presentations may be confusing. The  lesions may mimic other rectal pathologies,  including primary or metastatic malignancy, and  lead to wrong diagnosis.    1. Thomopoulos KC, et al. Changes in aetiology and  clinical outcome of acute upper gastrointestinal  bleeding during the last 15 years. Eur J  Gastroenterol Hepatol 2004;16(2):177-82. [PMID:  15075991: Abstract],   2. Strate LL. Lower GI bleeding: Epidemiology and  diagnosis. Gastroenterol Clin North Am 2005;  34(4):643-64. [PMID: 16303575: Abstract],   3. Torres C, et al. Solitary rectal ulcer syndrome:  Clinical findings, surgical treatment, and  outcomes. Int J Colorectal Dis. 2007 Nov;  22(ll):1389-93. Epub 2007 Aug 14. [PMID:  17701045: Abstract],   4. Lis C, et al. Malignant tumors in the rectum  simulating solitary rectal ulcer syndrome in  endoscopic biopsy specimens. Am J Surg Pathol  1998;22(1):106-12. [PMID: 9422323: Abstract],   5. Al Qahtani AR, et al. Investigative modalities for  massive lower gastrointestinal bleeding. World J  Surg 2002 May; 26(5):620-5. Epub 2002 Mar 1.  [PMID: 12098057: Abstract],   6. Suryakanth R, et, al Obscure Gastrointestinal  Bleeding - The Role of Endoscopy. MedGenMed  2006; 8(2): 38. Published online 2006 May 11.   7. Laing CJ, et al. Acute gastrointestinal bleeding:  Emerging role of multidetector CT angiography  and review of current imaging techniques.  Radiographics 2007;27(4):1055-70. [PMID:  17620467: Abstract],   8. Duchesne J, et al. CT-angiography for the  detection of a lower gastrointestinal bleeding  source. Am Surg 2005;71(5):392-7. [PMID:  15986968: Abstract],   9. Zink SI, et al. Noninvasive evaluation of active  lower gastrointestinal bleeding: Comparison  between contrast-enhanced MDCT and 99m  Tc-labeled RBC scintigraphy. AJR Am J  Roentgenol 2008;191(4):1107-14. [PMID:  18806152: Abstract],   10. Li F, et al. Capsule endoscopy: A comprehensive  review. Minerva Gastroenterol Dietol 2007;  53(3):257-72. [PMID: 17912188: Abstract],   11. Hara Amy K, et al. Imaging of Small Bowel Disease:  Comparison of Capsule Endoscopy, Standard  Endoscopy, Barium Examination, and CT.  RadioGraphics 2005 25:697-711. [PMID: 15888619:  Free full text].    12. Morishima A, et al. Successful aortic valve  replacement for Heyde syndrome with confirmed  hematologic recovery. Ann Thorac Surg 2007;  83(l):287-8. [PMID: 17184682: Abstract],   13. Henne S. [Recurrent gastrointestinal bleeding  and aortic valve stenosis (Heyde syndrome):  Need for valve replacement?] Z Gastroenterol.  2007;45(3):245-9. [PMID: 17357954: Abstract],   14. Batur P, et al. Increased prevalence of aortic stenosis  in patients with arteriovenous malformations of the  gastrointestinal tract in Heyde syndrome. Arch  Intern Med 2003;163(15):1821-4. [PMID: 12912718:  Free full text].    15. Aljebreen AM, et al. Nasogastric aspirate  predicts high-risk endoscopic lesions in patients  with acute upper-GI bleeding. Gastrointest  Endosc 2004;59(2):172-8. [PMID: 14745388:  Abstract].   16. Witting MD. "You wanna do what?!" Modern  indications for nasogastric intubation. J Emerg Med  2007;33(l):61-4. Epub 2007 May 30. [PMID:  17630077: Abstract],   17. Boley SJ, et al. On the nature and etiology of  vascular ectasias of the colon. Degenerative lesions  of aging. Gastroenterology 1977 Apr; 72(4 Pt 1):650-  60. [PMID: 300063: Abstract],   The term headache may be defined as any painful  or nonpainful discomfort perceived more than  momentarily in the cranial vault, the orbits, and  the nape of the neck, i.e. from the orbits back to  the suboccipital area*.   It is often difficult to explain the pain of  headache. Hence it is sometimes equated to  'invisible misery', where quite often nothing is  seen from outside and nothing is measurable  on the inside. 1 Some terms used by patients to  explain their headache are— pressure, heaviness,  tightness, throbbing, pounding, boring, bursting,  or simply dull aching discomfort.   The diagnosis of headache nowadays is based  on the classification criteria of The International  Headache Society (IHS). The new International  Classification of Headache Disorders (ICHD-II)  published in January 2004 classifies headache  disorders into 3 parts: part 1: primary headache,  part 2: secondary headache, part 3: neuralgias  and facial pain, and appendix. In total 14 different  headache groups and more than 170 headache  types are separated. 2 " 4    The primary headache disorders — those not  associated with an underlying pathology— include  migraine, tension-type, and cluster headache.  Secondary headache disorders— those attributed to  an underlying pathologic condition— include any  head pain of infectious, neoplastic, vascular, drug-  induced, or idiopathic origin. The vast majority of  patients who present with headache have one of the  primary disorders, as serious secondary causes for  presentation with head pain are rare.   However, patients suffering from headaches  usually fear serious brain disease, and may in  fact be the harbinger of a life-threatening illness.  Further, besides the conventional CT, MRI, MRA,  PET, and SPECT scans, recent imaging modalities  such as functional MRI (f MRI) and voxel-based  morphometry (VBM) on MRI has the potential to  change our concept of primary headache  disorders, requiring a radical reappraisal of the  tenet of structural normality. 3   In the maze of such advanced neuroimaging  realities, their diagnostic outcomes, cost-  effectiveness, and their constant demand for  novel imaging strategies, "whether it's nobler  to scan the brain or suffer the slings and arrows  of the aggrieved patient or relative, that is the  clinical problem. 6, 7    Therefore, the clinician's prime concern while  examining headache patients is, to try and  distinguish the more common benign from the  less common serious life-threatening causes of  headache + , while maintaining a balanced  approach to diagnostic testing.   • CNS infections (i.e. meningitis: bacterial-  Streptococcus pneumoniae, H. influenzae typeb,  N. meningitidis ; TB; viral - HIV, HSV2, EBV;  parasitic - toxoplasma; fungal - cryptococcal* )   • Drug induced (nitrates; calcium channel  blockers; phosphodiesterase type 5 inhibitors:  sildenafil; insulin: hypoglycemia)   + The list of differential diagnoses is one of the longest in  all of medicine.   • Elevated ESR (61-80 mm/hr) is useful to  support the diagnosis of GCA.   • U seful if sinusitis is suspected - opacification,  fluid level, mucosal thickening may be  visualized.   • Electrolytes, urea, creatinine, blood glucose,  LFT, TFTs, and VDRL may be indicated to  exclude secondary causes of headache.   • Indicated in evaluating for PNS and  diagnosing SAH or intracerebral hemorr-  hage in patients with acute and severe  headache   • However, a normal CT scan, including fifth  generation multislice detector CT scan  investigations and reports does not rule out  an acute bleed; if the clinical suspicion  remains high, a LP should be performed   • Limitations of brain CT include inability to  identify small hemorrhages in areas  obscured by artifact or bone, inability to  diagnose other conditions such as idiopathic  intracranial hypertension, meningitis,  carotid or vertebral artery dissection, and  some cases of cerebral venous sinus  thrombosis or pituitary apoplexy, and decay  in sensitivity with time (sensitivity 92% day  of rupture and 58% five days later). 9   • CSF analysis is indicated when meningitis,  encephalitis, and SAH are diagnostic consi-  deration   • LP should not be performed when increased  ICP is suspected, until mass effect is ruled  out®   • The totality of the evidence suggests that  lumbar puncture must still be performed after  a negative CT scan result in patients being  evaluated for subarachnoid hemorrhage. 10    § Because a lumbar puncture can precipitate brain herniation  and death in the presence of increased intracranial  pressure, a CT scan is warranted before the lumbar  puncture is performed.    • The sensitivity of lumbar puncture appro-  aches 100% one to five days after the  hemorrhage when photospectrometry is  used to detect xanthochromia in the fluid  sample.   • It is useful in further enhancing lesions  detected by CT, especially in patients with  chronic headache   • MRI is superior in detecting posterior fossa  tumors and to demonstrate small aneurysms   • In patients with atypical or complicated  headache patterns, e.g. a history of seizures  and/or focal neurological signs or symptoms,  MRI is the preferred choice   • MRI is the modality of choice in the diagnosis  of headaches in patients with HIV/AIDS, who  have a wide variety of neuroimaging  abnormalities, and also coexistence of  multiple pathologies, e.g. tuberculoma with  cerebral infarcts.   • Giant cells may be seen in temporal arteritis.  However, a normal biopsy does not exclude  the disease as there may be segmental  involvement of the temporal artery.   • Nuclear medicine examinations of the  cerebral circulation and metabolism can be  carried out in subgroups of headache patients  for diagnosis and evaluation of complications,  when patients experience unusually severe  attacks, or when the quality or severity of  attacks has changed. 11   • In patients with glaucoma, tonometry will  show high intraocular pressure.   • Five questions need to be answered when  dealing with a patient with headache:   1. Is it the only symptom (e.g. tension  headache); or associated with other  symptoms (e.g. visual aura in migraine,  neurological deficit in stroke)?   2. Is it an acute, new-onset symptom (e.g.  CVD, temporal arteritis)?   3. Is it a chronic, recurring symptom (e.g.  migraine, substance use or abuse)?   4. Is it part of the systemic illness (e.g. SOL,  depression)?   5. Does it represent a potentially serious  threat to life (e.g. stroke, temporal arteritis)?   • In clinical practice, one useful guide in  determining the cause of headache is the time  course, which can be usually separated into  acute, subacute, and chronic (Table 23.1).  Generally, patients with acute or subacute  headaches are more likely to have significant  pathology   • Since most patients with primary headache  have very little by way of physical findings,  a good history is often the most important  part of the headache consultation. A carefully  taken history can establish the diagnosis of  migraine, cluster, or tension-type headache  with sufficient confidence that no need will  exist for additional evaluation 12 (Table 23.2)   • The most common type of headache in patients  presenting for consultation is the non-  migrainous vascular headache secondary to  systemic infection. These patients typically are  febrile and have symptoms of systemic illness.  The neurological examination is normal and  there is no neck rigidity.   • Referred (sinuses, teeth, ears, jaws, cervical spine)  Chronic (lasting over months)   • History of trauma may cause concussion and  postconcussion headaches; intracranial SOL  (Table 23.3), and cervical sprain, can also  induce headaches   • History of substance abuse indicates the  possibility of 'hangover' headache   • History of bilateral, nonthrobbing headache  that is worse in the morning, may awaken  the patient at night, is typical of increased  ICP. Immediate neuroimaging is necessary  to ascertain the cause    Photophobia; phonophobia;  GI upset (e.g. anorexia, nausea,  vomiting); 'aura' with brain  dysfunction(e.g. headache,  vertigo, dysarthria)    Stressful event; food  (chocolate, red wine);  skipping meals; changes in  sleep/weather; hormone  fluctuations    Disturbed memory or  concentration; labile moods-  irritability, restlessness;  sleep disturbance; fatigue    Bilateral, all over the head;  weight-like or vise-like  pressure; nonpulsatile;  distracting, but not  debilitating   Daily or near daily; 30 min-  few days; may be constant    Parasympathetic overac-  tivity: all ipsilateral - lacrima-  tion; red conjunctiva; scleral  injection; nasal congestion/  rhinorrhea; ptosis; miosis of  the eye; forehead and facial  sweating   Always unilateral orbital,  supraorbital, and /or tem-  poral; severe excruciating  stabbing or burning pain   From 1 every day to 8 per  day; remission for few  months or even years; 15  min 2 hours    • New onset in adult life (>40 yr of age) or significant  change in established pattern   > Nausea or vomiting not explained by migraine or  systemic illness   • Horner's syndrome (triad of miosis, i.e. constricted  pupil; partial ptosis; and loss of hemifacial sweating,  i.e. anhidrosis    • Typical physical findings that may be noted  in secondary or symptomatic headache are listed  in Table 23.4   • The presence of nuchal rigidity should make  one think of a subarachnoid hemorrhage,  cerebral hemorrhage, meningitis, or cerebral  abscess   • An acute onset of a headache can be a serious  problem. It should be taken seriously because  an abrupt onset of a severe (worst headache  ever experienced) occipital or generalized  headache in a patient with no past history  of headache may mean a subarachnoid  hemorrhage or meningitis    An acute headache with papilledema and  focal neurologic signs, one should consider  cerebrovascular accident/hemorrhage,  cerebral abscess. With a chronic headache  and papilledema or focal neurologic signs,  one should consider a SOL such as a primary  brain tumor or metastatic neoplasm  Headache that is always on the same side,  associated with seizures, visual distur-  bances, focal neurological deficit, and audible  cranial bruit strongly indicates an arteriov-  enous malformation    • The presence of a tender superficial temporal  artery should make one think of GCA (temporal  arteritis), particularly in the elderly   • Cranial nerve palsies in the elderly are  usually due to ischemia, but when they occur  in conjunction with an elevated ESR and  headache, they could be associated with  GCA. However, when assessing an older  person with a headache, the information  obtained from the patient should be  considered as carefully as any ESR result   • In complicated migraine such as ophthalmic /  hemiplegic/basilar artery migraine, signi-  ficant neurologic complications may outlast  the headache phase. Very rarely there may  be permanent neurologic deficit   • A patient known to have migraine can  develop severe headache due to other  intracranial conditions, and hence if there is  any question about the diagnosis, further  neuroimaging may be necessary   • If headaches are chronic and episodic, and there  are no focal neurologic signs, papilledema, or  nuchal rigidity, an imaging study can be  postponed for a while until the response to  treatment is evaluated. However, if the  response to treatment is poor, neuroimaging is  indicated (Table 23.5)   • Establishing an open and honest physician-  patient relationship is essential for the proper  evaluation and management of headache  disorders. 13 The reason for brain scan - CT or  MRI— particularly with primary headache,  and its probability in the diagnosis should be  made clear to the patient. Failing to provide  such explanation could cause anxiety in a  patient, especially when the scans are either  reported as normal or incidental (nonpatho-  logic) findings are noticed 14   • Often, the most important therapeutic  intervention is confident reassurance about  the absence of serious underlying neurologic  disease.   • Patients with older age (over 50-60 years old) with  new headache   • Sudden onset severe headache (reaching maximum  intensity over seconds to a minute   • Any headache associated with systemic  symptoms or illness (including fever,  persistent or progressive vomiting, stiff neck,  pregnancy, malignancy, immunocom-  promised state, and anticoagulant therapy)   • Onset of new or sudden headache in an  elderly (especially in those age 40 years or  older) has to be evaluated with caution  because it could herald a serious problem  such as SOL, temporal arteritis, or vertebro-  basilar insufficiency   • Any headache with neurologic signs or  symptoms (including altered mental status,  focal neurologic symptoms or signs,  seizures, or papilledema)   • Prior headache history that is different (e.g.  headaches now are of different pattern or are  rapidly progressive in severity or frequency)   • A negative temporal artery biopsy should  not delay treatment when clinical suspicion  is strong   • Benign coital headache — Unless a clear  history of benign recurrent events can be  obtained, the presentation of severe  thunderclap headache during intercourse  may require a full diagnostic assessment to   Thunderclap headache (TCH) — As the name  suggests (a single loud sound of thunder) TCHs  are hyperacute, severe headaches — like a boom  of thunder, becoming severe in intensity within  seconds to a minute of onset and usually fade  over several hours. Some of these headaches,  however, can last for more than a week. Clues  in history and physical examination can point  to a possible serious underlying cause of TCH,  such as subarachnoid hemorrhage, intracranial  hematoma, cerebral venous sinus thrombosis,  cervical artery dissection, ischemic stroke,  pituitary apoplexy, acute arterial hypertension,  spontaneous intracranial hypotension, third  ventricle colloid cyst, and intracranial  infections. Patients with TCH, who have  evidence of reversible, segmental, cerebral  vasoconstriction of circle of Willis arteries, and  normal or near-normal cerebrospinal fluid  evaluation are considered to have reversible  cerebral vasoconstriction syndrome (RCVS)”. Primary  TCH is diagnosed when no underlying etiology  is identified. In accordance with the increased  utilization of cerebral imaging and availability  of noninvasive techniques to image the cerebral  vasculature, and interest in identifying causes  of thunderclap headaches, the list of potential  causes is growing rapidly. Although  uncommon, patients with thunder-clap  headache are to be evaluated in an emergent  fashion as many of the underlying causes are  associated with a serious underlying brain  disorder . 16, 17    ""Reversible cerebral vasoconstriction syndromes  (RCVS) comprise a group of diverse conditions, all  characterized by reversible multifocal narrowing of the  cerebral arteries heralded by sudden (thunderclap), severe  headaches with or without associated neurologic deficits.    1 . Ravishankar K. J Assoc Phy India. Optimizing Primary  Headache Management. 2006;54:928-34.   2. Web site - http://216.25.100.131/ihscommon/  gui delines/p dfs/ihc_II_main_no_pr in t. pdf.  Accessed on 15-10-08.   4. Evers S. The new IHS classification. Background  and structure. Schmerz. 2004;18(5):351-6.  [PMID: 15349761 Abstract],   5. Desai SB. Primary headache and radiologist.  Indian J Radiol Imaging 2004;14:353-4. Available  from: http://www.ijri.Org/text.asp72004/14/4/353/  29519. Accessed on 15.10.08.   6. Goadsby Peter J. To scan or not to scan in  headache. BMJ 2004;329:469-70, doi: 10.1136/  bmj.329. 7464. 469.] Free full text]   7. Freeman JW. Headache reflections: The role of  classification, narrative and focused intervention.  SD Med. 2008;61(8):301-3, 305. [PMID:  18819319 PubMed - in process. Abstract],   8. Chakravarty A. Primary headaches associated  with sexual activity— some observations in Indian  patients. Cephalgia. 2006;26(2):202 -7. [PMID:  16426276 Abstract],   9. American College of Emergency Physicians.  Clinical Policy: Critical issues in the evaluation  and management of adult patients presenting to  the emergency department with acute headache.  June 24, 2008.   10. American College of Emergency Physicians.  Clinical Policy: Critical issues in the evaluation  and management of adult patients presenting to  the emergency department with acute headache.  June 24, 2008. Available at: www.acep.org/  workarea/downloadasset.aspx?id = 8802.  Accessed on 18-10-08.   11. Sandrini G, et al. Neurophysiological tests and  neuroimaging procedures in nonacute headache:  Guidelines and recommendations. Eur J Neurol  2004;ll(4):217-24. [PMID: 15061822 Abstract],   12. Gerald W. Smetana. The Diagnostic Value of  Historical Features in Primary Headache Syndromes:  A Comprehensive Review. Arch Intern Med. 2000;  160(18):2729-2737.[ Free full text]   13. Marks DR, et al. Practical evaluation and  diagnosis of headache. Semin Neurol. 1997;  17(4):307-12. [PMID: 9474710 Abstract],    14. Goadsby Peter J. To scan or not to scan in  headache. BMJ 2004;329:469-470, doi: 10.1136/  bmj. 329. 7464.469. [Free full text]   15. Banerjee A. Coital emergencies. Postgrad med J.  1996;72(853):653-6. [PMID: 8944205 Free full  text].    16. Matharu MS, et al. Thunderclap headache: An  approach to a neurologic emergency. Curr Neurol  Neurosci Rep. 2007;7(2):101-9.[PMID: 17324359  Abstract]   17. Schwedt TJ. Clinical spectrum of thunderclap  headache. Expert Rev Neurother. 2007;7(9):1135-  44. [PMID: 17868012 Abstract],   Hearing loss is the subjective complaint of total or  partial inability to hear sound in either one or both  ears. It can occur at any age; sudden or gradual in  onset; its severity may vary from mild to severe to  profound; and can be reversible, temporary, or  permanent, and make verbal communication difficult.   The intensity of sound is measured with the  'decibel', i.e. dB— a logarithmic unit (and not in  percentage linear scale)— whose reference unit is  0 on the audiogram. Generally, normal hearing is  from 0 to 20 dB, about the loudness of a soft  whisper. The thresholds in the 20 to 40dB region  constitute a mild hearing loss (e.g. with trouble  hearing ordinary conversation); 40 to 60 dB region  constitute a moderate hearing loss (e.g. where  voice must be raised to be heard); and thresholds  greater than 60 dB are considered severe hearing  loss (e.g. where people must shout to be heard).   The term 'deafness' is used strictly when there  is little or no hearing at all. According to the   *Hearing loss is deterioration in hearing. Deafness is  profound hearing loss.   The term impaired hearing generally describes a wide  range of hearing losses, except deafness, and denotes  disability that is commonly called as handicap by the  society.    World Health Organization, the term "deaf" +  should only be applied to individuals with  hearing impairment so severe that they cannot  benefit from sound amplification or hearing aid  assistance; their sense of hearing is non-  functional for ordinary purposes of life. The  cases included in this category will be those  having hearing loss more than 80dB (i.e.  profound impairment) in the better ear, or total  loss of hearing in both ears.   WHO grades of hearing impairment 1 on the  basis of pure tone audiogram is listed in the Table 24. 1 .   Hearing loss can be classified as conductive,  sensorineural, (Table 24.2) or both (mixed loss).  Conductive hearing loss (CHL) occurs secondary to  lesions in the external auditory canal, tympanic  membrane, or middle ear. These lesions prevent  sound from being effectively conducted to the  inner ear. Sensorineural hearing loss (SNHL) is caused  by lesions of either the inner ear (sensory - due to  deterioration of the cochlea) or the auditory  nerve (neural - lesions of the eighth cranial nerve).    + The distinction between the terms "deaf", "Deaf",  "deafened", and "hard of hearing" are based principally  on the individual's preferred language (spoken or sign)  rather than on the actual degree of hearing loss.   Audiometric ISO value  (average of 500, 1000, to  2000, 4000 Hz)    This distinction is important, because sensory  hearing loss is sometimes reversible and  seldom life-threatening. A neural hearing loss  is rarely recoverable and may be due to a  potentially life-threatening brain tumor —  commonly a cerebellopontine angle tumor.  Mixed hearing loss (MHL) may be caused by severe  head injury, with or without fracture of the skull  or temporal bone, by chronic infection, or by one  of many genetic disorders. It may also occur  when a transient conductive hearing loss,  commonly from otitis media, is superimposed  on a sensorineural hearing loss.    Other common symptoms which may be  associated with hearing loss include headache,  otalgia, otorrhea, tinnitus, vertigo, development  of weakness or asymmetry of the face, and an  abnormal sense of taste.   The significance of hearing loss and its  impact on the health and productivity of those  affected by it often go unrecognized. Although  loss of vision is readily acknowledged and  vigorously treated, loss of hearing is often denied,  minimized, or ignored . 2 Since either ignored or  undiagnosed hearing loss— both in the young  and the old— besides causing physical disab-  ility, can also lead to multiple consequences,  including social isolation and depression, it is  vital that early diagnosis is made, particularly  of reversible causes, in addressing these issues.   • Ototoxic drugs (aspirin, loop diuretics, amin-  oglycosides, phosphodiesterase-5 inhibitors,  and chemotherapeutic agents)   • Recurrent otitis externa raises suspicion of  diabetes mellitus and warrants blood glucose  monitoring.   • Useful test for discriminating the cause of  hearing loss. It measures the threshold levels  (i.e. the intensity at which the patient is able  to perceive sound correctly 50% of the times)  by presenting pure tones (i.e. electronically  generated sounds of specific frequencies), the  intensity of which can be increased or  decreased in 5dB steps. Air conduction and  bone conduction thresholds for preset  frequencies for both the ears are assessed and  charted in the form of a graph called  audiogram. The threshold for bone conduc-  tion is a measure of cochlear function. The  difference in the thresholds of air and bone  conduction (A-B gap) is a measure of degree  of conductive deafness. The normal thre-  shold is considered 0 dB hearing level (HI);  hearing loss is considered present if the  patient's threshold is >25 dB HI. When  hearing loss is such as to require loud test  tones, intense tones presented to one ear may  be heard in the other ear. In such cases, a  masking sound, usually narrow band noise,  is presented to the nontest ear to isolate it.   • In this test the patient's ability to hear and  understand speech is measured. Here  phonetically balanced words (single syllable  words, e.g. pin, thin, day, bus) and words  with two equally accented syllables  (spondees), such as railroad, staircase, and  baseball are delivered at 30 or 40 dB above  the patient's speech reception threshold (SRT)  and the percentage of words correctly heard  by the patient is his discrimination sore (DS).    • A person with normal hearing or conductive  deafness will hear 95-100% of the words  correctly. DS falls markedly in sensorineural  deafness, particularly of the neural type.  Poor DS (below 85%) will affect the ability to  understand speech, which is more marked  in the presence of noise.   • Measures the compliance of the tympanic  membrane to ambient air pressure, and does  not require patient participation. A probe  containing a sound source, microphone, and  air pressure regulator is placed snugly with  an airtight seal into the ear canal. The probe  microphone records the reflected sound from  the tympanic membrane while pressure in  the canal is varied. Normally, maximal  compliance of the middle ear occurs when the  pressure in the ear canal equals atmospheric  pressure. Abnormal compliance patterns  suggest specific anatomic disruptions, e.g.  reduced compliance at ambient pressure is  seen in otosclerosis or malleus fixation;  increased compliance at ambient pressure is  seen in ossicular discontinuity. In eustachian  tube obstruction and middle ear effusion,  maximal compliance occurs with a negative  pressure in the ear canal.   • A CT scan is used to examine bony detail in  patients with suspected malformation of the  external auditory canal, middle ear, or inner  ear, and to delineate bone erosion secondary  to infection, cholesteatoma, or tumor.   • To detect lesions of the cerebellopontine  angle, MRI of the head and internal auditory  canal may be needed in cases of unexplained,  unilaterals SNHL that is associated with a    disparity in speech discrimination between  ears, abnormal neurologic examination, or  a combination of such symptoms.   • BAERs are tested by placing electrodes on the  scalp overlying the auditory cortex and  measuring the conduction of sound from the  cochlea to the brain using a probe placed in  the ear canal. A slowing in conduction between  ears may indicate retrocochlear pathology,  such as an acoustic neuroma. It has decreased  sensitivity in the detection of small acoustic  tumors when compared to MRI scanning. The  main indication for this test is in evaluating  asymmetric or unilateral SNHL when MRI is  medically contraindicated or not tolerated by  a claustrophobic patient.   • Measures the earliest evoked potentials  generated in the cochlea and the auditory  nerve with an electrode placed on or through  the eardrum. It can be used to assess and  monitor patients with Meniere's disease.   • It is important that a proactive approach is  adopted during consultation to detect  hearing loss initially because the number of  people — especially the elderly— who seek  help for hearing symptoms is only a fraction  of those affected. Few patients may complain  of decreased hearing or abnormal hearing;  on many occasions it is the family member  or the caregiver who initiates the assessment  for hearing loss   • During consultation, eliciting history, or  counseling, it is important to remember that  individuals with hearing disability have    diverse degree of hearing loss, and their  communication may be unintelligible.  Patience, understanding, and conversing  slowly and clearly (do not follow the natural  instinct to shout) in patient's first language  are extremely important in establishing  meaningful communication   • Screening in adults can be successfully  carried out using the questionnaire from the  Hearing Handicap Inventory for the Elderly  Screening (i.e. HHIE-S) Version (Table 24.3). 5-7   Table 24.3: Hearing handicap inventory for the elderly —  screening (HHIE-S) version-questionnaire   1 . Does a hearing problem cause you to feel embarrassed  when you meet people?   2. Does a hearing problem cause you to feel frustrated  when talking to a family member?   5. Does a hearing problem cause you difficulty when  visiting friends, relatives, or neighbors?   6. Does a hearing problem cause you to attend  religious services less often than you would like?   7. Does a hearing problem cause you to have  arguments with family members?   8. Does a hearing problem cause you difficulty when  listening to television or radio?   9. Do you feel that any difficulty with your hearing  hampers your personal or social life?   10. Does a hearing problem cause you difficulty when  in a restaurant with relatives or friends?   The patient responds to each question with "no" (0  points), "sometimes" (2 points), or "yes" (4 points).  Interpretation of Total Scores: 0-8 = no handicap;  10-24 = mild to moderate handicap; 26-40 = severe  handicap. Scores >10 suggest significant hearing  impairment and necessitate follow-up.   • History — Onset - age of onset helps to differentiate  congenital and acquired causes of hearing loss,  e.g. unilateral hearing loss since birth is most  likely congenital, whereas adult onset unilateral  hearing loss should raise suspicion of a tumor.  Sudden onset may due to viral infection,  perilymphatic fistula, barotrauma, stroke, or  hemorrhage. A gradual onset is suggestive of    causes such as presbycusis, noise trauma,  ototoxicity, tumor, or autoimmune disorders.  Some forms may be intermittent, e.g. Meniere's  syndrome. Unilateral hearing loss is most often  associated with conductive causes, Meniere's  disease, trauma and acoustic neuroma. Bilateral  hearing loss is common with presbycusis,  ototoxic drugs, noise trauma, and autoimmune  disorders. History of fever, ear discharge, pain  is associated with ear infection   • Associated neurological symptoms — Tinnitus is  common with Meniere's syndrome; vertigo  is associated with labyrinthitis. Focal  neurologic deficit suggest CNS tumor or  vascular insufficiency, whereas fluctuating  neurologic deficit may suggest multiple  sclerosis   • Work history — Factory workers, pilots,  firefighters, engine drivers, and those  exposed to chronic, recurrent loud sound are  prone to hearing loss, especially without the  use of protective equipment   • Current and past medications should be  reviewed. Aspirin, loop diuretics, aminogly-  cosides, chemotherapeutic agents, etc. are  known to be ototoxic. FDA has received  reports of cases of sudden decreases or loss  of hearing following the use of PDE-5  inhibitors (sildenafil, tadalafil, and  vardenafil) for the treatment of erectile  dysfunction and for the treatment of  pulmonary arterial hypertension 8   • Family history — May be positive in  presbycusis, Meniere's syndrome, otoscle-  rosis, and acoustic neuroma   • Physical examination — Evaluation of the external  ear to detect obvious causes of CHE, e.g.  congenital malformations, atresia, obstruc-  tion, infection, and tympanic membrane for  perforation, otitis media, and cholesteatoma.  A pneumatic bulb (pneumoscopy) is required    to accurately assess the tympanic membrane  and the aeration in the middle ear   • Cranial nerve testing— Particular attention  should be paid to facial nerve function,  because cranial nerves VII and VIII are closely  associated at the brainstem and in the  temporal bone. Unilateral V, VII and VIII  involvement suggests a cerebropontine angle  lesion (usually a tumor). The trigeminal (V)  and lower cranial nerves (IX through XII) can  also be affected by a lesion at the brainstem,  such as acoustic neuroma presenting as  hearing loss   1. Stand behind the patient, 3 feet away, i.e.  about an arm's length and request him  to close his eyes. (It is important that he  cannot see your face as many deaf  patients can lip read).   2. You need to mask the nontest ear, say by  inserting your finger into it.   3. Whisper a few words at random from  behind the test ear, (e.g. 31, 45, 17, 64, etc).   4. The patient should be able to repeat these  back accurately.   5. Then perform the same test for the other  ear to get a rough measure of their hearing.   You could report this as (for example) " able  to hear a quiet whisper (i.e. 0-20dB) at arms  length on the right ear, but only able to hear  a loud conversational voice (i.e. 40-60dB) at arms  length on the left".   • Alternately, place your fingers approxi-  mately 5 cm from one ear and rub them  together. The patient should be able to hear  the sound generated. Repeat for the other ear.  However, hearing levels are objectively and  accurately assessed by pure tone audiometry   • Tuning fork tests — To assess air conduction  (AC) and bone conduction (BC). Rinne's test    and Weber's test are performed to differentiate  between CHL and SNHL. Table 24.2 illustrates  common causes of CHL and SNHL   1 . A positive Rinne test, i.e. AC> BC (normal  pattern will be retained)   • Earwax impaction should never be missed,  but it is common 9 ' 10   • Otitis media in the adult is uncommon; such  presentation in an elderly should be referred  for further evaluation to rule out an underlying  obstructive lesion of the eustachian tube, e.g.  nasopharyngeal carcinoma   • If patient is elderly and diabetic, be  suspicious of malignant otitis externa   • Patients who present with sudden SNHL  should have a CT/MRI scan to exclude  vascular ischemic event, acoustic neuroma,  multiple sclerosis, perilymph fistula, and  other CNS disorders   • In elderly people, physical examination and  investigations should be focused to search for  alarming symptoms, which may suggest the  cause of hearing impairment is something  other than age-related presbycusis   • An individual's confused behavior, poor job  performance, social isolation, depression, etc.  may be atypical presentation of hearing loss    Table 24.4: Some signs of hearing impairment in infants  and young children   Parents should be alert to any signs of hearing impairment  and discuss them with their child's health care provider.  Some signs include:   • Not turning toward the sound of a voice or imitating  sounds after about 6 months of age   • Using gestures instead of words to express needs  Parents should be concerned about hearing impairment  in older children if they:   • Have speech that is difficult to understand or that is  too loud or too soft   • Appear inattentive at school and have difficulties  learning to read or perform simple mathematics   Startles to a nearby loud sound, stirs or  awakens from sleep when someone talks  or makes a sound, is soothed by mother's  voice   Looks toward an interesting sound, turns  when name is called, makes "moo,"  "ma," "da," "di" sounds to toys, and  "coos" when listening to music    "Children who do not pass these minimal performance  standards or whose parents suspect there is a hearing  loss at any age should be referred for testing.    • Early identification of infants and children who  are at risk of congenital or acquired hearing  loss, and arranging for their timely referral is  extremely important. (Tables 24.4 and 24.5). 1 2 3 4 5 6 7 8 9 10 11    1. Global burden of hearing loss in the year 2000.  Web site: http://www.who.int/healthinfo/statistics/  bod_hearingloss.pdf. Accessed on 18-09-08.   2. Shohet Jack A, et al. Hearing loss: The invisible  disability. Postgrad Med Vol 104/No. 3/Sept.  1998.   3 . Nelson DI, et al. The global burden of occupational  noise-induced hearing loss. Am J Ind Med 2005;  48(6):446-58. [PMID: 16299704],   4. Salama OE, et al. Cellular phones: are they  detrimental? J Egypt Public Health Assoc 2004;  79(3-4):197-223. [PMID: 16918147],   5. Lichtenstein MJ, et al. Validation of screening  tools for identifying hearing-impaired elderly in  primary care. JAMA1988;259(19):2875-8. [PMID:  3285039],   9. Mahoney DF. Cerumen impaction. Prevalence  and detection in nursing homes. J Gerontal Nurs  1993;19(4):23-30. [PMID: 8473711],   10. Al Khabori M, et al. Magnitude of impacted earwax  in Oman, its impact on hearing impairment and  economic burden of earwax on health services.  Indian J Med Sci 2007;61(5):278-85. [PMID:  17478958],   11. Task Force on Newborn and Infant Hearing,  Newborn and Infant Hearing Loss: Detection and  Intervention. Pediatrics 1999;103:527-30.   Blood in the urine, i.e. presence of red blood cells  (RBCs) in the urine is called hematuria. A person  with hematuria may complain of voiding high  colored or altered urine color; it may be  described as yellow, orange, brown, brownish-  black, greenish, or frankly red. These obser-  vations must be given their due clinical  significance. 1 As Dr. Michael Farber, Director of  the Executive Health Program at Hackensack,  University Medical Center in Hackensack, NJ,  states," The appearance and smell of your  urine— as well as the frequency with which you  have to go— can provide many clues to what else   is going on in your body a trip to the toilet   A normal healthy adult at his normal activity  excretes up to 2 million RBCs per day, which  corresponds to 1 to 3 RBCs per high power field  (HPF) on microscopic examination of urine  specimen ; anything more than this is considered  to be abnormal hematuria.    * The efficacy of hematuria screening using the dipstick  method to identify patients with significant urologic disease  is controversial. The dipstick results should be confirmed  with a microscopic examination of the centrifuged urinary  sediment.    Hematuria can be classified as gross or  microscopic depending on whether or not blood  is visible to the naked eye.   Gross (macroscopic) hematuria, i.e. urine visibly red  with intact RBCs on microscopic examination can  result from as little as 1 ml of blood in a liter of urine;  therefore, the color does not reflect the quantity of  blood loss. Besides, urine color changes can be  affected by a variety of drugs, foods, and  endogenous resources; the resultant abnormal urine  coloration has been termed as pseudohematuria.   Microscopic hematuria is defined as three or  more RBCs/HPF on microscopic examination  from two of three freshly voided, clean catch,  midstream urine samples. Confirmation on repeat  testing is indicated to account for some degree of  hematuria noticed in normal healthy persons, as  well as the intermittent nature of hematuria that  is found in some urological diseases.   Physiological or benign hematuria is common and  can result from menstruation, febrile episode,  vigorous exercise, and bleeding from ejaculation.  However, patient should undergo repeat  urinalysis, i.e. sequential urine microscopy, 48 to  72 hours after cessation of such activity. No  additional evaluation is necessary if the hematuria  is resolved. Patients with persistent hematuria  require evaluation.    Isolated hematuria denotes hematuria without  proteinuria or casts. Although such patients may  have structural glomerular abnormalities, they  appear to have low risk for progressive renal  disease. Nevertheless, these patients should be  followed up for the development of proteinuria,  hypertension, and renal insufficiency. 4   Asymptomatic microscopic hematuria is without  features of significant renal disease (no  proteinuria, normal renal function, and no  hypertension), and malignancy has been  excluded. Although no major organization  currently recommends screening for microscopic  hematuria in asymptomatic adults, risk factors for  significant disease should be taken into  consideration, and such high risk patients should  be considered for full urological evaluation after  one properly performed urinalysis documenting  the presence of at least 3 RBCs/HPF. 3 " 7   Hematuria may originate anywhere in the  urinary tract, i.e. kidney, ureter, bladder, prostate  gland, or urethra. At times it may reflect a  generalized disorder of the clotting mechanism.  However, the overall objective in dealing with  hematuria is to differentiate minor incidental  findings that do not require treatment to highly  significant lesions that are potentially serious by  considering risk factors, comorbid conditions,  complications of procedures, and cost-effective  outcomes.   • Hereditary (Polycystic kidney disease;  Hereditary nephritis, i.e. Alport's syndrome  : vide infra li; IgA nephropathy, i.e. Berger's  syndrome: vide infra -1-4-; Thin basement  membrane nephropathy: vide infra 4^)   • Hb% reduced due to gross hematuria,  malignancy, blood dyscrasias, and CRF   • Hematuria with pyuria without bacteriuria  (i.e. sterile culture) suggests renal TB   • Phase contrast microscopy — May be helpful  in differentiating glomerular from lower tract  hematuria (after excluding UTI).   • Often the first choice for renal imaging. It can  differentiate cysts from solid lesions. The  renal size, position, collecting system,  prostate, and bladder can be visualized.  Other abdominal and pelvic organs can also  be assessed for their disorders   • Very helpful if the patient is allergic to IVP  dye, has compromised renal function, and for  evaluating hematuria in pregnancy   • In prospective studies, when US was  combined with a single plain abdominal  radiograph, it proved to be superior to  urography as the primary imaging study in  this series. 8 ' 9   • Plain X-ray can detect radiopaque calcium  stones (>2 mm in size), occasionally cystine  stones, and foreign bodies   • Blood urea, creatinine, electrolytes, coagul-  ation factors, ANA, and PSA to assess renal  function; to exclude blood dyscrasias;  collagen diseases, and to screen for prostatic  carcinoma.   • The current procedure of choice for the  detection of urinary tract calculi   • It can also detect diseases that are mistaken  for renal colic, e.g. appendicitis, diverti-  culitis, AAA.   • For evaluation of urolithiasis, renal tumors,  bladder tumors, and renal trauma   • Studies have suggested that the omission of  IVU as a routine investigation for painless  hematuria does not dramatically reduce the  detection rate of malignant conditions 10   • Not indicated in patients with history of allergy  to IV contrast and compromised renal function.   > Patients older than age 40 with negative  microscopic hematuria, IVP, and US reports   > Patients suspected of having bladder  carcinoma even with negative IVP or  cystourethrogram results.   • This diagnosis can be made after schistosome  eggs are detected in 10 ml of urine, ideally  collected between 10 am until 2 pm, passed  through a polycarbonate membrane filter.   • First void urine collected in the morning on  three consecutive days enhances its sensitivity  and specificity   • Indicated in all patients who have risk factors  for renal carcinoma, especially in the  evaluation of carcinoma in situ   • If malignant or atypical cells are identified,  follow-up cystoscopy is indicated.   • Indicated in persistent hematuria with  negative investigation findings, and evidence  of progression (increasing proteinuria,  creatinine, and blood pressure), and here-  ditary nephropathies 11   • Bladder biopsy for evidence of malignancy,  and granuloma (tubercular, sarcoid, schisto-  somiasis)   • The red urine of hematuria must be  distinguished from hemoglobinuria and  myoglobinuria by demonstration of RBCs in  the freshly voided urine. The presence of RBCs  establishes the diagnosis of hematuria. If  RBCs are absent, examination of the serum  will distinguish hemoglobinuria from  myoglobinuria. A sample of freshly voided  urine is obtained and centrifuged. In  hemoglobinuria (e.g. intravascular hemolysis  due to sickle-cell disease, malaria), the  supernatant will be pink; and in myoglobinuria   • History should focus on any ingested  substances ( e.g. beets, food coloring agents,  rifampicin, phenolphthalein, phenazopyri-  dine) which may be the cause abnormal urine  color, i.e. pseudohematuria, that can be  mistaken for blood; awareness of such a  possibility can spare further evaluation   • Type of hematuria (gross or microscopic), its  relationship to urination or timing of  hematuria, associated symptoms (recent sore  throat, fever, chills, loin pain, and radiation)  is important   • Three tube test — The source of hematuria may  be ascertained by this test: predominantly,  initial hematuria results from anterior  urethral disease; final hematuria results from  diseases of the bladder neck or the prostate  gland; and hematuria throughout the stream  suggests a lesion higher in the bladder, ureter,  or kidney   • Menstrual history— It is important in women  of childbearing age with history of blood in  the urine to ascertain that bleeding is from the  urinary tract and not vaginal in origin; cath-  eterization may be required to differentiate  vaginal bleeding from other sources   > Painful hematuria is usually caused by  UTIs, nephrolithiasis, renal infarction.   > Hematuria with dysuria, frequency,  urgency, and suprapubic pain usually  denotes cystitis.   > Hematuria occurring two to three days after  a nonspecific infection of the upper  respiratory tract suggests IgA nephropathy.   > A rash, joint pain, photosensitivity, or  Raynaud's phenomenon point to a  collagen vascular disease.   > History of bleeding elsewhere such as  bruising of the skin or nose bleed  indicates blood dyscrasias.    > Painless hematuria may signify primary  renal disease such as tumor, polycystic  kidney disease, or TB.   > Foul smelling vaginal or urethral discharge  may indicate risky sexual behavior or  presence of foreign body   • Family history of nephrolithiasis, polycystic  kidney disease, TB, or sickle-cell anemia  suggests that these conditions as possible  causes of hematuria. Flearing loss and renal  failure in male members in the family is seen  in Alport's disease. Hematuria without such  disorders in the family members may suggest  thin glomerular basement membrane disease  (TBMD)   • Past history of travel to endemic areas (Schis-  tosome hematobium in Egypt); exposure to  chemical carcinogens (aniline dyes, tobacco  smoke) is suggestive of bladder tumor. History  of medications, analgesic abuse (renal papillary  necrosis), diabetes mellitus (nephrosclerosis),  prostatic hypertrophy, trauma, etc. may be of  diagnostic value   • Painless gross hematuria in an elderly, in the  absence of infection, is caused by malignancy  unless proved otherwise   • Hematuria in elderly, which may be transient,  intermittent, or asymptomatic, always warra-  nts a comprehensive evaluation to exclude  malignancy   • Persistent hematuria warrants thorough  evaluation when found in patients of any age   • Hematuria associated with sterile pyuria is  genitourinary TB or interstitial nephritis until  proved otherwise   • Artifactual hematuria 12 though rare, is common  in people with Munchhausen syndrome,  psychiatric patients, and drug addicts,  suggesting renal colic. If suspected, requesting  the person to void urine in presence of a witness  clears the confusion.    collagen is abnormal. The disease is inherited as  an X-linked trait; in some families, however,  autosomal recessive and perhaps autosomal  dominant forms exist. The diagnosis of hereditary  nephritis is based on: a positive family history  (nephropathy, deafness particularly in male family  members); audiometry, which detects high  frequency deafness that is clinically not apparent;  abnonnalities of the eyes such as cataract, myopia;  and renal biopsy (Bx). End-stage renal disease  develops in persons 20 to 40 years of age.   primary renal disease of IgA deposition in the  glomerular mesangium, and a frequent cause of  glomerular hematuria; occurs predominantly in  men between the ages 20 and 30. An episode of  gross (cola-colored urine), or microscopic  hematuria 1 to 3 days after upper respiratory  infection, or GI symptoms is the commonest  presentation. Other findings include protein-  uria, hypertension, and abnormal renal function  tests. The serum IgA level is increased; serum  compliment levels are usually normal, and the  renal biopsy (Bx) is the standard for diagnosis.   It is also known as benign familial hematuria,  — an autosomal dominant nephropathy defined  by diffuse thinning of the glomerular basement  membrane at electron microscopy examination  (normal = 300 - 350 nm). Characteristic features  include: glomerular hematuria, minimal  proteinuria (<1.5 g/day), normal renal function,  and familial occurrence. Though mostly benign,  affected patient and family members should be  followed up for progressive hypertension or  disease progression.    1. Schimpf MO, et at. Can community-dwelling  women reliably identify infected urine? Int  Urogynecol J Pelvic Floor Dysfunct 2007;  18(11):1357-61. Epub 2007 Mar 14. [PMID:  17356798: Abstract],   2. Sally Wadyka for MSN Health & Fitness. What  Your Urine is Telling You about Your Health. URL:  http://health.msn.com/health-topics/  articlepage.aspx?cp-documentid=l 001 82486.  (accessed on 12-07-08)   3. Topham PS, et al. The value of urine screening in a  young adult population. Fam Pract 2004;21(1):18-  21. [PMID: 14760038: Abstract],   4. Chow KM, et al. Asymptomatic isolated micro-  scopic haematuria: Long-term follow-up. QJM  2004;97(ll):739-45. [PMID: 15496530: Abstract],   5. El-galley R, et al. Practical use of investigations in  patients with hematuria. J Endourol 2008;22(1):51-   6. Grossfeld CD, et al. Evaluation of asymptomatic  microscopic hematuria. Urol Clin North Am 1998;  25(4):661-76. [PMID: 10026773: Abstract],   7. Grossfeld GD, et al. Asymptomatic microscopic  hematuria in adults: Summary of the AUA best  practice policy recommendations. Am Fam Physi-  cian. 2001;63(6):1 145-54. [PMID: 11277551:  Abstract],   8. Andrews SJ, et al. Ultrasonography and abdominal  radiography versus intravenous urography in  investigation of urinary tract infection in men:  Prospective incident cohort study. BMJ 2002;  324(7335):454-6.[PMID: 11859046: free full text],   9. Spencer J, et al. Ultrasonography compared with  intravenous urography in the investigation of  adults with haematuria. BMJ 1990;301(6760):1074-  6.[ PMID: 2249070: Free full text],   10. Mishra VC, et al. Role of i.v. urography in patients  with haematuria. Scand J Urol Nephrol 2004;  38(3):236-9. [PMID: 15204378: Abstract],   11. ShenP, et al. Useful indicators for performing renal  biopsy in adult patients with isolated microscopic  haematuria. Int J Clin Pract 2007;61(5):789-94. Epub  2007 Mar 16. [PMID: 17362478: Abstract],   12. Englis M, et al. Simulated proteinuria and  haematuria. Int Urol Nephrol 1983;15(2):181-6.  [PMID: 6629694: Abstract],   Hemoptysis is defined as coughing up or  expectoration of blood from the respiratory  tract below the level of vocal cords, which can  be from the trachea, major airways, or lung  parenchyma, i.e. the tracheobronchial tree.   The amount of blood expectorated is  important because the rate of bleeding is a major  determinant of morbidity. The severity of  hemoptysis has been arbitrarily divided as mild,  moderate, or severe, depending upon the amount  of bleeding. It is mild if less than 30 ml of blood is  expectorated per day, or there is only streaking,  or only flakes of blood in the sputum is present.  Hemoptysis is moderate if bleeding is between 30  to 200 ml per day, and severe if bleeding occurs in  excess of 200 ml per day. Massive hemoptysis has  been variably defined as blood loss of 200 to 600  ml or more within 48 hours. Since any definition  is arbitrary, especially because the quantity of  blood expectorated is difficult to quantify,  Ibrahim WH 1 has proposed the use of the term  life-threatening hemoptysis ; so as to avoid the  difference of opinion (with regard to quantity of  blood expectorated) applied to the general term  massive which necessitates the identification of a    specific volume of blood. Life-threatening hemoptysis  may thus be defined as any hemoptysis that: (1) is  >100 ml in 24 hour; (2) causes abnormal gas  exchange/airway obstruction; or (3) causes  hemodynamic instability. The cut-off volume of  100 ml per 24 hours has been selected because it  is the smallest amount of hemoptysis that is  reported in literature to threaten the life of the  patient.   Hemoptysis has been further classified as  single if there is one episode of bleeding lasting  up to seven days, but usually 1 to 2 days. It is  called recurrent when the bleeding continues for  longer than seven days or there is break in the  continuity of at least 2 to 3 days. When pure  blood without sputum is expectorated, it is  called frank hemoptysis.   Considering that the anatomic dead space  in the airway is 100 to 200 ml in most adult  individuals, an amount of more than 300 ml.  poses the risk of aspiration into the lungs. The  threat to life is either by asphyxiation or  exsanguination. However, hemoptysis of any  degree and frequency needs thorough evaluation  because even a small amount of hemoptysis may  herald serious and incurable disease. 2 On the    other hand, even a moderate amount of  hemoptysis is life-threatening in those with  compromised respiratory system. Therefore,  the aim of evaluation is three fold:   • Decide the most suitable intervention/  treatment if bleeding persists, recurs, or is  massive, and when to treat.   Despite thorough evaluation, up to 30% of  patients show no identifiable etiology of their  hemoptysis; these patients are classified as  having cryptogenic hemoptysis, which may be a  harbinger of significant tracheobronchial  pathology. 3 " 5   • Other primary lung neoplasms (carcinoid  tumors: vide infra 4 - 4 -)   • May provide important information sugges-  ting the bleeding source by showing a lesion  with bleeding potential such as : patchy areas  of consolidation (pneumonitis); bilateral  basal congestion (pulmonary edema); apical  fibrocavitary lesion (TB); dilated bronchial  walls (bronchiectasis); mass or coin lesion  (neoplasm); or fungus ball in cavitary lesion  (aspergillosis)   • However, additional follow-up testing (e.g.  bronchoscopy, CT thorax) is recommended  in patients presenting with hemoptysis in  which the underlying cause was not detected  at initial radiography, especially in those with  risk factors : sex (male), age 50 years or older,  and >40 pack year smoking history. 7 ' 8   • This is the most important procedure for  localizing the site of bleeding. Also, the  bleeding sites may be sampled for  histopathological analysis   • When to use rigid or flexible fiberoptic  bronchoscopy or a combination of both is  controversial. 910 Generally, rigid bronchos-  copy is the preferred tool for massive  hemoptysis because of its greater suctioning  capacity of blood and clots, superior  visualization of the major airways, and  adequate ventilation and airway control    • Flexible bronchoscopy is preferable in  patients with hemoptysis originating from  the upper bronchi. Besides it can also be used  to provide direct therapy in cases of  continued bleeding   • Bronchoscopy is also indicated in cases of  persistent or recurrent bleeding, and for  smokers aged more than 40 years with a  negative CXR study, because of the higher  prevalence of lung cancer in this group. n ' 12   • Infecting organisms may be isolated such as  in cases with pneumonitis, lung abscess, TB,  or cytological features of malignancy may  be present.   • Eosinophilia in mycosis (allergic broncho-  pulmonary aspergillosis) or collagen-vascular  disease (Churg-Strauss syndrome: vide infra 4-i,  PAN)   • Prothrombin time (PT) or partial prothr-  ombin time (PPT) increased in disorders of  coagulation, and in patients with anticoagu-  lation therapy.    "■Molecular DNA technology (e.g. polymerase chain  reaction) may be performed on cultured specimens to  provide a more rapid and definitive diagnosis in  mycobacterial infection.   • Used as an initial screening test in patients  suspected with TB who have not received  BCG immunization.   • The classical SI Q3 T3 pattern indicative of  right heart strain with PE is rare; however,  nonspecific ST segment and/or T-wave  abnormalities are more common.   • This procedure is of immense value for the  detection of bronchiectasis and undiagnosed  lung malignancy, i.e. when clinical suspicion  for malignancy exists, but sputum and  bronchoscopy reports are noncontributory  or equivocal   • HRCT with IV contrast is presently  considered as an adjunct diagnostic  modality in patients with high probability  of PE presenting with hemoptysis   • Current opinion favors HRCT to bronch-  oscopy as the first-line procedure for  screening patients with large and those with  massive hemoptysis. 13 " 15   • Multidetector row CT with 3D volume  rendering has enhanced the conventional  roles of thoracic CT. It permits noninvasive,  rapid, and accurate assessment of the cause  and consequences of hemorrhage into the    airways and helps guide subsequent  management. It provides an excellent  anatomy of the thorax, thereby increasing  the diagnostic yield comprehensively. With  the advent of MDCT, there is paradigm shift  in vascular imaging from conventional  catheter angiography to MDCT angiog-  raphy, because this technique provides  image quality that equals or surpasses that  of conventional angiography. It is reliable  in depicting clot and the pulmonary  vascula-ture, and may also be used to  evaluate thoracic venous anomalies (e.g.  pulmonary arteriovenous malformations),  and to plan therapy. In diffuse lung disease,  this technique can increase nodule detection  and help differentiate between small  nodules and vessels. Recent advances in 3D  volume rendering allow a fly through the  tracheobronchial tree and the thoracic  great vessels generating virtual endoscopic  views in real-time.   • Used as an initial screening procedure; values  lower than the cut off level (<500 mg/ml or  500 pg /l, by ELISA) rules out PE and obviate  the need for other tests, e.g. pulmonary  angiography.   • To assess CHF with pulmonary edema and  valvular heart disease such as mitral stenosis.   • Can be used to diagnose PE, especially with  significant obstruction to pulmonary circul-  ation.   • Useful to diagnose PE although CT-pulmo-  nary angiogram is the current gold standard.   • May be essential to diagnose malignancy  (staging), sarcoidosis, and pulmonary  fibrosis.   • The first step in evaluating hemoptysis is to  ascertain that the blood is truly originating  from tracheobronchial tree, and the under-  lying cause of bleeding. Bleeding from  sources other than lower respiratory tract,  i.e. upper airways and GI tract is called  pseudohemoptysis (Table 26.1)   • If a clearcut source of the pseudohemoptysis  cannot be determined, the spitting of blood  is assumed to be true hemoptysis. The  possible symptom associated causes of  hemoptysis is given in Table 26.2   • The rate, amount of blood loss, and clinical  stability of the patient are critical parameters  to ascertain for any further evaluation. In  patients with massive hemoptysis or in those  with compromised respiratory functions,  the urgent need is to prevent aspiration and  stabilize the patient. The initial management  in such situations is not diagnostic but  therapeutic   • Characteristics of the sputum, in terms of  color and odor may be helpful in defining  the disease process causing hemoptysis: foul   • Respiratory symptoms less likely; other  GI symptoms — nausea, vomiting, pain  abdomen-more likely.    smelling sputum suggests a lung abscess;  pink, frothy sputum is suggestive of  pulmonary edema; slight blood streaking in  the sputum is most common with bronchitis;  frankly bloody sputum is seen in TB, PE, and  bronchogenic carcinoma   • Associated symptoms — History of cough,  dyspnea, sputum production over several  years may suggest chronic bronchitis or  bronchiectasis. Weight loss and fatigue may  suggest an underlying malignancy; fever and  night sweats might indicate TB   • History of smoking + , occupational exposures  (e.g. asbestos, silica), drug abuse (crack lung),  etc. are strong risk factors for massive  hemoptysis   Especially in a male sex, older than 40 years, and smoking    • History of coexisting disorders like cardiac  (valvular disease, heart failure); renal  (nephrotic syndrome); SLE; or previous  malignancy may give clues to the cause of  hemoptysis, which may indicate additional  investigations to arrive at the diagnosis   • Hemoptysis since childhood is likely due to  congenital heart defects, bronchiectasis,  cystic fibrosis, or blood dyscrasias   • Medications, especially anticoagulants,  might contribute to bleeding. Patients  belonging to this class of hemoptysis are  those suffering from PE, cardiac valvular  defects, or CHF   • Physical examination— Besides the vital signs  (tachycardia, tachypnea, and hypotension    with hypovolemia) which are critical in  stabilizing patients with massive hemoptysis,  other common physical findings and their  significance is given in Table 26.3.   • Any male smoker with significant hemoptysis  should have a CXR, particularly if associated  with weight loss   • In an acutely breathless patient with  hemoptysis, consider PE if there is no other  obvious explanation for his symptoms.  Indeed, no single symptom or sign or  combination of clinical findings is suggestive  of pulmonary thromboembolism; 20 further  testing is required in the majority of patients   • TB is on the increase with rising incidence of  HIV/AIDS infection; consider this possibility  in every individual with risky sexual  behavior   • Hemoptysis due to foreign body aspiration  can remain undiagnosed for years and may  lead to an incorrect diagnosis of asthma,  bronchitis, or recurrent pneumonia. A high  index of suspicion is the most important   • Despite the most extensive investigations  about 20-30% cases of hemoptysis remain  undiagnosed. Such patients should be  followed up closely for a period of time  sufficient to exclude significant underlying  disease such as bronchogenic carcinoma.^ 2   Carcinoid Tumor — A type of slow growing  neuroendocrine tumor, derived from primitive  stem cell, usually benign, and found in the  gastrointestinal system (most often in the  appendix), and sometimes in the lungs or other  sites; and characterized by attacks of severe  flushing of the skin, diarrheal watery stools,  bronchoconstriction, sudden drops in blood  pressure, edema, and ascites. Symptoms are  caused by tumor secretion of serotonin,  prostaglandins, and other biologically active  substances.   Churg-Strauss syndrome (allergic granulo-  matosis and allergic angiitis) — It is a disorder    that causes inflammation in blood vessels  (vasculitis), which restricts blood flow to  various organs. The disease can occur at any  age, but it's more commonly diagnosed in  middle-aged people. People older than 65  years are unlikely to develop Churg-Strauss  syndrome. Although the disease may involve  any organ, including lungs, skin, gastroin-  testinal system, kidneys, muscles, joints and  heart, most commonly it affects lungs and  skin. The restricted blood flow to these  organs can cause temporary or permanent  damage. There are three stages of Churg-  Strauss syndrome, namely, allergic (asthma,  itching, polyp); hypereosinophilia (fever, weight loss,  abdominal pain, GI bleeding); and systemic vasculitis  (cough, dyspnea, diarrhea, hematuria). Churg-  Strauss syndrome is progressive, but not  everyone develops all three phases, and the  phases don't always develop in order. Without  treatment, this disease may be fatal.   Cocaine lung— Popularly called as crack lung,  (the term crack characterizes the crackling sound  heard when cocaine freebase is smoked); cocaine  has multisystemic effects, and virtually every  organ system may be a site of action. Crack lung,  a syndrome usually occurring 1 to 48 hours after  heavy cocaine smoking, is a hypersensitivity  pneumonitis. It consists of the constellation of  chest pain, cough with hemoptysis, dyspnea,  bronchospasm, pruritus, fever, diffuse alveolar  infiltrates without effusion, and pulmonary and  systemic eosinophilia.   Factitious hemoptysis (Miinchhausen hemo-  ptysis)— When a patient presents with history  of hemoptysis, especially recurrent hemoptysis  with multiple normal reports from multiple  hospitals, a factitious cause should be considered  when the medical history or the patient's  behavior is unusual. Most patients are young in  age, and employees in the health care profession;  they generally have a somewhat reasonable    medical history, but discrepancies are detectable  upon careful evaluation. They usually and readily  provide consent for all invasive procedures,  including thoracotomy.   Paragonimiasis (pulmonary) — Caused by  Paragonimus westermani, a common lung fluke in  humans, commonly found in Asia, Africa, and  Latin America. Human infections occur where local  people consume improperly cooked freshwater  crustaceans such as lobsters and crabs. Usually no  symptoms are observed when the parasites  migrate in the peritoneal cavity. When parasites  invade the lung, several symptoms including  pleuritic and chest pain, cough, and rusty sputum  may be present. Pulmonary complications of  untreated heavy infection include interstitial  pneumonia, bronchitis, and bronchiectasis.  Secondary complications may include  bronchopneumonia, lung abscess, pleural effusion,  or empyema. Ectopic paragonimiasis results in  granulomatous lesions in the organs other than  the lung. The most commonly affected organs  include liver, spleen, omentum, and ovary. The most  serious illness is cerebral paragonimiasis.    1 . Ibrahim WH. Massive haemoptysis: The definition  should be revised (letter). Eur Respir J 2008;32(4):  1131-2: [PMID: 18827169: Free full text],   2. Jones R, et al. Alarm symptoms in early diagnosis  of cancer in primary care: Cohort study using  General Practice Research Database. BMJ 2007;  334:1040, doi: 10. 1136/bmj. 39171. 637106. AE.  [PMID: 17493982: Free full text],   3. Savale, et al. Cryptogenic hemoptysis: From a  benign to a life-threatening pathologic vascular  condition. Am J Respir Crit Care Med 2007;  175(ll):1181-5. Epub 2007 Mar 1. [PMID:  17332480: Free full text],   4. Loschhorn C Dieulafoy's disease of the lung: A  potential disaster for the bronchoscopist.  Respiration. 2006;73(4):562-5. Epub 2005 Aug  18. [PMID: 16141709: Abstract],   5. Alasaly K, et al. Cryptogenic organizing  pneumonia. A report of 25 cases and a review of  the literature. Medicine (Baltimore). 1995;  74(4):201-11. [PMID: 7623655: Abstract],    6. Tashkin DP. Airway effects of marijuana, cocaine,  and other inhaled illicit agents. Curr Opin Pulm  Med 2001;7(2):43-61. [PMID: 11224724:  Abstract].   8. Lee CH, et al. Airway lesions presenting with a  normal chest X-ray. Taiwan Yi Xue Hui Za Zhi.  1989;88(5):498-502. [PMID: 2794950: Abstract],   9. Pyng Lee, et al. Advances in Bronchoscopy-  Therapeutic Bronchoscopy. JAPI;2004;52:905-14.   11. Sen RP, et al. Fiberoptic bronchoscopy for  refractory cough. Chest 1991;99(l):33-5. [PMID:  1984981: Abstract],   12. Su WJ, et al. Chest roentgenographic guidelines  in the selection of patients for fiberoptic  bronchoscopy. Chest 1993;103(4):1198-  201. PMID: 8131465: Free full text],   13. Revel MP, et al. Can CT replace bronchoscopy  in the detection of the site and cause of bleeding  in patients with large or massive hemoptysis?  AJR Am J Roentgenol. 2002;179(5):1217-24.  [PMID: 12388502: Free full text],   14. McGuinness G, et al. Hemoptysis: Prospective  high-resolution CT/bronchoscopic correlation.  Chest 1994;1 05 (4): 1155-62. [PMID: 8162743:  Free full text].    1 5 . Tak S, et al. Haemoptysis in patients with a normal  chest radiograph: Bronchoscopy-CT correlation.  Australas Radiol 1999;43(4):451-5. [PMID:  10901958: Abstract],   16. Bruzzi JF, et al. Multi-detector row CT of  hemoptysis. Radiographics 2006;26(l):3-22.  [PMID: 16418239: Abstract],   17. Lawler LP, et al. Multi-detector row CT of thoracic  disease with emphasis on 3D volume rendering  and CT angiography. Radiographics 2001;  21(5):1257-73. [PMID: 11553832: Abstract],   18. Das CJ, et al. Thoracic application of multi-  detector CT. Indian J Chest Dis Allied Sci. 2007;  49(l):29-36. [PMID: 17256564: Abstract],   19. Boiselle PM. Multislice helical CT of the central  airways. Radiol Clin North Am 2003;41(3):561-  74. [PMID: 12797606: Abstract],   20. Tierney LM, et al. Current Med. Diag. & Treat.  2006;9:280 Disorders of the Pul. Circulation.   21. Willett LL, et al. An unusual cause of chronic  cough. Foreign body aspiration. J Gen Intern Med  2006;21(2):Cl-3. [PMID: 16606374: Free full  text],   22. Herth F, et al. Long-term outcome and lung cancer  incidence in patients with hemoptysis of unknown  origin. Chest 2001;120(5):1592-4. [PMID:  11713139: Free full text].   Hiccups (hiccough) or singultus may be defined as  a complex reflex arc phenomenon characterized  by involuntary, spasmodic contraction of  diaphragm, and respiratory intercostal muscles,  followed by abrupt closure of glottis, resulting in  the characteristic 'hie' sound.   The reflex arc involves afferents, which travel  along with the vagus and phrenic nerve fibers, the  pharyngeal plexus (C2-C4), and the sympathetic  chain (T6-T12) to the brainstem 'hiccup center'. The  phrenic nerve (C3-C5) serves as the efferent  pathway. Any irritation or stimulation along this  reflex pathway (i.e. peripheral— involving the vagus  or phrenic nerve and structures adjacent to the  diaphragm, or central— involving the CNS) can  result in hiccups (Table 27.1). Fluoroscopy reveals  that only one hemidiaphragm is affected, with the  left diaphragm being more frequently involved than  the right, although bilateral involvement may occur.   Fliccups are a common part of life, and  appear to serve no purpose in humans. It affects  everyone, at any age— and in utero 1 — sometime  or the other, with its frequency being between 4  and 60 per minute. Usually it is a short-lived  annoyance that resolves spontaneously,or  responds to one of several anecdotal remedies.    including a reported case of a man whose  intractable hiccups lasting for four days  completely ceased after sexual intercourse (i.e.  ejaculation) with his wife. 2   A hiccup bout is any episode lasting more  than a few minutes. Chronic hiccups or those  recurring as repetitive attacks are the ones  needing medical attention. Based on its duration,  hiccups are classified as:   Though usually benign and self-limiting  annoyance, they can be a major cause of distress,  interrupting talking, eating, and sleeping, resulting  in weight loss, exhaustion, and depression;  occasionally it may even reflect serious underlying  illness, often associated with organic conditions,   * The world record stands at 68 years, with a gentleman called  Charles Osborne, USA, who hiccupped continuously from 1922  to 1990. The hiccups started in 1922 at a rate of 40 times per  minute, slowing to 20 hiccups per minute and eventually  stopping on June 5, 1990, a total of 68 years. Despite his condition,  Osborne was able to lead a normal life, and was even married  two times. It has been estimated that Osborne hiccupped 430  million times over the 68 year period, [ref. - http://  enwikipedia.org/wiki/Charles_Osbome_ (hiccups)].    specially advanced tumors of the digestive tract . 3  Symptomatic relief to the exasperated patient while  conducting a judicious evaluation to determine the  cause is the initial approach in the management with  persistent hiccups.   • Sudden temperature changes (hot then cold  liquids, hot then cold shower)   • Malarial parasites may be seen on blood film  in patients with pyrexia as a cause of hiccups.   • A study shows that for every 10 mEq/1  reduction in serum sodium, patients likely  to be 17 times at risk of developing hiccups. 6   • Determine if unilateral or bilateral before  invasive therapy, e.g. phrenic nerve block  surgery or phrenic nerve or diaphragmatic  pacing.   • Consolidation, cavitation, hilar mass, media-  stinal mass, effusion, and collapse due to  various causes such as pneumonia, malig-  nancy, lymphoma, and aneurysm may be  noted as etiological factors   • Elevation of a hemidiaphragm may be due  to phrenic nerve palsy from carcinomatous  infiltration, diaphragmatic hernia, or hepato-  megaly on right side may be seen.   • To evaluate in patients with reflux, acid-peptic  disorder, and esophageal carcinoma. 8   • To evaluate diaphragmatic movements, and  subdiaphragmatic, hepatic, and gallbladder  lesions.   • To define and identify pulmonary infection,  tumors, mediastinal mass, and aortic  aneurysm.   • Indicated in patients with intractable hiccups  (with or without neurological signs), e.g.    raised intracranial pressure (with contrain-  dication to lumbar puncture), intracranial  bleeding, tumor, multiple sclerosis, and  encephalitis   • May be indicated to confirm a suspected lung  neoplasm with CT/MRI of chest with  subsequent biopsy (Bx).   • Hiccups commonly occur as an isolated brief  symptom; they self-terminate or respond to  simple maneuvers, and need no investiga-  tion or follow-up care.   • In contrast, patients with persistent  hiccups require thorough evaluation as  they are frequently associated with  underlying pathological process, mostly  related to respiratory, abdominal, and  nervous systems. Therefore, the history  and examination should be focused  similarly.   • History includes — Onset, duration, assoc-  iated symptoms and events (Table 27.2),  alcohol and drug abuse, surgery (craniotomy,  thoracotomy, laparotomy), and past history  of hiccups and its treatment.    Table 27.2: Symptoms and signs of common pathologic disorders associated with hiccups    • Cough, sputum, fever, chest pain; lung consolidation,  effusion, pleural rub   • Above symptoms, dyspnea, weight loss, with possible  hemoptysis in a smoker; clubbing, lymphadenopathy   • Above symptoms, stridor, hoarse voice, neck/chest  swelling, engorged veins over chest and neck, night  sweats; Horner's syndrome    • Physical examination includes head, neck  (thyroid, lymph nodes, neck vessels), ear  (tympanic membrane irritation by foreign  body), chest (consolidation, pleural effusion),  abdomen (hepatomegaly, mass, distension),  and CNS for neurologic deficit.   • Presence of hiccups during sleep usually  indicates an underlying organic cause;  whereas its absence during sleep indicates a  psychogenic or idiopathic etiology.   • Pathologic laughing occurs in approximately  10% of patients with multiple sclerosis,  especially when patients have entered the  chronic stage. 10   • Although benign hiccups occur less frequent  in adult life, intractable hiccups are more  common in adult life   • Exclude multiple sclerosis in any patient with  persistent hiccups as psychogenic, especially  in young adults   • Persistent hiccups are reported to be an early  manifestation of rare disorders such as  Addison's disease, 11 Parkinson's disease, 12  SLE, 13 and herpes zoster 14   • Drug-induced hiccups are a known pheno-  menon; hence suspect any medication that a  patient may be taking as a cause for persistent  hiccups   • In a patient with hiccups and hypercalcemia,  prompt work up is indicated to rule out  malignancy, notably breast and lung cancer  and multiple myeloma.    1. Marsal K. Ultrasonic assessment of fetal activity.  Clin Obstet Gynaecol 1983;10(3):541-63. [PMID:  6360464: Abstract],   2. Peleg R, et al. Case report: Sexual intercourse as  potential treatment for intractable hiccups. Can  Fam Physician. 2000;46:1631-2. [PMID: 10955182:  Free full article].   3. Martinez Rey C, et al. Hiccup: Review of 24 cases.  Rev Med Chil 2007;135(9):1132-8. Epub 2007 Nov  15. [PMID: 18064367: Abstract],   4. Thompson DF, et al. Drug-induced hiccups. Ann  Pharmacother. 1997;31(3):367-9.[PMID: 9066948:  Abstract],   5. Bagheri H, et al. Drug-induced hiccup: A review  of the France pharmacologic vigilance database.  Therapie. 1999;54(l):35-9. [PMID: 10216420:  Abstract],   6. George J, et al. Hyponatraemia and hiccups. Natl  Med J India. 1996;9(3):107-9. [PMID: 8664818:  Abstract],   7. Krysiak W, et al. Hiccups as a myocardial ischemia  symptom. Pol Arch Med Wewn 2008;118(3):148-51.  [PMID: 18476462: Abstract],   8. Khorakiwala T, et al. Hiccups: An unrecognized  symptom of esophageal cancer? Am J Gastroenterol.  2008;103(3):801. [PMID: 18341501],   9. al Deeb SM, et al. Intractable hiccup induced by  brainstem lesion. J Neurol Sci 1991;103(2):144-50.  [PMID 1880531: Abstract],   10. de Seze J, et al. Pathologic laughing and intractable  hiccups can occur early in multiple sclerosis.  Neurology. 2006;67(9):1684-6. [PMID: 17101907:  Abstract],   11. Hardo PG. Intractable hiccups — an early feature  of Addison's disease. Postgrad Med J 1989;  65(770):918-9[PMID: 2616432: Free full text],   12. Yardimci N. A diagnostic challenge of Parkinson's  disease: Intractable hiccups. Parkinsonism Relat  Disord. 2008; 14(5):446-7. Epub 2008 Mar 10.  [PMID: 18329942: Abstract],   13. Delevaux I, et al. Intractable hiccup as the initial  presenting feature of systemic lupus erythematosus.  Lupus 2005; 14(5):406-8. [PMID: 15934443: Abstract],   14. Reddy BV, et al. Persistent hiccups: A rare  prodromal manifestation of herpes zoster. Indian J  Dermatol Venereol Leprol 2007; 73:352-3.   Insomnia, commonly understood as insufficient or  unrestorative sleep, is a subgroup of various types  of sleep disorders as defined by DSM-IV-TR system.   The profile of insomnia differs from patient  to patient, and may even change over time  within a given patient. It is therefore important  to carefully categorize the individual's sleep  disorder. Specifically, insomnia is known as,  'Disorder of Initiation and/ Maintenance of Sleep,  i.e. DIMS. As is evident, insomnia consists of two  components: difficulty in initiating sleep (going  off to sleep) and difficulty in maintaining sleep  (remaining asleep).   “■Sleep disorders include 4 general groups: 1 — Primary  Sleep Disorders; 2 — Dyssomnias - (a) - insomnia, i.e.  DIMS; and (b)- Hypersomnia(i.e. disorders of excessive  sleepiness such as narcolepsy, sleep apnea, Kleine-Levin  syndrome, nocturnal myoclonus, e.g. restless legs  syndrome, periodic limb movement disorder); 3 —  Parasomnias (i.e. abnormal behaviors during sleep such  as somnambulism, night-terrors, nightmares, enuresis);  and 4 — Sleep Disorder Related to Another Mental  Disorder (i.e. secondary to medical/psychiatric disorders).    > Short-term insomnia— lasts for few days to three  weeks, e.g. medical illness, protracted stress, and   > Long-term insomnia (chronic insomnia) —  insomnia occurring at least three times per  week for more than four weeks, and that it  causes either marked distress or interference  with social or occupational functioning.   According to DSM-IV-TR criteria, primary  insomnia is sleeplessness that is not attributable  to a medical, psychiatric, or environmental  cause. Additionally:   > The predominant symptom is difficulty  initiating or maintaining sleep, or nonres-  torative sleep, for at least 1 month.   > The sleep disturbance (or associated daytime  fatigue) causes clinically significant distress  or impairment in social, occupational, or  other important areas of functioning.   > The sleep disturbance does not occur  exclusively during the course of narcolepsy,  breathing-related sleep disorder, circadian  rhythm sleep disorder, or a parasomnia.   > The disturbance does not occur exclusively  during the course of another mental disorder  (e.g. major depressive disorder, generalized  anxiety disorder, a delirium).    > The disturbance is not due to the direct  physiological effects of a substance (e.g.  drug abuse, medication) or a general  medical condition. Conversely, secondary  insomnia may arise from several recogni-  zable sources.   Patients with insomnia may present with  nonspecific or unusual symptoms. They range  from fatigue, lack of concentration, headache,  irritability, myalgias, GI upset, problems with  interpersonal relationship, and overall  decreased quality of life.   Most insomnia is transient or short-term in  duration; their diagnosis based mainly on  historical and physical findings. In problematic  or chronic insomnia, review of medical and  psychiatric history, and full polysomnography  in a sleep laboratory may be essential to  determine the source of sleep difficulty.   • Sleep preoccupation ('trying too hard to  sleep', unnecessary concern about inability  to sleep)   • Erythrocytosis may be seen in patients with  obstructive sleep apnea (OSA), or chronic lung  disease.   • Nocturnal oxygen desaturation (NOD) —  Evaluation of NOD may be used as a  screening test in patients with a high  probability of OSA or sleep disordered  breathing. The absence of desaturation (at  the rate of at least 10 to 15 events per hour)  may be used to exclude OSA   • NOD may be an important contributor to IHD,  coronary restenosis in patients treated with  stent placement, and metabolic syndrome.   • Maintained for a period of two weeks to  collect information on bedtime and time of  rising, duration and quantity of sleep, timing  and quantity of meals and exercise, and  ingestion of alcohol, drugs, and caffeine. The  findings are correlated with the patient's  subjective assessments of insomnia, and help  to determine sleep pattern of the patient, its  severity, and causes; and also provides  educative value to learn more about sleep  hygiene   • Other tools that may be used to assess  insomnia include — Epworth Sleepiness  Scale*, Sleep disorders questionnaire®.  Insomnia Severity Inventory, and the  Pittsburgh Sleep Quality Index .   • It involves monitoring and staging sleep, i.e.  by recording brain waves with EEC, eye  movements with electrooculogram (EOG),  and chin movements with EMG; breathing  patterns, e.g. airflow, respiratory effort,  pulse oximetry, heart rate; limb movements,  e.g. of the legs and occasionally arms with  EMG, and body position. Most patients are  also monitored with remote audio and video  recordings to observe for behaviors and  seizures. Polysomnography is used in  special circumstances, e.g. to exclude  primary sleep disorders.   • A new technique that records individual's  activities during sleep and waking; useful in  the diagnosis of primary sleep disorders,  hypersomnia, and parasomnia.   • In special circumstances such as history of  trauma, Alzheimer's disease, PD, MS, seizure  disorder, and mass lesion.   • In elderly patients these procedures may be  necessary to identify comorbid conditions  such as dementia and depression which  often result in insomnia.   • In occult cases of insomnia suspected to be  due to substance abuse.   • History — A comprehensive sleep history  obtained from both the patient and the  patient's bed partner is an important  component in the initial evaluation of  insomnia (Table 28.1)   • History should focus on age, onset and  duration, patient's perception of sleep  problem, coping mechanisms, day-time  naps, occupation, lifestyle, family and work-  related stress, habits, travel, medications,  addiction, and any medical illness. This step  helps to eliminate insomnia due to another  medical, psychiatric, substance abuse or  circadian rhythm disorder   • Nocturnal symptoms 6 — A specific enquiry  should be made from the patient as well as  bed-partner about 'nocturnal' symptoms  giving rise to transient or chronic insomnia.  These include respiratory distress, snoring.   • Do you go to bed at the same time every night?   • How long does it take to fall asleep? (Sleep latency;  related to initiating sleep- due to poor sleep hygiene,  stimulant medications, drugs, etc.)   • What do you do when you wake up at night?  Watching TV? Reading? Take sedatives?   • Duration of sleep— estimated time spent sleeping at  night (related to remaining asleep— due to alcohol,  anxiety, depression, asthma, BPH, etc.)   • Do you experience 'creeping, crawling feeling' in  the legs? (RLS)   • Do you fall asleep while driving, reading, watching  TV, or talking to friends? (narcolepsy)   • Loud snoring, gasping, chocking, or at times stop  breathing? (OSA)   • Temporary inability to talk or move when falling  asleep or awakening? (sleep paralysis, cataplexy)    gasping (OSA); jerking of feet and legs  (periodic limb movement disorder: vide  infra: 11); and dyspepsia, cough, chest  discomfort (GERD, CAD). Symptoms such as    bed-wetting, sleepwalking, night terrors,  night mares, etc. are typical of parasomnias   • Physical findings such as obesity, hyper-  tension, large neck, large tongue, or abnor-  malities in the ear-nose-throat examination  may be associated with OSA. Signs of  psychiatric disorders and medical diseases  related to coronary disease, obstructive  respiratory disease, and neurologic system  should be evaluated 7   • Sleep apnea when suspected needs further  evaluation of the predisposing factors for  obstruction to airways, including enlarged  tonsils and adenoids, micrognathia,  macroglossia, and endocrinopathies such as  hypothyroidism and acromegaly   • Although the need for sleep does not  necessarily decrease with age, the incidence  of sleep dysfunctions increases with age  which are normally related to pathologic  processes that are associated with aging, e.g.  OA, LVF, BPH, and psychiatric disorders   • Although insomnia is commonly viewed as  a symptom of anxiety and depression,  studies indicate that it often predates the  emergence of these disorders, suggesting  that insomnia treatment could possibly  prevent psychiatric morbidity.   • An insomniac should be differentiated from  a short sleeper who needs less than six hours  of sleep per night and has no symptoms or  dysfunction   • Potentially serious problems may be  associated with OSA such as systemic and  pulmonary hypertension, corpulmonale,  tachyarrhythmias, and IHD   • In patients with sleep apnea associated with  CNS disfunction, consider intracranial  lesion (e.g. thalamic tumor), nocturnal  seizures and drug abuse.   Chronic fatigue syndrome (CFS) — It is a clinical  diagnosis characterized by an unexplained,  persistent or relapsing chronic fatigue that is of at  least six months' duration, and characterized by  four or more of the following symptoms present  concurrently for at least six months, namely-  impairment of memory or concentration; diffuse  pain; sore throat; tender lymph nodes; new  headaches; and nonrestorative sleep. Infectious,  immunological, neuroendocrine, sleep, and  psychiatric mechanisms have been proposed as  etiological factors; however, a unifying etiology  for CFS has yet to emerge. Clinical evaluation is  based upon above standardized guidelines,  including an assessment of functional impair-  ments. Since there are no specific diagnostic tests  or biological markers for CFS, the diagnosis is  made by ruling out other causes of fatigue such as  eating disorders, psychotic disorders, bipolar  disorder, melancholic depression, and substance  abuse within 2 years of the onset of fatigue. Trigger  points, which suggest fibromyalgia, are absent in  patients with CFS and fibromyalgia rarely coexist  in the same patient.   Fatal familial insomnia (FFI) 8 — Fatal familial  insomnia is a rare inherited autosomal dominant  disorder characterized by degeneration of the  thalamus and progressive insomnia. It is caused  by a mutation in the prion protein. Patients  present in their 50's with a progressive sleep  disorder. There may be autonomic dysfunction.  Dementia and death usually occur within one year  following presentation. Measuring the cerebral  metabolic rate of glucose (CMRglc) with 2-[18F]  fluoro-2-deoxy-D-glucose PET in parallel with  detailed clinical, neuropsychological examinations  and polysomnography with EEG spectral analyses  may help in presymptomatic diagnosis of FFI.   Obstructive sleep apnea (OS A) — It is charact-  erized by episodes of partial or complete closure    of the upper airway that occur during sleep and  lead to breathing cessation (defined as a period  of apnea > 10 sec) despite persistent respiratory  efforts. Symptoms include restlessness, snoring,  recurrent awakening, morning headache, and  excessive daytime sleepiness. Anatomic risk  factors include obesity, an oropharynx  "crowded" by a short or retracted mandible, a  prominent tongue base or tonsils, a rounded  head shape and a short neck, a neck circum-  ference > 43 cm, thick lateral pharyngeal walls,  or lateral parapharyngeal fat pads. Other  identified risk factors include postmenopausal  status, aging, and alcohol or sedative use. A  family history of sleep apnea is present in 25 to  40% of cases. Many people with OSA have  disorders such as hypertension, stroke,  diabetes, gastroesophageal reflux disease,  nocturnal angina, heart failure, acromegaly,  and hypothyroidism. OSA can also be  associated with cardiac arrhythmias (e.g.  bradycardia, asystole). Diagnosis is based on  sleep history, and polysomnography.   characterized by bilateral repeated, rhythmic,  small-amplitude jerking or twitching movements  in the lower extremities and, less frequently, in  the arms. These movements occur every 20 to 90  seconds, mainly in nonrapid eye movement sleep,  and can lead to arousals, which are usually not  perceived by the patient. Rather, the presenting  complaint is poor sleep and daytime somnolence.   Occasionally, a bed partner may provide the  history of limb movements.   Physical and neurological examinations are  normal. In some cases, excessive somnolence  may be noted. Definitive diagnosis requires  polysomnography.   This condition and restless legs syndrome  are more common in older patients.   Restless Legs Syndrome (RLS)/Ekbom  syndrome — A disorder characterized by: (1) a    desire to move the limbs, often with pares-  thesias or dysesthesias; (2) symptoms exacer-  bated by rest and relieved by activity; (3) motor  restlessness; and (4) nocturnal increase in  severity of symptoms. Most patients, however,  simply relate a vague, nonpainful, indescribable  discomfort in the limbs and use terms, such as  crawling, creeping, jittery, tingling, burning,  itching, aching, etc. The unpleasant limb  sensations are precipitated by rest or inactivity,  especially in bed at night or in the car, airplane,  theater, etc. Motor activity characteristically  relieves the limb discomfort. Most patients  notice worsening of symptoms in the evening,  usually in bed before sleep or in the middle of  the night, followed by improvement early in  the morning. In severe cases, patients experience  symptoms both in the day and night. Although  RLS is idiopathic in most cases, it can be  associated with several conditions, particularly  iron, folate, and B 12 deficiency. The possible  secondary causes of RLS include cigarette  smoking, varicose veins, hypothyroidism or  hyperthyroidism, acute intermittent porphyria;  myelopathy or myelitis, carcinoma, and drug  withdrawal from vasodilators, sedatives,  imipramine, or opiates. This condition may be  associated with uremia, diabetes mellitus, and  rheumatoid arthritis. The diagnosis of RLS rests  largely on clinical history. Polysomnography is  rarely necessary.   Sleep apnea: central— A condition associated  with multiple episodes of sleep apnea which are  distinguished from obstructive sleep apnea (OSA)  by the complete cessation of efforts to breathe.  This disorder is associated with dysfunction of  central nervous system centers that regulate  respiration or cardiac dysfunction. This condition  may be idiopathic (primary) or associated with    lower brainstem lesions, stroke, Parkinson's  disease, COPD, CHF, diabetes mellitus, thyroid  disease, medication effect, and other conditions.  The most common reported symptoms are  insomnia, frequent awakenings, a nonrestorative  sleep, choking, shortness of breath, and excessive  daytime sleepiness or fatigue. Sometimes, bed  partners report witnessed apneas and mild  snoring. The laboratory findings are not helpful.  Primary central sleep apnea is frequently  associated with OSA. When both forms are  present the condition is referred to as mixed sleep  apnea, i.e. sleep apnea syndrome.    1 . Fanfulla F, et at. The relationship of daytime hypo-  xemia and nocturnal hypoxia in obstructive sleep  apnea syndrome. Sleep 2008;31(2):249-55.  [PMID: 18274273: Abstract],   2. Thomas VD, et al. Predictors of nocturnal oxygen  desaturation in chronic obstructive pulmonary  disease in a South Indian population. J Postgrad  Med 2002;48: 101 [Free full text],   3. Carney RM, et al. Insomnia and depression prior  to myocardial infarction. Psychosom Med 1990;  52(6):603-9. [PMID: 2287700: Free full text],   4. Hayashi M. Nocturnal oxygen desaturation as a  predictive risk factor for coronary restenosis after  coronary intervention. Circ J 2005;69(11): 1320-  6. [PMID: 16247205: Free full text],   5. Morgenthaler T, et al. Practice parameters for  the use of actigraphy in the assessment of  sleep and sleep disorders: An update for 2007.  Sleep 2007;30(4):519-29. [PMID: 17520797:  Abstract],   6. Pressman MR, et al. Nocturia. A rarely  recognized symptom of sleep apnea and other  occult sleep disorders. Arch Intern Med 1996;  156(5):545-50. [PMID:8604961: Abstract],   7. Budhiraja R, et al. Sleep-disordered breathing and  cardiovascular health. Curr Opin Pulm Med 2005;  ll(6):501-6. [PMID: 16217175: Abstract],   8. Cortelli P, et al. Presymptomatic diagnosis in  fatal familial insomnia: Serial neurophysiological  and 18FDG-PET studies. Brain 2006;129(Pt  3):668-75. Epub 2006 Jan 6. [PMID: 1639980 7:  Abstract].   Jaundice (icterus) is yellowish discoloration of the  tissues, noticed especially in the skin, sclera , and  mucous membrane, due to excess accumulation of  bilirubin— a reddish pigment of heme metabolism.   Hyperbilirubinemia may be due to excessive  hemoglobin degradation/bilirubin overpro-  duction, defective hepatic uptake/conjugation,  or impaired excretion of bilirubin by the  hepatobiliary system; i.e. interruption of the  breakdown pathway at any of a number of  steps— from hemoglobin breakdown to uptake  by the hepatocellular membrane to excretion into  the biliary system— will result in jaundice, with  an increase in serum bilirubin.   Patient occasionally present with complaints  of 'turning yellow'; usually the symptoms of  jaundice (excluding those in whom it is  secondary to hemolysis) referred by the patient  are nonspecific, such as loss of appetite, nausea,  vomiting, pain abdomen, lack of taste, lethargy.    * The usual term scleral icterus is misleading, since bilirubin  is actually deposited in the vascular conjunctiva rather than  the avascular sclerae. (Talley NJ et al. Clinical examination:  A Systematic Guide to Physical Diagnosis 2006, 5th ed.  P-18).    high colored urine (due to increased glomerular  filtration of conjugated bilirubin), pale stools (as  excretion of bilirubin into the intestine is  decreased), itching skin (presumably from the  deposition of bile salts), etc.   Very often family members notice a yellow  discoloring of the sclera or skin before the patient  notices. This objective or clinical jaundice is usually  evident when the serum (conjugated) bilirubin  reaches 2-4 mg/ dl (40-80 pmol/1). Because elastin  has a high affinity for bilirubin, and scleral tissue  is rich in elastin, jaundice is best detected by  examining the sclerae; a second place to examine  is underneath the tongue, i.e. frenulum of the  tongue. As jaundice deepens, the skin color may  change from a yellow tinge to deep yellow and  eventually, in long standing jaundice (e.g. chronic  extrahepatic biliary obstruction, primary biliary  cirrhosis), to a greenish hue due to oxidation of  bilirubin to biliverdin.   Although jaundice in adults is typically  classified into prehepatic (due to hemolysis),  hepatocellular (due to intrinsic liver disease),  and cholestatic (obstructive — intrahepatic or  posthepatic cholestasis) jaundice (Table 29.1),  multiple mechanisms may be operative  simultaneously; for instance in patients with   # Source: Kamath Patrick S. Clinical Approach to the Patient with Abnormal Liver Test Results. Mayo Clin Proc 1996; 71:1089-95.    acute hepatitis, cirrhosis, prolonged biliary  tract obstruction, familial and immaturity  defects, jaundice may result due to both  intrinsic hepatocellular failure as well as  hemolysis. In general, however, one mech-  anism predominates, so that knowledge of the  predominant form of plasma bilirubin  (conjugated or unconjugated) is of value in  evaluating possible causes of hyperbilir-  ubinemia. 1   • Secondary to systemic infections (malaria;  HIV; leptospirosis; infectious mononucleosis;  cytomegalovirus, i.e. CMV; Ebstein B virus,  i.e. EBV; herpes zoster virus, i.e. HZV; herpes  simplex virus, i.e. HSV; yellow fever)   • Secondary hepatic carcinoma (from breast,  stomach, bowel, lung, pancreas, and  ovary).   • Hemolysis (hemolytic anemia, G6PD defi-  ciency, sickle cell disease, thalassemia, ABO/  Rh incompatibility)    • Drug toxicity (paracetamol, erythromycin,  rifampicin, isoniazid, oral contraceptives,  anabolic steroids, statins, methotrexate,  phenothiazine, halothane)   • PS — atypical lymphocytes may be seen in  infectious mononucleosis.   • Presence of bile pigments, i.e. bilirubinuria  suggests conjugation is taking place.  Bilirubinuria is the earliest abnormality in  hepatitis. It is present even when the serum  bilirubin is normal. Hence, bilirubinuria in a  febrile patient is diagnostic of hepatitis. Late  in the course of the disease, when deltabi-  lirubin is formed, the test becomes negative,  even though the patient continues to be icteric   • Presence of urobilinogen, i.e. urobilinogenuria  eliminates the possibility of complete biliary  tract obstruction, i.e. bile has entered the  intestine, where it undergoes enterohepatic  metabolism. Urobilinogen appears in the urine  in the late preicteric phase of hepatitis, after  bilirubinuria. At the height of jaundice, the  hepatocytes cannot excrete bilirubin into the  bile and hence urobilinogen disappears from  the urine. It's reappearance in the urine  indicates that the patient is recovering   > Hepatocellular jaundice: Urobilinogen  positive (may vary according to phase of  disease), bile pigment positive;   • Total bilirubin and bilirubin fractions allow  determining whether the cause is due to  excess production (i.e. indirect/unconjugate  predominant) or impaired conjugation (i.e.  direct/conjugated predominant)   • If the conjugated fraction is more than 50%  of the total, patient has conjugated hyperbi-  lirubinemia; if the unconjugated fraction is  more than 90%, the patient has unconjugated  hyperbilirubinemia.   • It is a good indicator of hepatic functional reserve,  but because of its long half-life (20-25 days),  changes are slow in reflecting liver damage.   • Since the activity of coagulation factor  prothrombin is dependent on its synthesis by  the liver, its estimation, i.e. PT is helpful in  assessing the extent of damage in acute liver  diseases and their prognosis   • Determination of PT (Quick test) or partial  thromboplastin time (PTT) is generally  sufficient   • PT is prolonged in hepatocellular etiologies  and chronic liver disease   • PTT can be prolonged in vitamin K deficiency  (e.g. in obstructive jaundice). In this case, PTT    + When considered individually, none of the test analytes  in the LFT profile are biologically specific to liver tissues.  However, when considered collectively, certain patterns of  LFT abnormalities are suggestive of particular sub-groups  of hepatobiliary pathologies.    normalizes within 12-24 hours after IV  administration of 5-10 mg vitamin K.  Absence of normalization indicates serious  hepato-cellular damage (e.g. fulminant  hepatitis or liver cirrhosis).   • Aspartate aminotransferase (AST/SGOT)  and alanine aminotransferase (ALT/SGPT)  are the two enzymes which are sensitive  indicators of parenchymal cell integrity   • Although both transaminase enzymes are  widely distributed in the body, ALT is  predominantly confined to the liver, and  therefore, more specific for liver disease. Both  tests are sensitive indicators of hepatocellular  necrosis   • In general AST is more specific for chronic  liver disease and ALT for acute liver disease   • In acute hepatitis, the transaminases are 10  times above normal. In cholestatic jaundice,  they are about 5 times above normal. Very  high levels may be seen in drug-induced  hepatitis, especially paracetamol   • The HCV infection can also produce wide  fluctuations in transaminases enzymes,  ranging from normal to three to four times  the normal range. This yo-yo phenomenon is a  distinguishing characteristic of HCV  infection; therefore, the patient must undergo  serial testing for monitoring three to four  times yearly throughout his or her lifetime   • A sudden fall in the transaminases in a sick  jaundiced patient is indicative of a bad  prognosis, as it is seen in acute fulminant  hepatitis.   • Useful in detecting early intra- or extrahepatic  obstruction; high values (5 times normal) favor  obstruction, and a normal SAP virtually  excludes this diagnosis.   > Anti-hepatitis C virus antibodies — (Anti-  HCV; may need PCR for HCV-RNA).   • If HBsAg is present, testing for coexisting  HDV by anti-HDV is appropriate*   • For the diagnosis of presumed chronic viral  hepatitis, HBsAg and Anti-HCV serology,  using an approved enzyme immunoassay  (third generation, i.e. EIA-3), is the initial  step. Again, testing for HDV is appropriate  if HBsAg is present   • Acute HEV infection can be diagnosed by the  presence of IgM anti-HEV and, later in the  course, finding of IgG anti-HEV   • The interpretations of viral markers for acute  hepatitis A, B, and C, and chronic hepatitis  are summarized in Tables 29.2 to 29.4.   • This is the most important noninvasive  investigation in the evaluation of obstructive  (cholestatic) jaundice, e.g. gallstones and  choledochal cysts, by detecting dilated bile  ducts. False-negatives are generally due to  inability to visualize the biliary tree, often due  to interposed bowel gas   • It also detects focal liver and pancreas  diseases like tumors, abscesses and cysts,  (more than 2cm in diameter). It can identify  generalized parenchymal disorders like  cirrhosis and fatty change. It is also of great  help in diagnosing small quantities of ascites.    ^Hepatitis D can only exist in the presence of hepatitis B,  because it requires hepatitis B enzymes to replicate.   HAV: Hepatitis A virus, the infectious agent that causes HAV infection and hepatitis A.   Anti-HAV: Total antibody to hepatitis A virus (HAV) detected in serum of persons with acute or resolved HAV infection;  indicates a protective immune response to infection, vaccination, and passively acquired antibody.   IgM anti-HAV: Immunoglobulin M antibody to HAV; positive test indicates acute HAV infection.   HBV: Hepatitis B virus, the infectious agent that causes HBV infection, hepatitis B, and chronic liver disease.   HBsAg: Hepatitis B surface antigen; initial screening test; positive test indicates an active HBV infection; its presence  for more than six months in serum defines chronic infection.   IgM anti-HBc: Immunoglobulin M antibody to hepatitis B core antigen; positive test indicates acute HBV infection.   Anti-HBc: Antibody to hepatitis B core antigen; fractional into IgM and IgG components, i.e. IgM-anti-HBc and IgG-  anti-HBc. IgM usually indicates acute infection (in the previous six months); IgG indicates more distant infection  that may have been cleared by the immune system, or may persist, in which case +ve HBsAg, and +ve anti-HBc  IgG confirm persistent chronic HBV infection.   HBeAg : Hepatitis Be antigen; positive test correlates with HBV replication and high infectivity; often called "marker  of infectivity".   Anti-HBs: Hepatitis B surface antibody; positive test indicates immunity from hepatitis B vaccination (if antibody  concentration >10 milli IU/ml).   HBV/DNA: Deoxyribonucleic acid from HBV; positive test indicates active replication; useful in monitoring response  to treatment of HBV infection (by PCR-based assay).   Precore mutant: Term used for patients who are hepatitis B positive (more than 105 copies/ml) and hepatitis Be antigen  negative.   YMDD mutant: Term used for patients on lamivudine therapy who become hepatitis B DNA negative initially and  DNA positive subsequently.   HCV: Hepatitis C virus, the infectious agent that causes HCV infection, hepatitis C, and chronic liver disease.   Anti-HCV: Antibody to HCV; positive test indicates past or current infection with HCV.   HDV: Hepatitis D virus, a viroid (incomplete virus) that requires an active (acute or chronic) HBV infection to  replicate and cause delta hepatitis virus infection, delta hepatitis, and chronic liver disease.   HBsAg (-ve), Anti-HBc-IgM + IgG (-ve), IgM  anti-HAV (-ve), Anti-HCV (-ve)   Role out CMV, EBV, HZV, HSV; drug/  alcohol toxicity; sepsis; and incubating viral  hepatitis (i.e. before appearance of antigens)   *If positive, order test for IgM anti-HBc. (i.e. hepatitis B core IgM antibody; positive result indicate acute HBV infection)    • Duplex sonography is particularly helpful in  the diagnosis of portal hypertension, portal  vain thrombosis, and other venoocclusive  diseases, e.g. Budd-Chiari syndrome.   • Elevated in chronic liver disease and  extrahepatic obstruction, e.g. pancreatic or  common bile duct obstruction by stone or  carcinoma.   • CT scan is preferred where technical limitations  make ultrasound difficult to interpret. It detects  smaller focal lesions in the liver, especially  when combined with contrast injections, and  is useful for differentiating liver lesions  (abscess, hepatoma, metastases, hemangioma,  and adenoma).   • This procedure is used in patients with a high  likelihood of extrahepatic obstruction; it  allows therapeutic interventions such as  stone extraction, and stent placement.   • MRCP is indicated for patients with history of  contrast allergy, and patients with altered  anatomy, i.e. secondary to surgical procedures  or congenital abnormalities; but it does not  allow therapeutic interventions as in ERCP.   • An upper GI series may assist in finding a  primary neoplasm in the GI tract.   • Present in 85% of patients with primary  biliary cirrhosis. Although not specific for  this disease, absence of this antibody is strong  evidence against the diagnosis of primary  biliary cirrhosis.   • Autoimmune hepatitis is characterized by  positive test results for ANA, antismooth  muscle antibodies (ASMA), antibodies to  liver/kidney microsomes (LKM), liver cell  membrane antibodies (LMA), etc.   • Reduced in Wilson's disease; most patients  have a low ceruloplasmin level and low  serum copper, and high urinary copper  concentrations .   • Elevated in hemochromatosis due to  secondary causes that are associated with  jaundice such as chronic hemolytic anemias,  alcoholic liver disease, cirrhosis of liver, and  hepatocellular carcinoma.   • ELISA to detect IgM for leptospirosis may be  positive in 4-6 days; or PCR— most specific  and sensitive for diagnosis in early stages.   • May be done in patients with unconjugated  hyperbilirubinemia or hemolytic anemia.   • Laparoscopy or US-guided liver biopsy is  important to diagnose, grade, and stage a mass  in the liver, autoimmune hepatitis, hepatic  cirrhosis/fibrosis, HCV infection, hemochro-  matosis, congenital disorders, e.g. Wilson's  disease, and to evaluate abnormal or  inconclusive biochemical or serological tests.   • Look for the presence of scleral icterus as this  is a vital clue in distinguishing jaundice  from other conditions which impart yellow/  brown color to the skin (which is not  bilirubin), but the sclerae are spared, e.g.  carotenemia §, lycopenemia , hypothyroidism,  pernicious anemia, nephrotic syndrome,  xanthomata, hemochromatosis, Addison's  disease, paraneoplastic syndromes, and  drugs such as rifamycin, amiodarone, and  mepacrine   • History should always seek to evaluate risk  factors for hepatitis A, B, and C such as:   > Viral exposures (hepatitis B and C) —  illegal IV drug users, unsafe injection  practice, users of intranasal cocaine,  accidental needle-stick injury from a  person with hepatitis B/C, sexual  promiscuity, blood transfusion/receiving  clotting factors / transplant (especially  before 1992), dental extraction, kidney  dialysis, acupuncture, tattooing, body  piercing, health care workers in high-risk  areas (e.g. dialysis units), and birth to an  HBV/HCV-infected mother.   • Drug history— Especially antitubercular,  anti- leprosy, and antipsychotic drugs may  give a clue about the cause of jaundice   • Family history helps in the diagnosis of classic  genetic diseases such as Gilbert's disease  (vide infra -I-4-) or Wilson's disease,  hemochromatosis, and alphaj-antitrypsin  deficiency. When liver functions show only an   ^Jaundice is not to be confused with carotenemia in which  skin turns yellow/orange from carotene deposits but the  sclerae remain normal in appearance.   **Lycopenemia is orange-yellow skin discoloration due to the  ingestion of large amounts of tomatoes.    elevated (>80%) indirect bilirubin level,  Gilbert's disease or hemolytic anemia is  suggested; whereas direct hyperbi-  lirubinemia (>50%) suggests Dubin-Johnson  syndrome. A normal urine urobilinogen will  make Gilbert's disease even more likely.  Autoimmune hepatitis has a strong genetic  predisposition. Besides a variety of  autoimmune disorders can be associated with  autoimmune hepatitis, e.g. RA, thyroiditis.  Graves' disease, ulcerative colitis, vitiligo, etc   • Is the jaundice acute or chronic? Acute onset  of jaundice suggests HAV infection,  cholangitis, acute biliary tract obstruction, or  acute liver failure. Gradual onset of jaundice  points to alcoholic liver disease, chronic liver  disease (e.g. HBV/HCV infection, chronic  active/persistent hepatitis, autoimmune  hepatitis), liver failure, or malignancy. A  lifelong history of jaundice suggests an  inherited metabolic or hemolytic cause   • A patient with classical Charcot's triad of upper  abdominal pain, fever with chills, and jaundice  should be regarded as having ascending  cholangitis until proved otherwise   • A patient with anemia and jaundice with no  noticeable change in the appearance of the  urine and stools is suggestive of hemolytic  jaundice   • Is the gallbladder enlarged? The finding of  an enlarged gallbladder with jaundice  suggests obstructive jaundice due to  neoplasm, such as carcinoma of the pancreas,  carcinoma of the bile ducts, or ampulla of  Vater ( Courvoisier's laiv) n .    + Courvoisier's law states that, in the presence of jaundice,  an enlarged gallbladder is unlikely to be due to gallstones;  rather carcinoma of the pancreas or the lower biliary tree is  more likely. This may be explained by the observation that  the gallbladder with stones is usually chronically fibrosed  and so, incapable of enlargement. The converse of  Courvoisier's law is not true; the cause of jaundice in a  patient with a non-palpable gallbladder is not necessarily  gallstones as 50% of dilated gallbladders are impalpable.    • Identify stigmata of chronic liver disease such  as spider angiomata, palmar erythema,  gynecomastia, and testicular atrophy   • Identify signs of portal hypertension such as  dilated collateral abdominal veins, spleno-  megaly, and ascites; and coagulopathy, e.g.  bruising, bleeding, and petechiae   • Presence of a greenish-brown corneal deposit  of copper ( Kayser-Fleischer ring), which is  often discernible only with a slit lamp is  suggestive of Wilson's disease   • Imaging studies play a limited role, except  in suspected cases of malignancy or biliary  obstruction   • Because clinical signs are of little or no help  for identifying various causes of viral  hepatitis, accurate diagnosis can only be  achieved with serologic and molecular testing  (Table 29.5). Knowledge of the strengths and  limitations of these tests allows rational use  and interpretation of results. 3   • HCV infection (vide infra 4 - 4 -) must be ruled  out in an otherwise asymptomatic patient  with persistently elevated ALT   • All drugs, including herbal remedies and  illegal drugs, should be suspected as  potential hepatotoxins. Iatrogenic (drug)  jaundice is more dangerous than viral  hepatitis. This is because, if the diagnosis of  drug induced hepatitis is missed and the  drug is continued, the patient can die   • All patients with HIV infection should be  screened for viral hepatitis markers as  coinfection of HCV, HB V, and HIV is common  due to shared modes of transmission. These  coinfections accelerate the course of chronic  liver disease and facilitate progression to  cirrhosis and hepatocellular carcinoma 4 ' 5   • In a jaundiced patient, signs of liver failure,  such as encephalopathy, coagulopathy, GI    bleed, ascites, and renal failure indicate  severe fulminant acute hepatitis  • Beware of asymptomatic jaundice, especially  in an elderly, as neoplasm — primary or  metastatic— is a common etiology.   Gilbert disease — It is a chronic, benign,  intermittent, and familial (autosomal recessive)  condition, occurs predominately in men,  characterized by intermittent jaundice in the  absence of hemolysis or underlying liver disease.  Also known as unconjugated benign bilirubinemia  and familial nonhemolytic jaundice, the  unconjugated hyperbilirubinemia in Gilbert  syndrome has been recognized as due to  underactivity of the conjugating enzyme system  bilirubin - uridine diphosphate glucuronyl  transferase (UGT-1)— the enzyme that conjugates  bilirubin with glucuronic acid. The  hyperbilirubinemia is mild and, by definition,  less than 6 mg/dl. However, most patients exhibit  levels of less than 3 mg/dl. Patients may report  vague abdominal discomfort and general fatigue  for which no cause is found. Gilbert syndrome  is usually diagnosed around puberty, possibly  because of the inhibition of bilirubin glucur-  onidation by endogenous steroid hormones. In  older persons, the diagnosis is usually made  when unconjugated hyperbilirubinemia is noted  on routine blood test results or unmasked by an  intercurrent illness or stress. LFTs: with the  exception of unconjugated hyperbilirubinemia,  standard liver function test results are normal.  A diagnosis of Gilbert syndrome can be made in  the presence of (1) unconjugated hyperbilirubi-  nemia noted on several occasions; (2) normal  results from CBC count, reticulocyte count, and  blood smear; (3) normal liver function test  results; and (4) an absence of other disease  processes or causes of unconjugated hyper-  bilirubinemia. A simple and easily available    Ab = Antibody; Ag = Antigen; EIA = Enzyme immunoassay; RIBA = Recombinant immunoblot assay.    bedside oral ‘rifampin test ’ ++ is found to be useful  to primarily distinguish Gilbert's disease from  other causes of unconjugated hyperbilirubinemic  disorders. 6 Besides the usual laboratory methods,  genetic analyses of the UDP glucuronyl  transferase gene can help in the diagnosis. The  major importance of establishing this diagnosis  is to reassure patients that the disorder is benign  and inconsequential, that the prognosis is  excellent, and that further investigations are not  essential.   Hepatitis C viral infection— HCV infection is  not usually diagnosed in the acute phase because  most patients are initially asymptomatic, and  therefore, have not sought medical attention.    ++ Rifampin increases total serum bilirubin levels in patients  with and without Gilbert's syndrome. On fasting for 12 to  24 h, an absolute increase of bilirubin to >1.9 mg/dl 2 to 6 h  after the administration of 900 mg of rifampin distinguishes  patients with Gilbert's syndrome from those without it. In  the nonfasting state, an increase in total serum bilirubin to  >1.5 mg/dl 4 to 6 h after the administration of rifampin  distinguishes persons with Gilbert's syndrome from those  without it.    (HCV infection has been called a silent  epidemic). 7 Besides, because of the long lag time  between initial infection and clinically evident  liver disease (20-25 years), early diagnosis of  HCV infection can be missed or delayed  considerably. Production of antibodies against  HCV can be delayed by up to 12 weeks, and  about a third of infected individuals might not  have detectable antibody at the onset of  symptoms. 8 Further, if symptoms do occur, the  most common complaints such as fatigue,  abdominal pain, poor appetite, weight loss, and  pruritus are nonspecific; most HCV-infected  patients have no hepatic symptoms. However,  almost 40% of patients infected with HCV  develop at least one extrahepatic manifestation 9  during the course of the disease such as mixed  cryoglobulinemia, which is marked by skin  involvement, marked by rashes, purpura,  petechiae, urticaria, or necrotic ulcerations in  the lower extremities (i.e. leukocytoclastic  vasculitis); rheumatological manifestations  such as joint and muscle aches, fibromyalgia;  kidney disease such as membranoproliferative    glomerulonephritis, nephrotic syndrome;  peripheral neuropathy; sicca syndrome (i.e.  pseudo-Sjogren syndrome); and lichen planus.  Higher rates of non-Hodgkin's lymphoma,  thyroiditis, hypothyroidism, and diabetes  mellitus have also been observed in patients with  HCV infection. These syndromes are important  to recognise, as these extra-hepatic syndromes  may be the presenting features for which they  seek medical attention. Frequently, extrahepatic  manifestations are more serious than the hepatic  disease itself and present even in patients with  persistently normal ALT levels. A distinct and  major characteristic of hepatitis C is its tendency  to cause chronic liver disease (i.e. cirrhosis, liver  failure, and liver cancer) in the majority, in which  the liver injury persists for a prolonged period  if not for life. Thus, testing for HCV RNA by PCR  or transcription-mediated amplification (TMA)  is the only reliable test for the diagnosis of acute  infection.   Although, the annual incidence of acute HCV  has fallen in recent years, primarily because of  effective blood screening efforts and increased  education on the dangers of needle sharing,  hepatitis C infection is still relatively frequent  in certain populations. With more than 170  million chronic hepatitis C patients worldwide  and an increase in the related morbidity and  mortality projected for the next decade, an  improvement in our ability to diagnose and treat  patients with acute hepatitis C would have a  significant impact on the prevalence of chronic  hepatitis and its associated complications  particularly in countries with a high endemic    background of the infection. 1 2 3 4 5 6 7 8 9 10 It is, therefore,  mandatory for the physician to become more  aware of the optimal methods for screening,  diagnosing, and treating this potentially  devastating condition. 11    1. Crawford James M. The liver and the biliary tract.  In:Kumar, Cotran, Robbins, Eds. Basic Pathology,  6th edn. HARCOURT ASIA PTE. Ltd.   2. Riyaz A. Approach To jaundice (CME). Indian J  Dermatol Venereol Leprol 1997;63:288-95.   3. Saab S, Martin P. Tests for acute and chronic viral  hepatitis: Finding your way through the alphabet  soup of infection and superinfection. Postgrad Med  2000;107(2):123-30.   4. Rockstroh JK, et al. European AIDS Clinical  Society (EACS) guidelines for the clinical  management and treatment of chronic hepatitis B  and C coinfection in HIV-infected adults. HIV Med.  2008;9(2):82-8.[PMID: 18257771 Abstract],   5. Shrinivasan S, et al. Coinfection of hepatitis B and  hepatitis C virus in HIV-infected patients in South  India.World J Gastroenterol 2007;13(37): 5015-20.  [PMID: 17854146 Free full text],   6. Mousavi S, et al. Role of overnight rifampin test in  diagnosing Gilberts syndrome. Indian J Gastro-  enterol 2005;24:108-10.   7. Fabris P, et al. Acute hepatitis C: clinical aspects,  diagnosis, and outcome of acute HCV infection.  Curr Pharm Des. 2008;14(17):1661-5. [PMID:  18673189 Abstract],   9. Cumber SC, et al. Hepatitis C: A multifaceted  disease. Review of extrahepatic manifestations.  Ann Intern Med 1995;123(8):615-20. [PMID:  7677303 Free full text],   10. Kamal SM. Acute hepatitis C: A systematic review.  Am J Gastroenterol 2008;103(5):1283-97. [PMID:  18477352 Abstract],   11 . Szabo E, et al. Viral hepatitis: New data on hepatitis  C infection. Pathol Oncol Res. 2003;9(4):215-21.  Epub 2003 Dec 22. [PMID: 14688826 Abstract],   Myalgia may be described as a poorly localized  aching in a muscle or group of muscles, usually  characterized as a deep aching sensation, but  sometimes as a burning or electric sensation. In  addition to the origin of myalgic pain in muscle  tissue per se fi.e. myopathies), diseases of  subcutaneous tissue, facia, tendon, bones, joints,  and peripheral nerves may also produce pain  that is referred to muscle.   "■Myalgia should not be confused with muscle 'weakness',  i.e. reduction in muscle power; muscle 'fatigability', i.e.  inability to sustain the performance of an activity; or  'cramps', i.e. episodic involuntary contraction of muscles.    Diagnosis begins with patient's history,  distinguishing muscle pain from muscle  weakness, i.e. reduction in muscle power; muscle  fatigability, i.e. inability to sustain the  performance of an activity; or cramps, i.e.  episodic involuntary contraction of muscles. The  pattern and severity of muscular pain, associated  symptoms, medication use, and family history  are helpful to determine whether the cause of  myalgia is a normal reaction to physical exertion  or pathological infectious, inflammatory,  rheumatologic, endocrine, metabolic, electrolyte-  induced, drug-induced, neurogenic, or genetic  disorders.   Advances in techniques such as application  of molecular genetics, electrophy-siology, and  muscle biopsy have made a definitive diagnosis  possible for many myopathies. However, a  phenotypic approach to diagnosis according to  the patient's predominant pattern of weakness  is essential, which will be useful in selecting the  most appropriate diagnostic studies to establish  a precise diagnosis, and inform the patient about  the nature and evolution of the disease, the  therapeutic options, and to propose, when  indicated, genetic counseling. 1,2   • Delayed onset muscle soreness (DOMS: vide  infra 44 -) 3   • Postinfectious (viral: Dengue, Chikungunya,  HIV; bacterial: Influenza; nematode:  Trichinosis: vide infra 44 )   • Localized muscle pain (trauma; mass, e.g.  hematoma, neoplasm; fibrositis; tendinitis)   • Drug-induced/toxic myopathies 4 (stains:  rhabdomyolysis: vide infra 44 , steroids,  alcohol, diuretics, cimetidine, antiretroviral  therapy)   • Ischemic myalgia (DVT, intermittent  claudication due to occlusive arterial disease).   • Infectious myositis (poliomyelitis, rabies,  tetanus, Guillain-Barre syndrome, pyomyo-  sitis, gas gangrene. Toxoplasma myositis,  Cysticercosis, Lyme myositis)   • Eosinophil counts of 10,000-30,000 cells/pl  are not unusual in a rare case of EMS.   • More than 50 mm/hr. with no other  abnormality suggests PMR, though a normal  ESR does not rule out this diagnosis.   • The CK level may be highly elevated (10 -  100 times normal) in the inflammatory myop-  athies, and can be moderately to highly  elevated in the muscular dystrophies. Other  conditions that can be associated with  elevated CK levels include infections,  alcoholism, and adverse reactions to  medications. Metabolic (storage) myopathies  tend to be associated with only mild to  moderate elevations in CK levels. The CK  level usually is normal in the electrolyte and  endocrine myopathies (notable exceptions  are thyroid and potassium disorder  myopathies).    • However, the absence of an elevated serum  CK level does not exclude myopathy. In  addition, elevation of the serum CK does not  necessarily imply that the muscle is the  primary site of abnormality. 3 ' 6   • The serum CK level is the most sensitive for  muscle disease, and it is rarely necessary to  measure other enzymes that are released  from injured skeletal muscles such as AST,  ALT, or LDH, all of which are also elevated  in hepatic disease.   • May be abnormal before other abnormalities  of this disease are manifest.   • Hypercalcemia may be associated with hyper-  parathyroidism, or metastatic carcinoma.   • Usually elevated in osteomalacia, hyperpara-  thyroidism, metastatic carcinoma, Paget's  disease.   • High TSH values may be the only abnormality  of hypothyroidism; low TSH values with  corresponding high T3 and T4 values confirm  thyrotoxicosis.   • Likely to be positive in connective tissue  disorders; if RF/ANA assay is positive,  additional studies such as double-stranded  DNA, or antiphospholipid antibodies (lupus)  may be obtained.   • Although changes seen on EMG are not  pathognomonic for any specific disease  process, an abnormal EMG is useful to  evaluate the extent and pattern of myopathic  process, and to evaluate for a neuropathy or  a disease of the neuromuscular junction.   • Muscle imaging, in particular MR, provides  diagnostic and follow-up information,  especially in dystrophic, metabolic, and  inflammatory myopathies   • Useful to identify areas of abnormal muscle  that are amenable to biopsy.   • Where indicated, additional tests such as 24-  hour urine cortisol testing to rule out  Cushing's disease; oral glucose load/growth  hormone assay to rule out acromegaly; and  vitamin D assay to rule out osteomalacia may  be obtained.   • If the diagnosis is still inconclusive after the  history, physical examination, and laboratory,  radiologic, and electromyographic evalua-  tions, a muscle biopsy is required for patients  who have a suspected myopathy. The  pathologic analysis of biopsy specimens  focuses on the histologic, histochemical,  electron microscopic, genetic, and biochemical  changes that are found in the affected muscle.  Molecular analysis of candidate genes is  becoming a major diagnostic tool in many  muscle disorders.   • It is vital to distinguish myalgia from articular  symptoms; if the lesion is in the muscle, the  pain is greater during active than passive  movement of the affected muscle; if in the  ligament or joint, the pain is about equal   • It is also important to differentiate myalgia  and myopathies due to disease of nervous  system. The presence of muscle wasting®,  fasciculation, sensory and motor changes, as  well as associated neurologic evidence favors  neurogenic cause such as due to UMN, LMN,  neuromuscular, motor neuron, or peripheral  nerve disorder   > The age of the patient (myopathies since  birth and childhood, as against adult  onset— usually acquired myopathies).   > Recent events surrounding the occurrence  of myalgia (e.g. postexercise, new  vocational activities, new drug intake).   > Occupation, hobbies (gardening), sports  (DOMS), and recreational activities  (tennis/golf elbow).   • The muscle power should be tested at the  bedside by examining all muscle groups  bilaterally, which is usually graded as below:    ^Muscle wasting which occurs secondary to neurological  disease is usually referred to as amyotrophy.   • Characteristic facies and bone structure of  acromegaly suggest myopathy associated  with this disease. Lethargy, dry skin and hair,  nonpitting edema, a husky voice suggest  hypothyroidism   • A rapid onset of myalgia in an elderly female  involving the muscles of the neck, shoulder,  buttocks and thighs is diagnostic of PMR. The  muscles below the elbows and knees are not  affected in this condition   • Temporal artery thickening or tenderness  and bruits over carotid may be found in few  cases of PMR   • A gradual onset of generalized myalgia with  multiple tender spots on both sides of the  body, above and below the waist is typical of  fibromyalgia. The diagnosis of fibromyalgia  is clinical. There is no laboratory or imaging  tests to confirm this diagnosis   • Myalgia with significant and progressive leg  weakness causing difficulty in climbing  stairs, squatting, getting into or out of a car,  rising from a chair, raising hands above the  head, holding head up, combing hair, and  lifting objects strongly favor the diagnosis of  inflammatory muscle diseases such as PM  and DM. In contrast to myasthenia gravis, PM  and DM do not cause facial or ocular muscle  weakness   • In DM, cutaneous manifestations can  precede, follow, or develop together with  muscle weakness. Cutaneous findings  include rash on the neck (V sign), shoulders,  and upper back (shawl sign), a purplish  (heliotrope) effusion on the upper eyelids,  and scaly patches over the dorsum of  proximal and distal interphalangeal joints  (knuckles), called Gottron's sign    • Presence of associated symptoms or signs,  indicating involvement of organs or tissues  other than muscle, such as dyspnea, orthopnea,  respiratory failure, congestive heart failure,  arrhythmias, cataracts, mental retardation, and  hepatomegaly is valuable in the clinical  diagnosis of hereditary myopathies (e.g.  myotonic dystrophy, Duchenne's or Becker's  muscular dystrophies)   • Normal findings on a battery of investi-  gation do not rule out organic disease, but  strongly suggest psychogenic disorders.   • As there is a close relation of PMR with giant  cell arteritis (GCA), once the diagnosis of PMR  is entertained, it is prudent to question and  examine these patients for symptoms and  signs of GCA, such as headache, especially  in temporal region, scalp tenderness, jaw  pain, visual disturbance, tender temporal  arteries, and signs of ischemic retinopathy  on funduscopic examination. If GCA is  suspected, steroid therapy is indicated   • Since there is an increased risk of malignancy  in patients with DM and PM, they should be  offered age and risk specific cancer screening  tests, such as chest/abdomen/pelvis CT, GI  tract imaging and mammography. Malig-  nancies may be evident at the time of  presentation, but may not be detected until  months afterward in some cases.   a sensation of discomfort or soreness that occurs  1 to 2 days after exercise, commonly due to  microinjury to the muscle or eccentric activity.  It is most evident at the muscle/tendon junction  initially, and then spreading throughout the  muscle. Symptoms can range from muscle  tenderness to severe debilitating pain, usually    involving the quadriceps muscle group, but may  also affect the hamstring, and triceps surae  groups. Up to six hypothesized theories have  been proposed for the mechanism of DOMS,  namely: lactic acid, muscle spasm, connective  tissue damage, muscle damage, inflammation  and the enzyme efflux theories. The mechanisms,  treatment strategies, and impact on athletic  performance remain uncertain, despite the high  incidence of DOMS. Clinically, DOMS is a self-  limiting condition that usually requires no  treatment.   Eosinophilia-myalgia syndrome — The term  EMS was coined in 1989 after a cluster of cases  with symptoms of incapacitating myalgias and  eosinophilia were reported, most commonly in  people aged 35-60 years. This syndrome has been  only defined as varying degrees of myalgias and  peripheral eosinophilia. In November 1989, for  the purpose of nationwide surveillance, the US  Centers for Disease Control and Prevention  (CDC) defined this syndrome according to 3  criteria:(l) a blood eosinophil count greater than  1000 cells/ pi, (2) incapacitating myalgia, and (3)  no evidence of infection (e.g. trichinosis) or  neoplastic conditions that would account for  these findings. Studies confirmed a strong associ-  ation between the use of a specific brand of L-  tryptophan and development of EMS; the best-  characterized of these is 1,1-ethylidenebis (L-  tryptophan) (EBT), a tryptophan dimer. However,  contaminated L- tryptophan may not be the only  cause of EMS. Symptoms other than myalgia  include arthralgia, peripheral edema, alopecia,  scleroderma-like skin changes, and various GI,  pulmonary, and neurological manifestations.  Eosinophil counts of 10,000-30,000 cells/pl are  not unusual, and the bone marrow shows hyper-  plasia of eosinophil precursor cells. With the recall  of L-tryptophan from the market in November  1989, only a few new cases have been reported.   disorder characterized by acute damage of the  sarcolemma of the skeletal muscle, leading to  release of potentially toxic muscle cell components  into the circulation, most notably CK and  myoglobin, and is frequently accompanied by  myoglobinuria. Therefore, the term myoglobinuria  is often used interchangeably with the term  rhabdomyolysis. Myoglobinuria refers to an  abnormal pathologic state in which an excessive  amount of myoglobin is found in the urine,  imparting a cola-like hue, usually in association  with myonecrosis, and a clinical picture of  weakness, myalgias, and edema. The condition  is etiologically heterogeneous and may result  from a large variety of diseases affecting muscle  membranes, membrane ion channels, and muscle  energy supply, including acquired causes (e.g.  exertion, crush injury and trauma, alcoholism,  drugs, and toxins), and hereditary causes (e.g.  disorders of carbohydrate metabolism, disorders  of lipid metabolism, or diseases of the muscle  associated with malignant hyperthermia).   In many patients with idiopathic recurrent  rhabdomyolysis, specific inherited metabolic  defects have not been recognized up to now. Acute  renal failure is the most serious complication,  which can be prevented by prompt, aggressive  treatment. In patients surviving acute attacks,  recovery of muscle and renal function is usually  complete.   Trichinosis— It is the result of infection by the  nematode Trichinella spiralis. Humans are  infected incidentally when they eat inadequately  cooked meat that contains larvae of Trichinella  species. Most infestations do not cause  symptoms, although heavy exposure can cause  various clinical manifestations, including  diarrhea, fever, myalgias, and prostration.  Factors that may affect morbidity include the    quantity of larvae ingested, the species of  Trichinella (most notably T spiralis), and the  immune status of the host. After two weeks,  majority of the patients have fever that peaks  around the fourth week. Weakness and/or  myositis follow; the muscles become stiff, hard,  and edematous. Muscles with increased blood  flow, e.g. extraocular muscles, masseters, larynx,  tongue, neck muscles, diaphragm, intercostals,  limb flexors, and lumbar muscles are most  frequently involved. Involvement of the  diaphragm may result in dyspnea. Other  symptoms include: periorbital edema and rash  (macular or petechial). CK levels are elevated to  >15,000 U/l. Serology results are not positive  until 2-3 weeks after infection. They peak around  the third month and may persist for years. In  patients with CNS involvement, CT scanning  and MRI with contrast enhancement may reveal  3- to 8-mm nodular or ring-like lesions. Muscle  biopsy provides a definitive diagnosis; however,  it is rarely recommended except in difficult cases  when serology tests are unhelpful.    1. Jackson CE. A clinical approach to muscle diseases.  Semin Neurol 2008;28(2):228-40. [PMID: 18351524:  Abstract],   2. Kohler A, et al. How should a muscular disease be  studied? Rev med Suisse Romande 2003;123(1):45-  9. [PMID: 15095727: Abstract],   3. MacIntyre DL, et al. Delayed muscle soreness. The  inflammatory response to muscle injury and its  clinical implications. Sports Med 1995;20(1):24-  40.[PMId:7481277: Abstract],   4. Finsterer J. Medically induced myopathia.  Nervenartz 2006;77(6):682-6, 688-93. [PMID:  16575599: Abstract],   5. Draeger A, et al. Statin therapy induces  ultrastructural damage in skeletal muscle in  patients without myalgia.J Pathol 2006;210(1):94-  102. [PMID: 16799920: Abstract],   6. Dabby R, et al. Asymptomatic or minimally  symptomatic hyperklemia: Histopathologic  correlates. Isr Med Assoc J. 2006;8(2):110-3. [PMID:  16544734: Abstract],   Nausea is an unpleasant sensation and an  impending desire before vomiting, usually  accompanied by autonomic signs such as pallor,  hypersalivation, diaphoresis, tachycardia, and  tachypnea.   Vomiting is a physical event that results in the  speedy, forceful evacuation of gastric contents  through the mouth which may or may not be  preceded by nausea. Vomiting may be a  protective physiologic mechanism that prevents  entry of potentially harmful substances into the  GI tract. However, persistent vomiting can lead  to complications such as dehydration, metabolic  alkalosis, hyponatremia, hypokalemia, esophagitis,  gastritis, aspiration pneumonitis, and rarely  Mallory- Weiss syndrome, or Boerhaave syndrome  ( vide infra 11) — irrespective of the cause of  vomiting.   “■According to one Midwestern survey, nausea was not  understood by two-thirds of medical, surgical, and  gynecologic patients queried. The expression sick at stomach,  on the other hand, was the most common patient descriptor  of nausea, and the expression throw up was consistently  interpreted as vomiting.- Ref. RhodesVA et al. Nausea,  Vomiting, and Retching: Complex Problems in Palliative  Care.CA Cancer J Clin 2001 51: 32-248. [PMID: 11577489:  Free full text].    It is important to differentiate vomiting from  other physical phenomenon such as regurgi-  tation, rumination, and retching.   Regurgitation is a passive phenomenon  indicating an effortless reflux of gastric contents  into the mouth, which may be due to mechanical  obstruction of the esophagus, GERD, or  esophageal motility disorders.   Rumination is also a passive phenomenon,  during which recently ingested food is regurgitated  effortlessly into the mouth, whereupon it is re-  chewed and swallowed or spat out.   Retching (spasmodic respiratory and  abdominal movements) is a strong involuntary  effort to vomit, but occurs against a closed glottis,  without bringing up emesis.   Although nausea and vomiting are common  complaints + , they are usually self-limiting and  benign in nature. However, they may occasio-  nally herald serious etiologies. Hence careful  assessment is required; together with a  willingness to review and admit the patient if  the diagnosis remains unclear.   + Though nausea and vomiting may occur independently,  they are so closely related - produced by the same stimuli  and can be viewed as a progressive response to increased  stimulus - that they are considered together.    The American Gastroenterological Associa-  tion suggests a 3-step approach to the initial  evaluation of nausea and vomiting: 1   • Recognize and correct any consequences of  the symptoms, such as dehydration or  electrolyte abnormalities   • Try to identify the underlying cause and  provide specific therapy   • Gastritis ( H . pylori infection; aspirin; NSAID;  other drugs, e.g. oral steroids; excess alcohol;  stress; viral infections)   CNS disorders (migraine; CVD: infarction,  hemorrhage; Infection: meningitis- viral, bacterial,  TB; raised ICP: abscess, hematoma, and tumor)    • Obstruction (achalasia, pyloric stenosis,  small/large bowel obstruction, strangulated  hernia, volvulus).   • Malignancy (esophagogastricduodenal/  pancreatic carcinoma, hepatoma, metastasis,  paraneoplastic syndrome: vide infra 44-)   • Leukocytosis in inflammation; microcytic  anemia due to occult blood loss and malignancy.   • Severe or protracted vomiting of gastric  contents may lead to hypokalemia, uremia,  or metabolic alkalosis or acidosis.   • Hyponatremia or hyperkalemia (or both) is  commonly seen in adrenal crisis.   • Supine and upright AXRs are obtained in  patients with severe pain or suspicion of  bowel obstruction, perforation, or ileus — to  look for dilated loops of small bowel or  pneumoperitoneum.   • Urine hCG test for any women of child-  bearing age.   • Helpful in patients with gallbladder  (cholecystitis, cholelithiasis), hepatic (hepa-  titis, cirrhosis), and pancreatic disease (panc-  reatitis, carcinoma); may reveal urolithiasis.   • To evaluate mucosal lesions (ulcers, malig-  nancy), and to obtain biopsy specimens.   • In patients with suspected CNS cause or with  abnormal neurologic signs such as altered  consciousness and papilledema.   • With barium contrast and follow-through—  to detect mucosal lesions (ulcers), obstruc-  tion, or mass lesion.   • To evaluate serum levels of drug effect, e.g.  digoxin, theophylline, anticonvulsants or toxins,  e.g. pesticides, insecticides causing vomiting.   • The foremost aspect in history taking and  examination is an attempt to recognize and  correct any consequences of nausea and  vomiting such as dehydration or electrolyte  abnormalities, regardless of the underlying  cause (Table 31.1)   • Warning signs such as fever, hypotension,  severe dehydration, chest pain, severe    Table 31.1: Key questions in the evaluation of acute  nausea and vomiting   abdominal pain, CNS symptoms, history of  immunosuppression, or older age should  prompt immediate evaluation and treatment   • Evaluation of vital signs (fever, pulse, and  blood pressure to assess hydration, and  respiratory rate to look for acidosis-related  hyperventilation); skin, eyes, mucous mem-  branes (dehydration, jaundice); and signs of  systemic disease e.g. tachycardia, S 3 gallop,  pedal edema with CHF, are areas of key  importance   • Acute nausea and vomiting, i.e. symptoms  present for less than a week, is most often due  to GI infection, inflammation, obstruction;  systemic illness; drug toxicity; alcoholism;  labyrinthine disorders; and occasionally  psychogenic conditions   • Chronic nausea and vomiting, i.e. presence  of symptoms over a week, may be due to a  number of different conditions; the patient  may describe intermittent symptoms lasting  months or years. The common causes include  gastritis, mechanical obstruction, gut motility  disorders (including diabetic gastroparesis),  drugs, labyrinthine disorders, and uremia. A  thorough history and physical examination   •• The precise features of vomiting, and its  temporal relationship to food intake  generally provide a clue to the diagnosis  (Table 31.2).   gastritis, ulcer disease,  gastric outlet obstruction,  gastroparesis, gastric  carcinoma, psychogenic  • Intestinal obstruction    • Associated symptoms such as fever,  headache, and myalgia (viral); severe  abdominal pain (obstruction); weight loss,  hematemesis, melena (ulcer, malignancy,  Mallory-Weiss tear); jaundice (hepatitis,  hepatoma, and extrahepatic causes); diarrhea  (gastroenteritis); vertigo (labyrinthine  disorders); photophobia (migraine); and  drug ingestion may suggest the cause of  underlying disease   • History of peptic ulcer is an indicator of  further ulceration, while patients with  functional dyspepsia tend to be depressed or  anxious, and tend to exhibit somatization,  characterized by multiple symptoms and  frequent consultations   • An inquiry into patient's psychological and  social history, and of symptoms that may  indicate a psychological disorder is important.  Psychogenic vomiting is characterized by a    combination of features such as a lengthy  history of vomiting, superstitious vomiting,  often self-induced, evidence of psychological  disorders (anxiety, depression), and main-  tenance of normal health despite long-  standing vomiting   • Though nausea and vomiting associated with  pronounced weight loss (>3 kg) seemingly  indicates serious disorders such as obstruction,  malignancy, or mesenteric ischemia, it is  common in functional or psychogenic dyspepsia  due to sitophobia *, i.e. an aversion to food or  refusal to take nourishment   • Physical signs of pregnancy, alcoholism,  abdominal mass, peritonitis, obstruction,  neurological signs (altered mental state, neck  stiffness, papilledema, and nystagmus), ear  examination (middle ear disease), ophthal-  mic and funduscopic examination (raised  ICP, glaucoma), generally indicate the  underlying diagnosis   • A distended abdomen associated with nausea  and vomiting may indicate paralytic ileus or  mechanical obstruction of the intestine.  Abdominal tenderness, distension, and  occasionally visible peristalsis suggest GI  obstruction. A succussion splash suggests  diabetic gastroparesis.   • Acute nausea and vomiting may subside  within days, only to recur later to present a  chronic disorder, posing a more challenging  diagnostic dilemma   • Persistent vomiting with hypercalcemia may  be the initial presentation of asymptomatic  hyperparathyroidism, underlying neoplasm  or paraneoplastic syndrome   • In an intoxicated alcoholic patient with  nausea and vomiting-acute pancreatitis and    i Other terms used for 'food' phobia include 'phagophobia',  i.e. fear of eating and 'cibophobia', i.e. fear of food.    intracranial hemorrhage (subdural hematoma,  intracerebral bleeding, or contusion) must be  ruled out.   Acute intermittent porphyria— It is inherited as  an autosomal dominant pattern, caused by partial  deficiency of porphobilinogen deaminase activity,  leading to increased excretion of aminolevulinic  acid and porphobilinogen in the urine. It remains  clinically silent in the majority, but may manifest,  usually in women beginning in the teens or 20s.  Clinical features include intermittent abdominal  pain (may mimic acute abdomen), vomiting, and  neurologic manifestations such as seizures, muscle  pain, tingling, numbness, weakness, paralysis, and  psychosis. Attacks are precipitated by numerous  factors, including drugs and intercurrent  infections. In contrast to other forms of porphyria,  cutaneous hypersensitivity is absent in acute  intermittent porphyria. Diagnosis can be  confirmed by demonstrating increased amount of  porphobilinogen in the urine during an acute  attack.   Adrenal crisis— It is characterized by profound  asthenia, severe pain in the abdomen, muscle  cramps, nausea, vomiting, diarrhea, peripheral  vascular collapse, and finally, renal shutdown  with azotemia. Body temperature may be low,  although severe fever often occurs, particularly  when crisis is precipitated by acute infection.  Adrenal crisis may result from an acute  exacerbation of chronic insufficiency, usually  caused by sepsis or surgical stress, adrenal  hemorrhage (e.g. Waterhouse-Friderichsen  syndrome [fulminant meningococcemia]) and  anticoagulation complications. Steroid with-  drawal is the most common cause of adreno-  cortical insufficiency, and it almost exclusively  causes a glucocorticoid deficiency. Sometimes, the  diagnosis is considered only on discovery of  characteristic abnormalities of serum electrolytes.    including low Na (< 135 ruEq/1 ), high K (> 5 mEq/1),  low HC0 3 (< 15 to 20 mEq/1), and high BUN  (>20 mg/dl). A high index of suspicion is  therefore required in patients with unexplained  fatigue, hyponatremia or hypotension.   Boerhaave syndrome (Pronunciation: bu’r'hah-  ve') — It denotes esophageal perforation or  rupture of the esophagus caused by increased  intraluminal pressure and distension during  retching or vomiting. The presence of a hole or  other type of opening in the esophageal wall  facilitates the passage of esophageal contents into  the mediastinum resulting in mediastinitis. The  most common cause of esophageal perforation is  injury during a medical procedure such as  esophagoscopy or placement of a nasogastric  tube, and pathologic process such as neoplasm  or gastric reflux with ulceration. Less common  causes include injuries from penetrating or blunt  trauma or injury to the esophagus during an  operation on another organ, mechanical problem  such as violent retching or vomiting; ingestion of  a foreign body or caustic agents. The condition  often results in infection of the mediastinum and  mediastinitis. The Mackler triad is the classic  presentation of spontaneous esophageal rupture  is in a middle-aged man with a history of recent  vomiting or retching after dietary overindulgence and  overconsumption of alcohol, with chest pain and  subcutaneous emphysema.   Cyclic vomiting syndrome— CVS causes bouts  or cycles of severe nausea and vomiting that last  for hours or even days, and alternate with longer  periods of no symptoms. The disorder which has  no known cause typically begins between the  ages of 3 and 7 years. Children tend to outgrow  CVS when they are teenagers. While the disorder  occurs most often in children, CVS can begin at  any age. Adult episodes tend to occur less often  than they do in children, but they usually last  longer. Furthermore, the events or situations that  trigger episodes in adults such as coryza.    sinusitis, emotional stress, excitement, physical  exhaustion, foods such as chocolate or cheese,  menstruation, hot weather etc. cannot always be  pinpointed as easily as they can in children. Each  episode is similar to the previous ones. The  episodes tend to start at about the same time of  day, last the same length of time, and present  the same symptoms at the same level of intensity.  CVS appears to be linked to migraines in some  cases. Treatment with migraine medications  often helps. Because other more common  diseases and disorders also cause cycles of  vomiting, many people with CVS are initially  misdiagnosed until the other disorders can be  ruled out. To be diagnosed with CVS, a person  must have experienced at least two episodes of  intense nausea and unremitting vomiting or  retching lasting hours or days. These episodes  must be separated by weeks or months of  symptom-free intervals. There is no specific test  that will confirm the diagnosis of CVS. Other  conditions that can produce vomiting, such as,  labyrinthine disease, metabolic disorders, CNS  tumors, and pregnancy must be excluded.   Gastroparesis — Literally translated, it means  stomach paralysis — is a digestive disorder in  which the motility of the stomach is either  abnormal or absent. Normally, the stomach  contracts to move food down into the small  intestine for digestion. The vagus nerve controls  the movement of food from the stomach through  the digestive tract. Gastroparesis occurs when  the vagus nerve is damaged, and the muscles of  the stomach and intestines do not work normally.  Food then moves slowly or stops moving  through the digestive tract (delayed gastric  emptying). The most common cause of  gastroparesis is diabetes mellitus; other causes  include hypothyroidism, vagotomy, gastric  bypass surgery, viral infections, medications such  as anticholinergics and narcotics, smooth muscle  disorders such as amyloidosis and scleroderma;    Parkinson's disease; multiple sclerosis; and  idiopathic gastroparesis. Signs and symptoms of  gastroparesis are: heartburn, pain in the upper  abdomen, nausea, vomiting of undigested  food — sometimes several hours after a meal;  early feeling of fullness after only a few bites of  food; weight loss due to malnutrition; abdominal  bloating, lack of appetite, and gastroesophageal  reflux. Gastric emptying scintigraphy of a  radiolabeled solid meal for 2 hours confirms the  diagnosis of gastroparesis. Performing the test  for a longer duration, up to 4 hours, has been  proposed to increase the yield in detecting  delayed gastric emptying in symptomatic  patients.   Paraneoplastic syndromes— PNS can be defined  as a group of symptoms that may develop due  to indirect and usually remote immune-  mediated effects produced by tumor cell  metabolites or other products which disrupt the  normal function of surrounding cells and tissue.  Body systems that may be affected by PNS  include neurological, endocrine, cutaneous,  renal, hematologic, gastrointestinal, and other  systems. The most common manifestations of  PNS are cutaneous, neurologic, and endocrine  disorders. An example of a cutaneous paraneop-    lastic disorder is telangiectasis, which can be  caused by breast cancer and lymphomas.  Lambert-Eaton myasthenic syndrome is a  neurologic PNS that can be caused by a variety  of tumors including small cell lung cancer,  lymphoma, breast, colon and other cancers.  Syndrome of inappropriate antidiuretic  hormone (SIADH) is an endocrine PNS, which  is seen in as many as 40% of patients diagnosed  with small cell lung cancer. Symptoms generally  develop (depending on body system affected)  over a period of days to weeks and usually occur  prior to tumor detection, which can complicate  diagnosis. Some paraneoplastic syndromes may  be confused with metastatic disease or spread  of the cancer. The presence of the syndrome may  be the only indication that a patient has a  malignancy or that a malignancy has recurred.  Specific diagnosis depends on demonstration of  specific autoantibodies in various tissues of the  body and imaging studies such as MRI, PET, and  SPECT scans.   1 . Quigley EM, et al. AGA technical review on nausea  and vomiting. Gastroenterology 2001;120(1):263-  86. [PMID: 11208736],   Pain is defined by the International Association for  the Study of Pain as, "an unpleasant sensory and  emotional experience associated with actual or  potential tissue damage, or described in terms of  such damage. It is unquestionably a sensation in a  part or parts of the body, but it is also always  unpleasant, and therefore also an emotional  experience ". 1 In other words pain is an inherently  subjective phenomenon characterized by dis-  comfort (sensory), and distress (emotional feeling).   Many people report pain in the absence of  tissue damage or any likely pathophysiological  cause; usually this happens for psychological  reasons. There is usually no way to distinguish  their experience from that due to tissue damage.  "Many have a profound distrust of a diagnosis  based on symptoms alone when the symptom  is pain, and basic research has not uncovered a  test that would yield an unequivocal sign ". 2  Further, it is counterproductive to speculate  about whether the pain is 'real'. It is real to the  patients —if they regard their experience as pain,  and if they report it in the same ways as pain  caused by tissue damage, it should be accepted  as pain . 1,3    Pain is generally divided into three  categories: nociceptive, neuropathic, and  mixed. Nociceptive pain develops from body  tissue or organ— injured or damaged — and is  further divided into somatic and visceral pain.  Somatic pain is typically related to specific  anatomic areas or structures, and therefore  well-localized, aching, stabbing, or throbbing  in nature, e.g. fibromyalgia, osteoarthritis, and  rheumatoid arthritis. Visceral pain is organ  based, less well localizes, dull, and cramping  in nature, e.g. irritable bowel syndrome, colitis,  and diverticulosis. Neuropathic pain, on the other  hand, involves damage to the nervous system  characterized as burning, tingling, and  lancinating, and often occurring in the nerve  dermatome, e.g. trigeminal neuralgia, posther-  petic neuralgia, diabetic neuropathy, and  phantom limb. This pain may be associated with  sensory deficit, and occur with or without  nociceptive component. Metastatic cancer pain,  low back pain, non-cardiac chest pain may be  of mixed pain origin.   Clinically, pain can be categorized as acute  or chronic. In general, acute pain is distinguished  as being of recent onset; originating from an  identifiable biologic component such as an injury.    infection, metabolic, or degenerative disorder;  self-limited, the pain tends to abate as the tissue  heals; does not have much of psychological  component; and is more amenable to pharma-  cologic intervention.   Chronic pain can be described as, "persistent or  recurrent pain, lasting beyond the usual course of  acute illness or injury or more than 3 to 6 months,  and which adversely affects the individual's well-  being. A simpler definition for chronic pain is—  pain that continues when it should not". 4   The biological component of chronic pain is  less well-understood than that of acute pain. It  appears that chronic pain constitutes a complex  mixture of pathophysiologic factors interacting  with numerous psychological, social, and cultural  factors, and also influenced by past experience  and cognitive function, which can modulate the  patient's pain threshold, either upward or  downward (Table 32.1). The biopsychosocial  factors related to chronic pain is given in Table  32.2. These characteristics necessitate a systematic  multidisciplinary approach by physicians (such  as neurologists, anesthesiologists, oncologists);  and nonphysicians (psychologists, chiropractors,  acupuncturists, and hypnotists) to achieve a  satisfactory outcome. It is in this context that in  the diagnosis and management of chronic pain  disorders the biopsychosocial approach is very  much useful. 5,6 However, diagnosis of the  etiology for chronic pain— biological or otherwise  -is crucial on several stages such as investigations,  treatment, and rehabilitation. Hence, it is essential  to exclude, especially progressive or serious  conditions as soon as possible, so that intervention  can be timely.    * Biopsychosocial approach — symptoms are viewed as a  product of multiple dynamic factors that develop  synergistically in combination with certain genetic,  psychological, and environmental vulnerabilities".  (Weisberg MB, Clavel AL Jr. Why is chronic pain so difficult to  treat? Postgrad Med 1999; 106(6):141-64).    *Source : Robert T. Introducing Palliative Care, 3rd ed.;  Symptom Management, p.66.   **Adopted and modified from International Association  for the Study of Pain (IASP-1994).   • Chronic low back pain (lumbosacral disk  lesions, postlaminectomy syndromes, spon-  dylopathies, spinal stenosis)   • Central post-stroke pain (i.e. thalamic pain,  or Dejerine and Roussy syndrome)   • Da Costa syndrome (neurocirculatory  asthenia, effort syndrome. Soldier's heart.  Gulf war syndrome) 7-9   Cancer pain syndromes (bone pain secondary to  metastasis, visceral pain secondary to mass  effect).   • Musculoskeletal (compression fracture of  lumbar vertebrae, seronegative spondylosis,  temporomandibular joint dysfunction, phan-  tom limb pain)   • To evaluate for inflammatory conditions;  elevated in temporal arteritis, rheumatoid  arthritis, and malignancy.   • Metastatic bone disease (e.g. from breast,  lung, or kidney tumor) is the commonest  cause of elevated serum calcium and alkaline  phosphatase levels   • In patients suspected with Paget's disease -  bone-specific alkaline phosphatase is more  specific.   • Elevated in myopathies (polymyositis,  metabolic disorders, drugs, alcohol, and  muscular dystrophy).   • In patients suspected with bony abnormalities,  e.g. cervical, lumbosacral disk lesions; thoracic  outlet syndrome; compartment syndromes,  and neoplastic lesions   • Lytic lesions may be the only finding early  in Paget's disease.   • To further evaluate CT scan lesions related  to discogenic pain; spinal canal stenosis;  various bone and joint lesions; avascular  necrosis, etc   • MRI is extremely helpful in the evaluation  of pain that may be due to intracranial mass  lesion; bony or soft-tissue lesions, abscess,  metastatic deposits; facial pain due to  posterior fossa lesions; facial nerve lesions;  orbital pain; abdominal and pelvic pain due  to inflammation or malignancy.   • Helpful in evaluating pain due to a stress  fracture, infection (osteomyelitis); and  chronic pain in bone cancer patients -  most commonly due to secondary deposits  in spine, pelvis, extremities, ribs, and skull   • Bone scanning is the most sensitive test  for evaluating the extent of lesions in  the whole skeleton affected by Paget's  disease.    + Because of heterogenicity of the chronic pain and its  presentation, specific laboratory and imaging evaluation  must be targeted to specific condition and to rule out other  life-threatening illnesses.   • These two studies, which compliment one  another, can often distinguish between  neurogenic and myogenic disorders   • NCS distinguish between mononeuro-  pathies (e.g. due to trauma, compression, or  entrapment) and polyneuropathies (e.g. due  to metabolic, toxic, malignant, nutritional,  autoimmune, or hereditary disorders)   • In addition, they may also be helpful in  excluding organic disorders when psycho-  genic pain or functional syndrome is suspected.   • Age and gender related cancer screening, e.g.  breast mammography. Pap smear, PSA, etc.;  and tumor markers, e.g. alpha-fetoprotein, beta  chorionic gonadotropin, carcinoembryonic  antigen, etc. may be helpful in the evaluation  of patients suspected with cancer pain.   • Although most patients have great difficulty  in describing pain sensation, its assessment  is important and helpful diagnostically.  Therefore, evaluation of a patient with  chronic pain should include the following:   > Quality (pricking, lancinating, burning,  etc., i.e. somatic, visceral, or neuropathic,  as explained above);   > Is it bone pain ? Bone pain may begin as a  dull, constant ache that grows worse; it feels  deep with boring, stabbing, throbbing,  cramping or gnawing sensation; usually  increases at night and may not subside  when sleeping; mostly due to metastatic  deposits; referred to a different area from  the site of the problem;   > Patient's functional status (i.e. the impact  of pain on patient's daily activities such as    ability to perform household chores, work  tasks, leisure in interests, sleep, etc. with  the help of VAS, i.e. visual analog scale; *   > A review of previous diagnostic studies  (careful reviewing of prior test reports is  essential to eliminate unnecessary  repetition);   > An assessment of coexisting diseases and  conditions (i.e. biological causes such as  musculoskeletal, neurologic, cardiovas-  cular, respiratory, gastrointestinal, and  gynecological disease).   > "P" refers to precipitating or palliative  factors; this information may provide  clues for possible etiologies or associated  disorders;   > "Q" refers to quality of the pain (nocicep-  tive, neuropathic, or mixed - as described  above);   > "R" stands for radiation and original  location of pain; radiating pain is  characteristic of neuropathic pain;   '> "S" stands for severity of pain: many special-  ized clinical tools in multiple languages  are available for pain assessment. 10  Examples include unidimentional scales  such as the visual analog scale (VAS),  verbal rating scale (VRS), numerical  rating scale (NRS), and the pain faces  scale, etc. (use score l-to-10 rating scales:  severe pain is defined as pain that is rated  as 7 to 10 on a 0 to 10 VAS);   > "T" stands for timing, including onset,  duration, and frequency— daily, paroxys-  mal, seasonal, nocturnal, or diurnal.    *VAS: A tool used to help a person rate the intensity of  certain sensations and feelings, such as pain. The VAS for  pain is a straight line with one end meaning no pain and  the other end meaning the worst pain imaginable. A patient  marks a point on the line that matches the amount of pain  he or she feels. It can also be used to help choose the right  dose of pain medicine.    • Assess patient's psychosocial status— A good  psychosocial and psychosexual history is  needed when organic diseases are excluded or  coexisting psychiatric disorders are suggested.  Obtain sufficient history to evaluate depression;  anxiety disorder; somatization; physical or  sexual abuse; drug abuse/dependence; and  family, marital, or sexual problems   • History of onset — Discord in family dynamics,  difficult social interactions, stressful work  environment, strained marital relationship,  sexual problems, and history of substance abuse,  domestic violence, and absence of a clear  pathophysiologic mechanism suggest a primary  psychosocial cause   • Circumstances associated with the onset of  pain is important; it helps to identify whether  the patient's complaints are related to  biologic process, or is predominantly psyc-  hological or psychosocial in origin   • Physical examination— Its main purpose is  to determine the possibility of underlying  biologic process. Each system, particularly  the ones pertaining to the patient's  presentation, and including complete  mental state examination (affect, mood,  ideation, and insight) is performed. Any  evidence of primary biologic process  responsible for chronic pain is subjected to  further appropriate physical examination  and investigations. Table 32.3 illustrates  location-wise classification of common  biological causes for chronic pain   • Assess for Waddell's signs 11 (Table 32.4), and  inconsistencies in the above examination;  positive Waddell's signs generally indicate a  nonphysiological etiology of pain.   • Any patient with unexplained, persistent  pain— somatic, visceral, or bone pain— should  be suspected of having malignant disease and  appropriate investigations performed.   Waddell's signs are special nonphysiologic maneuvers  used to evaluate persons when exam findings are  inconsistent. They are:   2. Nonanatomic tenderness— Deep tenderness over  a wide area, crossing multiple anatomic  boundaries; often extending cephalad to the  thoracic spine or caudad to the sacrum   3. Axial loading— Eliciting low back pain when  pressing down on the top of the patient's head.   4. Rotation — Back pain when the shoulders and  pelvis are rotated passively in the same plane with  the feet together. Normally, rotating the shoulders  and pelvis together should not be painful as it does  not stretch the structures of the back.   5. SLR— Observing an improvement of 30-40° when  the patient is distracted, i.e. distracted straight leg  raise, compared with formal testing.   6. Weakness — Cogwheeling, i.e. weakness that is  jerky, with intermittent resistance, of many muscle  groups upon manual muscle testing of strength   7. Sensory — Diminished light touch or pinprick  sensation in a stocking pattern, rather than a  dermatomal pattern, in an individual who is not  diabetic   8. Overreaction— During the examination may be  observed in several manifestations (e.g. dispro-  portionate verbalization, facial grimacing, muscle  tension and tremor, collapsing, sweating).   Although Waddell's signs can detect a nonorganic  component to pain, they do not exclude an organic cause.  The presence of three or more positive findings may be  clinically significant in terms of psychosocial issues or possible  illness behavior. Isolated positive signs are of limited value.    • Beware of the high rate of psychiatric  comorbidities that exist with chronic pain  disorders; and even when an organic cause  for a patient's pain can be found, it is still wise  to look for other factors 12   • Beware of involvement of litigation or  evidence of secondary gain, e.g. issues such  as indemnity, loss of financial stability, and  relationships   • Chronic pain may trigger fear of death,  disability, or disease progression; therefore,  support and education may be important  even for mild pain; stress that pain does not  always equal harm.   Complex regional pain syndrome * 1 2 3 4 5 6 7 8 — The   CRPS 13 ' 14 is a neurologic disorder affecting  central and peripheral nervous systems — a  common mechanism may be injury to central or  peripheral neural tissue — such as due to head  injury, stroke, tumor, burns, fractures, sprains,  operative procedures, trivial soft tissue injury,  vaccination, and microtrauma. Persons of all  ages and both sexes are affected, and can involve   8 The terms currently in favor are complex regional pain syndrome  I (the equivalent of Reflex sympathetic dystrophy) and complex  regional pain syndrome n, also known as causalgia.    either the arms or the legs. CRPS is characterized  by pain, edema, stiffness, and discoloration. Pain  is intense and burning, out of proportion to the  injury, allodynia (perception of pain from a  nonpainful stimulus), or hyperalgesia (disprop-  ortionate to the inciting event). Edema is usually  one of the earliest findings. Stiffness may occur.  Discoloration may vary from intensely  erythematous to cyanotic, pale, purple, or gray.  The syndrome progress through a series of stages:   Acute stage — Usually warm phase of 2-3  months: Pain is more severe than would be  expected from the injury; burning or aching  quality; may be increased by dependency of the  limb, physical contact, or emotional upset. The  affected area becomes edematous, may be  hyperthermic or hypothermic, and shows  increased nail and hair growth. Physical  findings may be minimal; radiographs may  show early bony changes.   Dystrophic phase — Vasomotor instability for several  months: Edematous tissue becomes indurated; skin  becomes cool and hyperhidrotic with livedo  reticularis or cyanosis; hair may be lost, and nails  become ridged, cracked, and brittle. Hand dryness  becomes prominent, and atrophy of skin and  subcutaneous tissues becomes noticeable. Pain  remains the dominant feature. It usually is constant  and is increased by any stimulus to the affected area.  Stiffness develops at this stage. Radiographs may  show diffuse osteoporosis. The 3-phase bone scan  is usually positive. Duration is 3-12 months from  onset.   Atrophic phase — Usually cold extremity with  atrophic changes: Pain spreads proximally, may  diminish in intensity, but persists with occasional  flare-ups. Skin is thin and shiny; edema is absent;  contractures may occur. Radiographs indicate  marked demineralization.   The diagnosis of CRPS is excluded by the  existence of any condition that would otherwise    account for the degree of pain and dysfunction.  A single, reliable, sensitive, and specific  diagnostic test for CRPS is not available;  however, the disease is not fatal.    1 . International Association for the Study of Pain. Web  site: http://www.iasp-pain.org/AM/Template.  cfm?Section=General_Resource_Links&emplate=/  CM/HTML Display.cfm & ContentID=3058#Pain.  Accessed on 04-11-08.   2. Bennett GJ. Neuropathic pain: A crisis of  definition? Anesth Analg. 2003;97(3):619-20.  [PMID: 12933371: Free full text],   3. Eisendrath SJ, et al. Chronic pain disorders. In:  Tierney Jr et al, Eds. Current Medical Diagnosis  and Treatment. 2006, 45th edn. The McCraw Hill  Companies, Inc. p. 1050.   5. Turk DC, et al. psychological approaches in the  treatment of chronic pain patients - when pills,  scalpels, and needles are not enough. Can J  psychiatry 2008; 52(4):213-23.   6. Gatchel RJ, et al. The biopsychosocial approach to  chronic pain: Scientific advances and future  directions. Psychol Bull. 2007;133(4):581-624.  [PMID: 17592957: Abstract],   7. Wooley CF. Where are the diseases of yesteryear?  DaCosta's syndrome, soldier's heart, the effort  syndrome, neurocirculatory asthenia — and the  mitral valve prolapse syndrome.Circulation 1976;  53(5):749-51.   8. Thomas HV, et al. Pain in veterans of the Gulf War  of 1991: A systematic review. BMC Musculoskelet  Disord. 2006; 7:74. [PMID: 16987407: Free full text],   9. Stimpson NJ, et al. Prevalence of reported pain,  widespread pain, and pain symmetry in veterans  of the Persian Gulf War (1990-1991): The use of pain  manikins in Persian Gulf War health research. Mil  Med 2006;171(12):1181-6. [PMID: 17256678:  Abstract],   11. Fishbain DA, et al. A structured evidence-based  review on the meaning of nonorganic physical  signs: Waddell signs. Pain Med 2003;4(2):141-81.  [PMID: 12911018 Abstract],   12. Kasper DL, et al (Eds). Harrison's Prin. of Internal  Med. 2005, 16th edn. Vol. I: p.75.   The term palpitation refers to conscious awar-  eness of one's own heartbeat, usually with an  increase in frequency or force, with or without  irregularity in rhythm. It is generally an  unpleasant feeling. However, individual patients  vary greatly in sensitivity to palpations— healthy  patients may be concerned with even isolated  ectopic beats, e.g. patients with cardiac neurosis;  while patients with higher risks and advanced  heart disease, e.g. hypertrophic cardiomyopathy  may be completely unaware of serious  arrhythmias such as AF and even VT. Thus, the  intensity of the symptoms does not necessarily  correlate with the seriousness of the underlying  condition.   Palpitations mean different things to different  people. It is described by a variety of sensations,  e.g. pounding, thumping, fluttering, jumping,  racing, or skipping a beat. It is, therefore,  important to establish exactly what is meant.  Though it is classically suggestive of an  arrhythmia (i.e. loss or abnormality of rhythm),  it occurs in a wide variety of disorders of cardiac  and noncardiac origin.    closely related phenomenon, they are not  synonymous. The symptom of palpitation  does not necessarily mean that an arrhythmia  is present, e.g. sinus tachycardia with anxiety;  conversely, an arrhythmia can occur without  the sensation of palpitation — an entity described  as asymptomatic or silent arrhythmia, e.g.  sudden cardiac death (SCD) due to ventricular  fibrillation (VF) in diabetics, and asymptomatic  atrial fibrillation (AF) in untreated patients with  a history of AF.   The causes of palpitation vary from benign  conditions requiring no therapy to life-threat-  ening conditions requiring urgent monitoring,  treatment, and referral.   However, in the vast majority of patients,  palpitation is benign, and expensive and costly  investigation is not warranted. Attention to  characteristics that identify patients at high  risk for serious causes of palpitations will help  define the much smaller percentage of patients  who require more extensive diagnostic testing  and management of their condition . 1   *"A11 palpitations are not arrhythmias and many  arrhythmias do not palpitate".   • Coronary artery disease (CAD: stable angina,  unstable angina, MI, SCD)   • Psychiatric disease (generalized anxiety disorder,  panic attack, depression, and somatization)   • Metabolic disorders (hypoglycemia, hyper-  thyroidism, menopause, electrolyte imba-  lance-hypokalemia, hypomagnesemia)   • Pacemaker syndrome (endless-loop tachy-  cardia: vide infra 4 - 4 -)   • Palpitations may or may not be associated  with ECG changes. In the majority of patients  there are no ECG changes at rest while    asymptomatic/ In the event of a patient  experiencing palpitations, a concurrent ECG  may be diagnostic, but this is often difficult,  as the timing of palpitations may not coincide  with the ECG recording.   > Marked LVF, deep septal Q waves in I,  aVL, and V4-6, indicating HOCM with  AF.   > Pathological 'q' waves, indicating prior  MI, and therefore a focus for ventricular  arrhythmias.   • Hb <10 g/dl; blood smear suggestive of iron  deficiency anemia.   • Generally indicated if symptoms due to  arrhythmia are occurring at least daily,  particularly when associated with organic  heart disease. Heart rhythm is monitored for  24 to 48 hours. Patients are asked to maintain   + Although a normal ECG cannot exclude the possibility of  an arrhythmia or CAD, it tends to imply preserved left  ventricular systolic function.   (1) Patients with unexplained syncope, near syncope or  episodic dizziness without obvious cause.   (1) Patients with episodic shortness of breath, chest pain  or fatigue that is not otherwise explained.   (2) Patients with neurologic events when transient atrial  fibrillation or flutter is suspected.   (3) Patients with symptoms such as syncope, near syncope,  episodic dizziness or palpitation in whom a probable  cause other than an arrhythmia has been identified but  in whom symptoms persist despite treatment of this  other cause.   (1) Patients with symptoms such as syncope, near  syncope, episodic dizziness or palpitation in whom  other causes have been identified by history, physical  examination or laboratory tests.    ## Class I - general agreement is that the test is useful and  effective. Class II - frequently used, but there is a divergence  of opinion with respect to its utility. Class Ha - weight of  evidence/opinion is in favor of usefulness/efficacy. Class  lib - usefulness/efficacy is less well established by evidence/  opinion. Class III - general agreement that the test is not  useful, and in some cases may be harmful.   a diary documenting the time and describing  the symptoms during the monitoring period.  Subsequently the patient's symptoms are  correlated with documented rhythm abnor-  malities.   • Indicated in patients with potentially life-  threatening arrhythmias and episodes of SCD  with successful resuscitation; EPS assist in  their subsequent management by means of  antiarrhythmic drugs, pacemakers, or  implantation of automatic implantable  cardioverter defibrillator (AICD). Common  indications/contraindications for EPS appear  in Table 33.2.   • Evaluation of efficacy of pharmacotherapy in patients  with life-threatening arrhythmias-   • Evaluation of patients for catheter ablation  procedures or antitachycardia devices   • The event monitor is a patient activated  (i.e. conventional) device. These monitors  are generally worn for a period of up to  30 days, continuously recording the  patient's under-lying rhythm, but require  the patient to manually trigger, i.e. to  activate the device to save the inform-  ation. The loop recorder provides the  rhythm strip generated during the two  minutes preceding and following the  episode of palpitation. Conventional event  monitoring is successful only when the  patient is aware of symptoms as they occur.    and is capable of pressing the signal button  promptly. Newer event recorders have  programmable automatic triggers for rapid  and slow heart rates. The advantages over  Holter monitoring are that, a symptom  dairy is not needed and the higher yield of  collected data is useful for detecting  arrhythmia associated with palpitation.   • It has several advantages over traditional  ambulatory monitoring systems in the  diagnostic evaluation of symptoms such as  palpitations, dizziness, and syncope. MCOT  can detect asymptomatic clinically significant  arrhythmias, and was especially useful to  identify the cause of presyncope/syncope,  even in patients with a previous negative  workup. This outpatient monitoring system  allows patients to undergo daily medication  dose titration in the outpatient setting, thus  avoiding hospitalization.   • Indicated in patients who are known to have  or suspected to have CAD.   • May be indicated in patients suspected of  valvular heart disease, CHF, or any structural  abnormality. The ACC/ AHA Guidelines for  the Clinical Application of Echocardiography  state that, "Unless there are other indications  for testing, echocardiography need not be  performed in a subject with palpitation for  which an arrhythmic basis has been ruled  out. 3 " The ACC/AHA indications for  echocard-iography in patients with    Table 33.3: Recommendations for echocardiography in  patients with arrhythmias and palpitations 5   2. Arrhythmia in a patient with a family history of a  genetically transmitted cardiac lesion associated  with arrhythmia, such as tuberous sclerosis,  rhabdomyoma, or hypertrophic cardiomyopathy   3. Evaluation of patients as a component of the work-  up before electrophysiological ablative procedures   1. Arrhythmias commonly associated with, but  without clinical evidence of heart disease   2. Evaluation of patients who have undergone radio-  frequency ablation in the absence of complications  (In centers with established ablation programs, a post-  procedural echocardiogram may not be necessary)   3 . Postoperative evaluation of patients undergoing the  Maze procedure to monitor atrial function   1. Palpitation without corresponding arrhythmia or  other cardiac signs or symptoms   2. Isolated premature ventricular contractions for  which there is no clinical suspicion of heart disease   • An important step in the evaluation of  palpitation is to establish or exclude the  presence of underlying structural heart  disease such as CAD, CHF, valvular stenosis  or regurgitation, cardiomyopathy, and  congenital cardiac disorders, and to detect life-  threatening cause of palpitation that place  patients at risk of sudden death— VT and VF   • Any evaluation of palpitations must first  confirm that the patient is hemodynamically  stable, and that the symptoms are not life-  threatening, which in many cases can often  be made from history, physical examination,  and ECG findings, which are sufficient to  determine the nature of the problem   • A patient with palpitation is usually asympt-  omatic at the time of physical examination,  and the diagnosis of arrhythmia may pose a  real problem if the arrhythmia is not present  at the time of examination. One solution is  to request the patient to present as soon as  possible at the onset of palpitation. However,  if the history and physical evaluation  indicates the possibility of any serious  arrhythmia, it is prudent to monitor the  patient (Table 33.4)   • History — In a study reported by Summerton  N et al, 6 characteristic historical factors  contributory to new-onset clinically signif-  icant palpitations include:   > Current medical problems, e.g. thyroid  disease, asthma, anemia, anxiety,  depression, perimenopause   > Past history of hypertension, CAD,  valvular heart disease, congenital heart  disease, cardiomyopathy   > Current medications, e.g. benzodiaze-  pines, ACE-inhibitors, diuretics, OHA,  insulin, beta-blockers, antianginals,  thyroxin, antidepressants.   pheochromocytoma  Ventricular arrhythmias;  heart blocks  Digitalis toxicity;  hypokalemia of diuretics  Hypoglycemia  Bronchodilators  (methylxanthines, beta-  agonists)   Sinus tachycardia. Atrial  fibrillation  Congenital long QT  syndrome  Acquired long QT  disorder  Hypokalemia  Reentry tachycardias    • Associated symptoms such as chest pain (angina,  MI); dyspnea (LVF, MI, pulmonary embolism);  lightheadedness, dizziness, or sweating (syncope,  hypoglycemia, pheochromocytoma); may  indicate hemodynamic instability and mandate  further evaluation   • Evidence of anxiety or depression should be  sought in patients presenting with palpita-  tions without clinical evidence of cardiov-  ascular disease. Psychological factors may  influence the perception of palpitation as  unpleasant and abnormal and thereby  prompt consultation. Psychological factors  should therefore be integrated into the  diagnosis of palpitation   • A family history of SCD or syncope may  suggest an inherited dilated or hypertrophic  cardiomyo-pathy (HCM)*, congenital LQTS,  or Brugada syndrome (BrS: vide infra 44 -). In  general, first-degree relatives under 40 with  a family history of SCD must be investigated    i The apical variant of HCM, also known as 'Japanese or  Asian variant', is rare and often poses a diagnostic  challenge.    • Palpitations since childhood suggest an  idiopathic SVT, WPW syndrome, or LQTS   • Resolution of symptoms due to palpitation  with vagal maneuvers such as breath-holding  or the Valsalva maneuver in hemodyna-  mically stable patients suggests PSVT   • An episode of palpitation on assuming an  upright position after bending over, and  aborted by lying down suggest 'postural  orthostatic tachycardia syndrome (POTS: vide  infra 1!)', i.e. atrioventricular nodal reentry  tachycardia (AVNRT)   • An episode of polyuria that follows  palpitations may suggest supraventricular  arrhythmias   • Palpitations associated with restlessness,  warm and sweaty palms, fine termer,  protruding eyes, and enlarged thyroid  (goiter) is due to hyperthyroidism   • The use of medications, drugs, and stimulants  should be questioned and quantified. Almost  all antiarrhythmic drugs have a proarrhy-  thmic potential, i.e. they may worsen existing  arrhythmia or provoke new arrhythmias in  some patients. Phenylpropanolamine, a  frequent ingredient in diet pills and cold  remedies, is one of the many sympatho-  mimetics that can cause arrhythmias.  Eyedrops that include beta-blockers have been  blamed in some cases of bradycardia   • Palpitations as a result of varieties of arrhythmias  may be provoked by excess consumption of  alcohol even in healthy individuals (holiday  heart syndrome: vide infra 11)   • Palpitations due to AF are the most common  arrhythmia in the elderly (secondary to  hypertension, and CAD)   • To help characterize the palpitations,  requesting the patient to simulate their rhythm  by tapping his finger on a hard surface can be  quite informative. The physician can also help  the patient by tapping out examples of rapid  or irregular rhythm that has been experienced    • Physical examination— Possible evidence of  organic heart disease may include:  hypertension; signs of CHF (rales, cardio-  megaly, acute pulmonary edema, third heart  sound, jugular pressure greater than 16 cm,  and positive hepatojugular reflex); and  cardiac murmurs. Other signs may include  tachycardia/bradycardia, pedal edema,  hepatomegaly, and pleural effusion. Some  clinical disorders associated with palpita-  tions may provide clues to the nature of the  arrhythmia (Table 33.5)    Missed beat followed by heavy  beat, or thump in the chest   Sinus tachycardia  Supraventricular tachycardia  Ventricular tachycardia  Atrial fibrillation  Atrial tachycardia with varying  block   Atrial flutter with varying block  Paroxysmal supraventricular  tachycardia  Reentry tachycardia  Tachy-brady of sick sinus  syndrome   Triple apical impulse, loud S 4 ,  harsh, holosystolic murmur  along left sternal border,  increased with Valsalva  maneuver, decreased with  squatting, associated with  mitral regurgitation, AF, VT   impulse, S 3 , S 4 gallop, CHF,  associated with AF, VT   • Any person, including a child, with symptoms  of palpitations, recurrent loss of consciousness,  collapse associated with exertion, atypical  seizures with a normal EEG, or with any  documented arrhythmia must be thoroughly  evaluated by cardiologists, especially to  screen for inherited cardiac diseases such as  WPW syndrome, HOCM, LQTS, and BrS.  Screening should be considered in all first-  degree relatives (parents, siblings and  children) of anyone who has died under  40 yrs from an inherited heart condition or  unexplained sudden cardiac episode   • Do not overlook MI, including silent MI and  unstable angina as a cause of arrhythmia  manifesting as palpitations, especially in the  elderly   • Palpitations associated with syncope and  presyncope merit a complete cardiovascular  evaluation; sustained or nonsustained VT  must be ruled out   • Sudden onset of palpitations in an apparently  healthy person associated with ECG evidence  of PSVT is suggestive of WPW syndrome.  Following the termination of the tachycardia,  an ECG should be performed during the sinus  rhythm to screen for WPW syndrome. They  need periodic observation as they are  potentially at an increased risk of dangerous  ventricular arrhythmias, including SCD.  Although relatively uncommon, SCD may be  the initial presentation in patients with  tachyrhythmias due to WPW syndrome   • Although an underlying psychiatric illness  should be considered in appropriate patients,  it does not obviate the need for a complete  evaluation to exclude a cardiac origin of  palpitation; true arrhythmias do occur in such  patients; PSVT may masquerade as panic  attack, leading to misdiagnosis 7   Brugada syndrome (BrS)— Since its intro-  duction as a clinical entity in 1992 (originally  described by Pedro and Joseph Brugada), the BrS  has attracted great interest because of its high  incidence in many parts of the world, and its  association with high risk for sudden death in  young and otherwise healthy adults, and less  frequently, in infants and children. Sudden and  unexpected death syndrome (SUDS) of young  adults during sleep is endemic in Japan and  Southeast Asia. SUDS characteristics include the  following: (1) victims are relatively young,  healthy men leading normal lives; (2) death often  occurs during sleep late at night; and (3) autopsy  findings are usually negative. The syndrome  typically manifests during adulthood, with a  mean age of sudden death of 41±15 years. The  youngest patient clinically diagnosed with the  syndrome is 2 days old and the oldest is 84 years  old. BrS is a primary electrical disease resulting  in abnormal electrophysiologic activity in right  ventricular epicardium. Recent genetic data  linking the BrS to an ion channel gene mutation  (SCN5A) provides further support for the  hypothesis. The syndrome is characterized by —   (a) a peculiar ST segment elevation in the right  precordial leads; often accompanied by apparent  conduction block in the right ventricle;   (b) structurally normal heart; and (c) a propensity  for life-threatening ventricular tachyrhythmias.  The higher intercostal space V (1) to V (3) lead  ECG could be helpful in detecting Brugada  patients. Although two types of the ST-segment  elevation are present, the coved type is more  relevant to the syndrome than the saddle-back  type. ST segment elevation in the right chest    leads is observed in a variety of clinical settings  (e.g. acute septal ischemia, pericarditis,  ventricular aneurysm, and in some normal  variants like early repolarization), and is not  unique or highly specific for the BrS. A clear  distinction cannot be made on the basis of an  ECG alone. However, ST segment elevation in  the right precordial leads in the absence of  ischemia, electrolyte or metabolic disorders,  pulmonary or inflammatory diseases or  abnormalities of central or peripheral nervous  system may identify the BrS. In such cases, the  term "idiopathic" is appropriate. The ECG  manifestations of BrS are often dynamic or  concealed, and may be unmasked or  modulated by sodium channel blockers  (ajmaline, procainamide and flecainide), a  febrile state, vagotonic agents, a-adrenergic  agonists, (3-adrenergic blockers, tricyclic or  tetracyclic antidepressants, a combination of  glucose and insulin, hypo- and hyperkalemia,  hypercalcemia, and alcohol and cocaine toxicity.  Imaging techniques, endocardial biopsy and  cardiac catheterization are useful in ruling out  structural cardiac abnormalities. Finally,  extension of the testing to family members is also  important because of high incidence of familial  occurrence. Currently, implantable cardiac  defibrillator implantation is the only proven  effective therapy in preventing sudden death in  patients with the BrS, and is indicated in  symptomatic patients, and should be considered  in asymptomatic patients in whom VT/VF is  inducible at time of electrophysiologic study.   Holiday heart syndrome — The association  between alcohol use and rhythm disturbances,  particularly supraventricular tachyarrhythmias  in apparently healthy people is called "holiday  heart syndrome". The syndrome was first  described in persons with heavy alcohol  consumption, who typically presented at  weekends or after holidays, but it may also occur    in patients who usually drink little or no alcohol.  Recently, similar reports indicated that  recreational use of marijuana may have similar  effects. Palpitations are the most common  symptom. These can be intermittent or  persistent, depending on the presence or absence  of sustained arrhythmia and the ventricular  response to atrial fibrillation. Patients with rapid  ventricular responses can present with near  syncopal symptoms, dyspnea on exertion, and  angina. The most common rhythm disorder is  atrial fibrillation, which usually converts to  normal sinus rhythm within 24 hours. Atrial  flutter, isolated ventricular premature beats,  isolated atrial premature beats, junctional  tachycardia, and various other rhythm distur-  bances may occur with less frequency. The  holiday heart syndrome should be considered  particularly as a diagnosis in patients without  overt heart disease presenting with new onset  atrial fibrillation. Though recurrences occur, the  clinical course is benign and specific antiarr-  hythmic therapy is usually not warranted.  Arrhythmia monitoring and observation are  adequate in many patients.   Pacemaker syndrome —First described in 1969 by  Mitsui et al as a collection of symptoms associated  with right ventricular pacing. In a general sense,  pacemaker syndrome can be defined as the  symptoms associated with atrioventricular  dyssynchrony. The symptoms of pacemaker  syndrome included dyspnea on exertion,  paroxysmal nocturnal dyspnea, orthopnea,  palpitations, hypotension, pre-syncope, and even  syncope. Heart failure signs include elevated neck  veins, rales, and pedal edema. Physical exam can  often reveal cannon A-waves. Additional  symptoms attributed to pacemaker syndrome  include easy fatigability, malaise, headache, and  the sensation of fullness and pulsations in the  head and neck. In the era of physiological dual  chamber pacing, the diagnosis is often forgotten.    but pacemaker syndrome may still occur. The  diagnosis of pacemaker syndrome requires a high  index of suspicion and the correlation of symptoms  or relative hypotension with periods of ventricular  pacing. The electrocardiogram should be  inspected carefully for loss of atrial capture,  particularly when anti-arrhythmic drugs which  increase the pacing threshold have been  prescribed. In addition, environmental sources of  electromagnetic interference, both within and  outside the hospital environment can result in  pacemaker malfunction and aggravating  symptoms of pacemaker syndrome.   Postural orthostatic tachycardia syndrome  (POTS) —It is an under recognized but persistent  autonomic disorder in young patients, usually  females aged 15 to 50 years, with a variety of  symptoms and variable outcome. Patients with  this condition exhibit orthostatic intolerance (OI)  and excessive tachycardia. Excessive tachycardia  with POTS has been defined as a rapid (within 10  minutes) increase in heart rate by more than 30  beats per minute or a heart rate that exceeds 120  beats per minute. Patients with POTS can  experience difficulty with daily routines such as  housework, shopping, eating, and attending work  or school. The possibility exists that all forms of  OI, including POTS, result from central  hypovolemia even without tachycardia. Adults  with POTS do not have hypotension, whereas  children may exhibit hypotension. Many patients  with POTS are intolerant of exercise. "Idiopathic"  POTS must be distinguished from other  conditions that can reduce venous return to the    heart and produce similar signs and symptoms  such as dehydration, anemia, or hyperthyroidism.    1. Zimetbaum P, et al. Evaluation of patients with  palpitation. NEJM 1998;338(19),1369-73.   2. Crawford MH, et al. ACC/ AHA Guidelines for  Ambulatory Electrophysiology. A report of the  American College of Cardiology/ American Heart  Association Task Force on Practice Guidelines. J  Am Coll Cardiol 1999;34(3):912-48. [PMID:  10483977], Website: http://content.onlinejacc.org/  cgi/content/short/34/3/912. (Accessed on 22-07-08)   3. Visit http://content.onlinejacc.org/cgi/content/full/  48/11/2360 for ACC/ AHA guidelines for the use of  EPS.   4. Olson JA, et al. Utility of mobile cardiac outpatient  telemetry for the diagnosis of palpitations,  presyncope, syncope, and the assessment of  therapy efficacy. J Cardiovasc Electrophysiol  2007;18(5):473-7. [PMID: 17343724: Abstract],   5. Cheitlin MD, et al. ACC/AHA Guidelines for the  Clinical Application of Echocardiography. A report  of the American College of Cardiology/ American  Heart Association Task Force on Practice Guide-  lines (Committee on Clinical Application of Echo-  cardiography). Developed in collaboration with the  American Society of Echocardiography. Circulation  1997;95(6):1686-744.[ PMID: 9118558], Web site:  "http://circ.ahajournals.Org/cgi/content/full/95/6/  1686. %20( Accessed on 22-07-08)   6. Summerton N, et al. New-onset palpitations in  general practice: Assessing the discriminant value  of items within the clinical history. Family Practice  2001;18;383-92.   7. Lessmeier TJ, et al. Unrecognized paroxysmal  supraventricular tachycardia. Potential for misdia-  gnosis as panic disorder. Arch Intern Med  1997;157(5):537-43. [PMID: 9066458: Abstract],   8. Masuki S, et al. Excessive heart rate response to  orthostatic stress in postural tachycardia syn-  drome is not caused by anxiety. I Appl Physiol  2007;102(3):896-903. [PMID: 17110507: Free full  text].   Polyuria is a highly subjective symptom, and  generally defined as the production of abnormally  large amount of urine, i.e. 3 liters or more in 24  hours in an adult.   Under normal physiological conditions urine  production is about 1-2 L per day. The chief  determinant of urine volume is the intake of fluids,  which in turn is influenced by individual's dietary  habits, temperature, mental state, physical activity,  general health, and medications.   It is important to differentiate true polyuria  from other similar urinary symptoms such as  urinary frequency, which is the need to urinate  many times during the day or night, but in  normal or less than normal volumes; and urinary  urgency, which implies a strong desire to void  urine with a sensation of impending micturition,  without a concomitant increase in the volume  of urine, e.g. in cystitis or benign prostatic  hypertrophy. Although polyuria may also  accompany nocturia, many individuals com-  plaining of the latter — sometimes called as  nocturnal polyuria syndrome — have no objective   *Polyuria is also defined as urine output > 50 ml/kg per  day.    evidence of increase in the total output of urine;  this phenomenon is attributed to multiple  factors, such as reversal of the normal diurnal  variation in urine flow, behavioral or environ-  mental factors, overactive bladder, and path-  ologic conditions, e.g. CHF, CRF, nephrotic  syndrome, anxiety, primary sleep disorders, and  sleep apnea. 1_J   Polyuria implies water or solute (i.e. osmotic)  diuresis, which can be differentiated by the  estimation of urine (and also serum) osmolarity. +   An average person excretes between 600 to  800 mOsm of solutes per day, primarily as urea  and electrolytes. Generally, increased urine  osmolarity (hyperosmolarity) is observed in  solute diuresis (i.e. rich in solutes), and  decreased values (hyposmolarity) in water  diuresis (i.e. poor in solutes). Table 34.1 classifies  polyuria and its differential diagnosis in terms  of solute verses water diuresis.   Though urine osmolarity can help distinguish  a solute (osmotic) from water diuresis, a urine  specific gravity (Usg) by urinometer also correlates   + The urine osmolarity is a measure of the concentration of  the urine and is primarily determined by the level of  antidiuretic hormone. Normal urine osmolality value  (random sample):100 - 1,200 mOsm/kg H,0.   1-A— Solute (osmotic) diuresis: (due to excessive filtration  of a poorly reabsorbed solute)   • Pituitary ablation, tumor, cyst, aneurysm, trauma,  meningitis, hemorrhage, thrombosis, metastasis,  Sheehan's syndrome.   • Acquired tubulointerstitial renal disease (e.g.  hypercalcemia, hypokalemia, analgesic nephropathy,  obstructive uropathy)    with urine osmolarity and gives important  information that reflects the concentrating ability  of the kidneys, provided there is no reason to  suspect increased excretion of larger solutes such  as glucose, urea, radiocontrast media, etc. A  random early morning Usg of 1020 (700 mOsm/kg)  or more in the absence of sugar or protein excludes  a serious concentrating defect. However, urine  osmolarity is a better measurement of renal  hydration status than Usg. 4 " 6   When the initial evaluation fails to establish  the cause of polyuria, a water deprivation test is  necessary. Further, a vasopressin test enables the  differentiation between cranial diabetes insipidus,  i.e. CDI, and nephrogenic diabetes insipidus, i.e.  NDI. (Table 34.2).   • Drugs (lithium, antibiotics: Demeclocycline;  antifungals: Amphotericin; antineoplastic;  and antivirals agents)   ^The ingestion of large quantities of beer, sometimes  referred to as beer potomania or binge beer drinking, can  produce polyuria with associated hyponatremia that may  be severe enough to produce CNS symptoms ranging from  confusion to seizures and stupor.    • CNS disorders (infections:meningitis,  cerebral malaria, 7 HIV; mass lesions; trauma;  postneurosurgery status).   • Genetic defects ( Wolfram syndrome, i.e. WS  or DIDMOAD syndrome: vide infra 44).   • Fasting, 2 hours post 75 g oral glucose, and  HbAlc. To confirm and monitor diabetes  mellitus.   • The total volume must exceed 3L in 24 hours  and helps to avoid errors attributable to  variations in circadian rhythm and also to  differentiate from urinary frequency   > On day 1, urinate into the toilet on getting  up in the morning.    > Afterwards, collect all urine in a special  container for the next 24 hours,   > On day 2, urinate into the container on  getting up in the morning,   > Cap the container. Keep in the refrigerator or  in a cool place during the collection period.   • Low levels of sodium suggest NDI or  compulsive water drinking.   • Contracted kidneys with loss of corticome-  dullary differentiation in CRF.   • Estimation of various urine components  permit calculation of the solute excretion rate  and thus lead to the cause of polyuria. These  tests may include: Volume, specific gravity,  osmolality, urea, creatinine, electrolytes,  calcium, glucose, ketones, and drug screen  for example, mannitol, and glycerol.    versions — in a well-hydrated patient, who is  likely to have one or the other. Steps include:   1. After an overnight solid food and water  (liquids) restriction , frequent (hourly)  body weight, and urine osmolarity are  measured, until 2-3 successive stable  values of urine osmolarity are obtained  or weight loss exceeds 3-5%. At this point  the test is completed (or terminated).  These values represent the patient's  maximum baseline osmolarity, and under  these conditions urine osmolarity should  be > 800 mOsm/kg. A value < 200 suggest  severe NDI or CDI; a value between 200-  800 may reflect partial NDI or CDI.   2. Desmopressin acetate, i.e. DDAVP  (l-deamino-8D-arginine vasopressin), is  given in an initial dose of 5-10 meg.  intranasally (or 1 meg subcutaneously or  intravenously). Two more hourly urine  osmolarities are recorded to determine  response to exogenous hormone:   • However, measuring osmolarity of plasma/  urine after water deprivation test does not  distinguish partial NDI from psychogenic  polydipsia.   • When results are ambiguous, the plasma  vasopressin assay is a useful adjunct in the  diagnosis of DI and psychogenic polyuria:    **In patients producing > 10 L of urine/day, water restriction  is only done during the day under close supervision and is  not done after midnight.    > High levels in NDI (partial or complete);  primary psychogenic polydipsia; ectopic  ADH syndrome; certain drugs, e.g.  chlorpropamide, phenothiazine.   • May be useful to locate parathyroid adenoma  in patients with hyperparathyroidism.   • May be indicated in patients with unexplained  polyuria, e.g. autoimmune disorders, acute  tubular necrosis, and to diagnose renal  dysfunction in transplanted kidney.   • The first differentiation that needs to be  clarified is that:' Is it truly polyuria or just  urinary frequency?   • History can sometimes distinguish true  polyuria (i.e. frequent passage of large  quantity of urine) from frequency of urination  (i.e. frequent passage of small amounts of  urine). If essential, a 24 hours urine collection  (see above) objectively confirms true polyuria  when volume is > 3 L. Associated symptoms  include polydipsia, urgency, frequency,  nocturia, and incontinence   • Massive polyuria (10-20 L/day) is usually due  to DI, diabetes mellitus, (especially Type 1),  or psychogenic polydipsia   • Mild polyuria would suggest mild diabetes  mellitus, chronic nephritis, renal tubular  acidosis, and hyperthyroidism   • A transient polyuria is sometimes noticed in  migraine, asthma, and supraventricular  tachycardia    Table 34.3: Classification of causes of diabetes insipidus on basis of water deprivation 8   POsm = Plasma osmolarity (mOsm/kg); UOsm = Urine osmolarity (mOsm/kg);*= At the end of water deprivation period,  prior to exogenous vasopressin, administration.    Abrupt onset of polyuria with craving for ice  water (due to stimulation of osmoreceptors in  the back of the throat) suggests CDI, e.g. due  to pituitary disorders. Nocturia is common  The next step, i.e. after confirming true  polyuria is: Is this water diuresis or solute  diuresis? Generally:   > Urine osmolarity between 250-350 mOsm/L  may be due to either water or solute  diuresis. This differentiation can be by  calculating total solute excretion on a 24  hr urine collection (see 24 hr urinalysis  above).   Further, water diuresis needs to be  differentiated from CDI and NDI. Patient's  history, investigations, and in selected cases  water restriction test/ desmopressin test help  to achieve this objective  History of head trauma; transsphenoidal  surgery; CNS disease (e.g. meningitis,  tuberculosis, CVA, multiple sclerosis, parkin-  sonism, pituitary-hypothalamic tumor,  metastatic deposits); psychiatric illness,  diabetes mellitus, renal disease (e.g. chronic  nephritis); malignancy (hypercalcemia);    endocrine and autoimmune disease is an  important lead to the diagnosis of CDI / NDI  Drug history— A significant number of drugs  precipitate polyuria by various mechanisms.  Over-vigorous diuretic therapy in edematous  states is a common cause of polyuria.  Anticholinergics produce dryness of mouth;  patients may therefore ingest excessive  quantity of water, causing polyuria.  Nephrotoxic drugs such as NSAIDs, ACE  inhibitors, aminoglycosides may precipitate  acute tubular necrosis, which can result in  severe polyuria in the recovery phase. Opiates  inhibit ADH secretion and may produce CDI,  whereas lithium and demeclocycline may  produce NDI   > Hydration status, i.e. body weight, pulse,  BP, mucous membrane, skin turgor, and  urine output.    > Genitourinary exam — for penile, scrotal,  testicular, prostate, and pelvic masses.   > The occurrence of dilute urine in the  presence of normal or increased  osmolarity, and   • Think beyond diabetes mellitus in patients  with polyuria with urine negative for  glucose, consider DI. Review history; refer  for more detailed investigations as indicated   • Unexplained polyuria in any patients with  hypercalcemia — investigate for multiple  endocrine neoplasia (Chapter 14, Page no. 95  "Dyspepsia". Review family histories in detail  endocrine tumors (thyroid, parathyroid,  pituitary) are often present in other family  members   • Beware of complications in patients with  psychogenic polydipsia. Though DI has not  been reported to result in renal failure,  psychogenic polydipsia may result in water  intoxication, leading to hyponatremic  encephalopathy with headache, weakness,  nausea, vomiting, diarrhoea, confusion,  seizures, coma, and even death.   Wolfram syndrome (WS) — It is a rare, autosomal  recessive, and neurodegenerative disease. The    syndrome is also known as DIDMOAD, the  acronym for diabetes insipidus, diabetes mellitus,  optic atrophy and deafness, which summarizes the  main clinical features in WS patients, although some  patients have additional clinical findings including  ataxia, hypogonadism, hydronephrosis and  psychiatric illnesses. The gene associated with the  syndrome, called WFS1, is located in the 4pl6.1  region. Patients present with diabetes mellitus  followed by optic atrophy in the first decade, cranial  diabetes insipidus and sensori-neural deafness in  the second decade, dilated renal outflow tracts early  in the third decade, and multiple neurological  abnormalities early in the fourth decade. Other  abnormalities include primary gonadal atrophy.  Death occurs premat-urely, often from respiratory  failure associated with brainstem atrophy. Most  patients eventually develop all complications of this  progressive, neurodegenerative disorder. Though  there is no treatment to reverse the underlying  mechanism of neurodegeneration, early diagnosis  and adequate hormonal replacement could improve  quality of life and survival. 9, 10    1. Natsume O. A clinical investigation of nocturnal  polyuria in patients with nocturia: A diurnal  variation in arginine vasopressin secretion and its  relevance to mean blood pressure. J Urol 2006;  176(2):660-4. [PMID: 16813917: Abstract],   2. Asplund R. The nocturnal polyuria syndrome  (NPS). Gen Pharmacol 1995;26(6):1203-9. [PMID:  7590108: Abstract].   3. Weiss JP, et al. New aspects of the classification of  nocturia. Curr Urol Rep 2008;9(5):362-7. [PMID:  18702919: Abstract],   4. Shirreffs SM. Markers of hydration status.Eur J Clin  Nutr 2003;57 Suppl 2:S6-9. [PMID: 14681707:  Abstract],   5. Voinescu GC, et al. The relationship between urine  osmolality and specific gravity. Am J Med Sci  2002;323(l):39-42. [PMID: 11814141: Abstract],   6. Chadha V, et al. Measurement of urinary  concentration: A critical appraisal of metho-  dologies. Pediatr Nephrol. 2001;16(4):374-82.  [PMID: 11354785: Abstract],    Schubert S, et al. Central diabetes insipidus in a  patient with malaria tropica. J Endocrinol Invest.  2006;29(3):265-6. [PMID: 16682843: Abstract],  Tzamaloukas AH, et al. Physiology of urinary  concentration and dilution and diabetes insipidus.  In: Mandal AK, Ed. T B of Nephrology for Asian-  Pacific Physicians.2nd edn. p.18, Jaypee; 2004.    9. Barrett TG, et al. Wolfram (DIDMOAD) syndrome.  J Med Genet 1997;34(10):838-41. [PMID: 9350817:  Free full text],   10. Viswanathan V, et al. Wolfram syndrome. J Assoc  Physicians India 2008;56:197-9. [PMID: 18697639:  Abstract],   Pruritus is defined as an unpleasant cutaneous  sensation that provokes the desire to scratch or  rub the skin to obtain relief. As a physiological  nociception, pruritus leads to the removal of  harmful agents such as insects, and irritant  substances such as dust and dirt from the skin  surface, and thus helps defend the skin against  harmful external agents.   Pruritus is the cardinal symptom of most  dermatologic disorders, and may be further  qualified as burning, tingling, or pricking by the  patient. In addition to the skin, it can occur on any  epithelial surface, such as the conjunctiva (e.g.  allergic conjunctivitis); oropharynx (due to food  allergy, or oral allergic syndrome: 1 vide infra 4 - 4 -);  and anogenital region (sea below). It may be  localized, generalized, paroxysmal, or unremitting.  It may be associated with a primary dermatological  disorder, or manifest as a symptom of an internal  systemic process.   Based on advances in the understanding of  the peripheral and central origin, itch is classified   “■Some authors use the term itch if there are skin lesions  expressed, and pruritus if there are no primary skin  alterations, known as "pruritus sine materia"; however, its  common practice to use these two terms — pruritus and  itch — as synonyms.    into four categories: cutaneous itch ( pruritoceptive ,  e.g. scabies, urticaria, insect bite, dermatitis);  neuropathic itch (e.g. postherpetic neuropathy,  multiple sclerosis); neurogenic itch (e.g.  cholestasis, uremia); or psychogenic (e.g.  delusional state of parasitophobia ). 2   Most pruritic disorders can be diagnosed  with high degree of accuracy based on history,  physical features of dermatosis, and appropriate  investigation. However, a minority of patients  presenting with itching per se, without any rash,  or with scanty clinical findings can pose a  particularly challenging diagnostic and  therapeutic dilemma, besides significantly  affecting their quality of life.   + The terms atopic dermatitis and atopic eczema have been used  synonymously; however, dermatitis denotes inflammation  of the skin, and eczema, besides itching, shows ill-defined  areas of redness, scaling, crusting, and lichenification.  Dermatosis is defined as any disease of the skin in which  inflammation is not necessarily a feature.   • Food allergy (peanuts; eggs; food additives,  preservatives, and flavoring agents)   • Infections (folliculitis; dermatophytosis, e.g.  tinea corporis, tinea cruris, tinea pedis)   • Intestinal parasites/helminthic infections  (hookworm, giardia, strongyloidiasis,  trichinosis, cutaneous larva migrans)   • Psychogenic (anxiety, depression, psychosis,  delusion of parasitosis: vide infra ii,  dermatitis artefacta).   • In PVR: RBC count increased (often 7 to 10  million/cu mm), hematocrit above normal (at  times >60%), increased Hb, WBC and platelet  counts also invariably elevated   • May reveal proteinuria, hematuria, and  granular or red blood casts in patients with  renal disease.   • Ova and/or cysts of helminthic or protozoan  disease may be found   • Stool for occult blood in patients aged 40  years or older. A positive result suggests  possible malignancy in the GI tract.   • The mite, ova, and feces may be identified  under light microscope in Scabies infestation.   • Elevated with hyperparathyroidism secondary  to renal disease, paraneoplastic syndromes,  malignancies, and Paget disease.   • Elevated conjugated serum bilirubin, alkaline  phosphatase, AST, ALT, and PT with hepatic  cholestasis, cirrhosis, and viral hepatitis.   • Low TSH and high T4 with hyperthy-  roidism; high TSH with low T4 with  hypothyroidism.   • May reveal hilar lymphadenopathy, or a mass  lesion in patients with Hodgkin's disease, or  bronchogenic carcinoma.   • Decreased values confirm IDA; low serum  ferritin levels in elderly patients with  chronic pruritus may assist in diagnosing  malignancy.   • To rule out HBV (HBsAg), HCV (anti-HCV),  and HIV infection in patients with risk  factors.   • Increased levels of urinary 5-HIAA may be  detected in patients with liver metastasis, or  carcinoid syndrome.   • Dilated bile ducts indicate biliary obstruction;  the site and cause of obstruction may be  visualized. Decreased renal size in chronic  renal disease and in patients suspected with  polycystic kidney disease, multiple cysts may  be visualized. US of the neck provides  information regarding enlarged parathyroid  glands, thyroid nodules, and lymph nodes.   • HRCT of the chest (when abnormal findings  are noted on CXR examination) to confirm  hilar lymphadenopathy or mass lesion in  patients with Hodgkin's disease, or bron-  chogenic carcinoma respectively. HRCT of the  abdomen and pelvis to visualize the mesenteric,  hepatic, portal, and splenic hilar lymph nodes  in patients with Hodgkin's disease and non-  Hodgkin's lymphoma.   • Should be performed in patients suspected with  primary sclerosing cholangitis, choledocholi-  thiasis, or obstructive malignancy.   • May be indicated to establish the presence  of myelofibrosis (e.g. PVR, chronic myeloid  leukemia).   • May be needed to confirm primary derma-  tologic conditions such as dermatitis herpe-  tiformis, mycosis fungoides, Paget's disease of  the nipple, and bullous pemphigoid; or to  confirm a systemic cause such as mast-ocytosis.   • Positive patch test may support offending  cause for allergic contact dermatitis.   • Age appropriate cancer screening such as  PSA, alfa fetoprotein may be indicated in few  patients with obscure cause.   • History suggests whether pruritus is primary  (i.e. dermatological), or secondary (i.e.  systemic), and often provides clues to its cause.  Common questions include the following:*   > Location, duration, and timing of sym-  ptoms of pruritus, e.g. day, night,  seasonal, at work, or at home.   structured questionnaire such as 'Eppendorf itch  questionnaire' is found to be a valuable tool for evaluating  chronic idiopathic pruritus and its unique features (Ref.  PMID: 12100181).    worsening in winter suggest xerosis;  itching worse in the evening may be  associated with scabies; itching awakening  the patient at night may represent  systemic disease; bath itch, i.e. itching that  typically occurs during cooling after a hot  shower may precede the development of  PVR by several years.   > Drugs (erythromycin, INH, anabolic  steroids, oral contraceptives), including  recreational drugs (opioids, alcohol) —  current and/or recent past.   > OTC products the patient uses on his / her  skin, or scalp.   > History of any systemic illness (bronchial  asthma; thyroid, hepatic, or renal disorder;  erythropoietic porphyria, HIV).   > History of previous skin disease (e.g.  vitiligo, ichthyosis) or atopy.   • The diagnosis of most pruritic disorders is  possible on the basis of pattern distribution,  i.e. basic morphology, shape, size, color, and  predilection to specific sites of the skin.  Tables 35.1 and 35.2 illustrate common causes  of localized and generalizes pruritus   • In addition to the skin, examination of other  organ systems for organomegaly, lympha-  denopathy, goiter, pregnancy, and signs of  anemia, arthritis, or psychiatric disorders is  important   • Pruritus associated with generalized rash is  common with urticaria, atopic dermatitis.   - Anorectal disease (hemorrhoids, fissure, fistula,  rectal prolapse, polyps, warts, malignancy)   - Valval disease (atrophic vulvovaginitis; VIN, i.e.  vulva intraepithelial neoplasia; malignancy)   - Intrahepatic cholestatic pruritus (e.g. viral  hepatitis, drug-induced cholestasis, carcinoma of  liver, biliary cirrhosis)   - Extrahepatic cholestatic pruritus (e.g. common  bile-duct calculus, stricture, carcinoma of pancreas)    scabies, and pemphigus. Presence of hepato-  megaly or jaundice is indicative of obstructive  jaundice, hepatitis, malignancy of liver, or  biliary cirrhosis. Symptoms of polyuria,  polyphagia, and polydipsia would suggest    diabetes mellitus, hyperthyroidism, and  pregnancy. Fine stippling (pitting) of the nails  is highly suggestive of psoriasis   • Of all the malignancies known to induce  pruritus, Hodgkin's disease is the most  common   • Carcinoma of any organ may produce  itching, but this is most frequently associated  with involvement of the stomach, liver, and  pancreas   • Pruritus of the nostrils is characteristic of  fourth-ventricle tumors of the brain; it can  be extremely severe and is a sign of an  advanced tumor   • Patients with Parkinson's disease, patients  who become acutely ill and are hospitalized,  and patients with HIV infection often have  seborrheic dermatitis   • Uremic pruritus is most often seen in patients  receiving hemodialysis. However, the  condition is not due to elevated serum urea  levels. Pruritus is relatively absent in persons  with acute renal failure   • Dermatitis herpetiformis is usually  associated with celiac disease (i.e. gluten  sensitive enteropathy, which commonly  presents with gastrointestinal symptoms  including chronic diarrhea, weight loss,  abdominal bloating and anorexia, and  deficiency related signs to malabsorption  of iron, folic acid, vitamin E> 19 and vitamin  D, such as osteoporosis)   • While dealing with dermatological diseases  suspected due to psychiatric disorder,  physicians should be aware that the skin  lesions are often an appeal for help; direct  confrontation should be avoided if possible,  and instead, a supportive environment and a  stable physician-patient relationship should   A sign on the back of the patient, i.e.  upper mid-back area between the  scapula, of relative hypopigmentation  or normal skin in combination with  areas of postinflammatory  hyperpigmentation in surrounding  locations accessible to the patient's  hands. As most patients cannot reach  the upper mid-back area between  the scapulas, an examination of this  area can help ascertain if a skin disease  is present, because any lesions found  in that area are unlikely to have been  caused by scratching. Conversely, if the  skin there is clear but the surrounding  area is damaged, this is a strong  indicator of an organic or psychological  disorder.   Yellowish brown or brown black  macules or plaques which tend to  become red, itchy, and urticate easily  if they are rubbed, e.g. urticaria  pigmentosa (cutaneous  mastocytosis).   Light pressure or rubbing causing  widespread weal-and-flare reactions  with itching and burning; e.g.  atopy, thyroid diseases, diabetes,  menopause, infectious, systemic or  malignant diseases, scabies,  drug reaction, and psychic disorders.  Development of new plaques in  response to external trauma, e.g.  psoriasis, lichen planus, bullous  pemphigoides, sarcoidosis, Kaposi's  sarcoma.   An abrupt appearance of multiple  seborrhoic keratoses (also known as  seborrheic warts, keratosis  pigmentosa, and verruca senilis) that  rapidly increase in their size  and number. Pruritus may be the only  symptom of the sign of Leser-Trelat.  This sign is linked to a variety of  cancers but is it's rare, even among  patients with cancer.   Pressure applied in a sliding motion  to the lateral aspect of the blister leads  to extension of the blister and or  removal of the epidermis in the area   immediately surrounding the blister.  In pemphigus vulgaris this sign is  positive, whereas in bullous  pemphigoides it is absent.   polygonal, well-demarcated papules  of variable size, marked by criss-cross  whitish streaks, e.g. lichen planus.   be fostered, often initially through short  frequent office visits. 4, 3 Once the patient  establishes trust in the physician by means of  a stable relationship, the physician can help  recognise the psychological impact of the  disorder and recommend consultation with a  psychiatrist.   • Itching in elderly individuals, especially  persistent and generalized itching, should be  screened for an underlying systemic disease  (see table above), including malignancy.   • The incidence of non-Hodgkin's lymphoma  is significantly increased in patients with  dermatitis herpetiformis. 6   • If lesions of atopic eczema involve the nipple,  which may be either retracted or obliterated,  Paget's disease must be excluded by biopsy.  Unilateral eczema may be the only indication  of a ductal adenocarcinoma.   • Psychopathologic dermatological disorders  such as delusion of parasitosis, psychosis; as  well as due to systemic disease such as HIV,  uremic pruritus, carcinoid syndrome can be  severe enough to cause the patient to commit  suicide. 7   first time used this name for pollen-food cross-  reactive reactions. Since then many kinds of    reactions between pollens and different food  have been described. The OAS is an adverse  reaction to the ingestion of certain "trigger"  foods (fresh, raw fruits or vegetables), and is  especially prevalent in atopic individuals such  as in people with asthma or hay fever. Most  patients give a history of oral symptoms like oral  irritation, throat tightness, lips, oral and throat  swelling, oral mucosal blebs. These local  symptoms quickly disappear and are not  particularly serious, but they may proceed to  urticaria, asthma, abdominal pain. Severe  forms of OAS may resemble or precede food-  induced anaphylaxis (which suggested the  term 'oral allergy syndrome'). Thus, detection  and recognition of OAS is important. OAS  diagnosis is based on the patient's history and  RAST. Treatment of OAS includes food  avoidance, drugs and specific immunotherapy.  Patients with pollen allergy should be informed  about the possibility of hypersensitivity to  certain fruits and vegetables.   Delusion of Parasitosis— It is a rare psychiatric  disorder in which the patient has a fixed, false  belief that he or she is infested by bugs, mites,  worms, parasites or other living creatures. Even  though it is a psychiatric disorder, these patients  usually present to a dermatologist because they  are convinced that they have a dermatological  problem. Patients with delusions of parasitosis  generally reject psychiatric referral. The  diagnosis of delusions of parasitosis can often  be made on the basis of the history alone;  however, these beliefs may be brought about by  drug use, or abuse, CVD, neurosyphilis,  schizophrenia, psychotic depression, hypoc-  hondriasis, or an obsessional fear that parasites  are present in the body. Therefore, it is important  to make sure that the patient does not have an  organic skin disorder, and the delusion is not  secondary to another mental or physical illness.    1. Amlot PL, et al. Oral allergy syndrome (OAS):  Symptoms of IgE-mediated hypersensitivity to  foods; Clin. Allergy. 1987;17(l):33-42. [PMID:  3829369: Abstract],   2. Twycross R, et al. Itch: scratching more than the  surface. QJM 2003;96(l):7-26. [PMID: 12509645:  Free full text],   3. Kimyai-Asadi A, et al. Poststroke pruritus;  Stroke, 1999;30(3):692-3 [PMID: 10066875: Free  full text],    5. Schneider G, et al. Psychosomatic cofactors and  psychiatric comorbidity in patients with chronic  itch. Clin Exp Dermatol 2006;31(6):762-7. [PMID:  17040260: Abstract],   6. Collin P, et al. Malignancy and survival in  dermatitis herpetiformis: a comparison with coeliac  disease. Gut. 1996;38(4):528-30. [PMID: 8707082:  Free full text],   7. Bellmann R, et al. Treatment of intractable pruritus  in drug induced cholestasis with albumin dialysis:  A report of two cases; ASAIO J. 2004;50(4):387-91.  [PMID: 15307554: Abstract],   8. Doroszewaka G, et al. Oral allergy syndrome —  problem; Otolaryngol Pol 2006;60(6):917-22.  [PMID: 17357673: Abstract],   The common term red eye, which is due to  hyperemia or engorgement of the superficial  visible conjunctival, episcleral, or ciliary vessels,  is applied to a variety of distinct infections and  inflammatory disease processes that involve one  or more tissue layers of the eye, i.e. eyelids,  conjunctiva, cornea, sclera, and uveal tract.   Most cases are due to benign or self-limiting  conditions; however, several signs and symptoms  may herald a serious ocular disorder, and a few are  vision-threatening, and can lead to permanent vision  loss, e.g. corneal ulceration and acute glaucoma.  "The emergency physician must be adept at  recognizing red flags from the history and physical  examination that necessitate immediate treatment  and referral. In addition, it is imperative for the  emergency physician to recognize the need for  immediate versus elective ophthalmologist  consultation for the various conditions." 1   • Conjunctivitis (viral, bacterial, allergic, and  Keyboard conjunctivitis): vide infra (ii ). 2-4   • Orbital cellulitis (due to paranasal sinusitis,  infected tooth ) 5   • Subconjunctival hemorrhage (blood dysc-  rasias; systemic febrile disease: Measles,  falciparum malaria, leptospirosis)    “■The most commonly associated serotypes include  adenovirus 8, 19, and 37.   + Corneal abrasions, i.e. superficial or partial trauma to  corneal epithelium; often caused by fingernails, makeup  applicators, dust, and vegetative matter.   • Keratoconjunctivitis sicca (old age; Serone-  gative spondyloarthropathies; Sjogren's  syndrome; medications — anticholinergics,  antihistamines, antidepressants)   • Orbital vascular tumors (cavernous hem-  angiomas, carotid-cavernous sinus fistula,  meningiomas, arteriovenous malformation).   • Elevated significantly in inflammatory and  autoimmune disorders, e.g. scleritis, uveitis.   • To detect diabetes and to monitor blood glucose,  especially in nonhealing comeal ulcers.   • May show predominant polymorphs and  bacteria in bacterial conjunctivitis; lympho-  cytes in viral conjunctivitis; and eosinophils  in allergic conjunctivitis.   • Especially in comeal disease and in cases that  are resistant to therapy.   • Red eye per se does not warrant US; but in  patients suspected with retinal detachment.    vitreous hemorrhage, intraocular foreign  bodies, orbital tumors and trauma, high  resolution ultrasound examination is found  to be a safe, noninvasive, inexpensive,  atraumatic and accurate means of evaluating  the eye. 6   • In orbital trauma, to rule out fracture of  orbital bones; or associated with intracere-  bral, or subarachnoid hemorrhage.   • If iritis/uveitis is suspected — to find the  underlying cause, e.g. HLA-B 27 typing for  ankylosing spondylitis.   • VDRL, fluorescent treponemal antibody  absorption (FTA-ABS) test in cases with  scleritis, and posterior uveitis.   > Onset — Conjunctivitis generally has rapid  onset (within hours), while a small FB will  produce a sudden hyperemia within  minutes. Abrupt onset with copious  purulent discharge in a sexually active  patient is typical of hyperacute bacterial  conjunctivitis, which is most often  associated with N. gonorrhoeae.   > Pain and photophobia — A patient with  conjunctivitis may complain of mild  irritation and has normal light sensitivity.  Their presence indicates serious under-   > Discharge — Patients will often complain that  their lids are stuck together in the morning  when they wake up. It is typically due to  matting of eyelashes on the discharge, and  does not occur in iridocyclitis or glaucoma.  A corneal ulcer may also be accompanied  by exudation. The type of ocular  discharge may be helpful to determine the  cause of conjunctival inflammation; e.g.  profuse purulent discharge is typical of  N. gonorrhoeae infection; a mucopurulent  or purulent discharge suggests a bacterial  infection; a serous, ropy (i.e. sticky  thread-like) discharge is most commonly  associated with viral or allergic ocular  conditions.   > Unilateral or bilateral — Conjunctivitis,  though initially present in one eye, the  second eye becomes involved a few days  later. However, chronic unilateral or  bilateral conjunctivitis (or red eye) may  be due to meibomianitis or less common  entities, e.g. occult FB, keratitis, nasol-  acrimal duct obstruction, or conjunctival  neoplasm.   > Visual changes — Do not rely on patient's  subjective assessment of blurring of  vision. Blurred vision (BV) often indicates  serious ocular disease, e.g. AACG. BV that  improves with blinking suggests a  discharge or mucus on the ocular surface;  otherwise, it's prudent to check the visual  acuity (VA) using Snellen's chart and pin  hole card.   > Colored halos — Rainbow as fringes or  colored halos seen around the point of  light are a danger symptom suggesting  AACG as a cause of the red eye.    > Ocular trauma— Any conjunctival and  corneal abrasion, contusion, and FB are  important causes of red eye.   > Contact lens use — They are prone to cause  infection or the contact lens-induced acute  red eye (CLARE: vide infra 4 - 4 -) or overwear  syndrome.   • Sexual history and history of urethral  discharge— It must be elicited in suspected  gonococcal infection; it is important to ask  about sexual contacts as this is a highly  contagious infection. Prompt investigation  must be ensured, which if left unnoticed,  could subject the patients to a great deal of  anxiety and distress   • Associated systemic problems may be  helpful to determine the possible cause; e.g.  recent URTI or history of atopy (viral  conjunctivitis); diabetes/hypertension  (subconjunctival hemorrhage, glaucoma);  thyrotoxicosis, rheumatoid arthritis and  other autoimmune diseases (keratocon-  junctivitis sicca, scleritis)   • Topical medications, i.e. conjunctivitis  medicamentosa, due to antiglaucoma drugs,  gentamicin, topical vasoconstrictors (rebound  hyperemia), topical drugs with preservatives,  artificial tears; and systemic drugs, e.g.  antiplatelet/ anti thrombotic agents, etc. can  cause red eye   > Visual acuity— VA must be recorded with  every patient with an eye involvement. It  is usually normal in conjunctivitis unless  cornea is involved and in AACG, and  uveitis.   > Pupillary abnormalities and corneal  opacities are explained in Table 36.1.    > IOP (tonometry) — Elevated in acute  glaucoma (normal IOP- 10-21 mm Hg).   > Fluorescein dye test — Every patient with  conjunctivitis should have fluorescein  staining in each eye to ensure that a  corneal aberration, ulcer, or herpetic  dendrites is not missed.   > Direct ophthalmoscopy —When performed  from a distance of 15 cm, can detect  opacities in the cornea, lens, and vitreous.  The fundus and optic disc, looking for  increase in the cup-disc ratio, which may  signify presence of acute glaucoma, can  also be evaluated.   • Periauricular lymph nodes may be palpable  in viral, chlamydial conjunctivitis, and acute  gonoccocal infection.   • All patients with severe eye pain (suggesting  increased IOP), photophobia, and corneal  haziness require immediate ophthalmic  referral.   • In a patient with acute onset, unilateral  headache, vomiting, acutely painful eye, or    persisting red eye, consider other causes such  as AACG, occult FB, trauma, and neoplasm.   • Recurrent subconjunctival hemorrhage with  no known cause, a work-up for hematologic  disorder is indicated.   • A gritty sensation is common in conjuncti-  vitis, but the presence of FB must be  excluded.   • FTyperacute bacterial conjunctivitis needs  emergent referral to prevent corneal  involvement, including perforation and  visual loss, which could also be due to  therapeutic misadventure with topical  steroid usage. Therefore, it's prudent to  refrain from treating any patients with  steroids without consultation.   • Beware of allergy or toxicity to topical  medications, i.e. iatrogenic, (including  cosmetics) as a cause of persisting symptoms.   • Never use mydriatics when examining red  eye — acute glaucoma may be precipitated;  they also act as temporary decongestants, and  mask hyperemia.   • Syphilis — It being a multisystem, multi-  symptom disorder is a great mimic. Therefore,  it is important to always keep this condition  in mind when encountering patients with    anterior uveitis, chorioretinitis, retinal  vascular occlusion, and chronic anterior  segment inflammation . 1 2 3 4 5 6 7 Further manifest-  ations of syphilis can be complicated by  concurrent HIV infection; hence, always  consider HIV infection, e.g. CMV retinitis and  Kaposi's sarcoma in patients with syphilis.   Contact lenses offer a unique and viable mode  of visual correction and are also of therapeutic  value in a range of ocular disorders. However,  several reports in the literature have clearly  shown that contact lens wear is not totally  compatible with ocular physiology, and is  associated with various complications. Evidence  also suggests that an increased number of these  complications are seen with hydrogel lenses  used on an over-extended contact lens wearing  time or improperly used contact lenses in a  closed eye environment (during sleep). Some of  these conditions include inflammatory responses  such as Contact Lens Induced Acute Red Eye  (CLARE), and Culture Negative peripheral  Ulcers (CNPU), and sight threatening responses  such as infectious keratitis. While the etiology  of a CLARE response is not clearly understood,  it is seen that the condition is distinct and  typically presents with the patient waking in the  early hours with discomfort and pain in the  involved eye. Other symptoms include an  intolerance to lens wear associated with redness,  lid swelling and mild to moderate amount of  photophobia. Clinical signs include severe  bulbar and limbal injection, and the presence of  diffuse subepithelial to anterior stromal  infiltration in the periphery of the cornea. Most  often the presentation is unilateral and epithelial  involvement is usually minimal. Further, patient  who has endured an episode is susceptible to    repeat occurrences. Patient who have had a  CLARE should be educated and fitted with daily  wear lenses.   Keyboard conjunctivitis — An inconspicuous  way of spread of conjunctivitis— by the use of  keyboards of shared computers, at places like a  library, internet cafe, classrooms, etc. Shared  keyboards and mouse are usually the culprits.  Transmission of conjunctivitis is nearly certain,  if a patient with conjunctivitis/ carrier used the  same keyboard earlier. Other examples of  conjunctivitis (i.e. red eye) due to fomite  transmission include objects such as mobile  phones, land phones, TV remote tools, fridge or  door handles, contaminated vehicles, shovels,  clothing, bowls/buckets, brushes, tack, and  clippers. Symptoms of conjunctivitis usually  start within a day or two.    1. Mahmood AR, et al. Diagnosis and management  of the acute red eye. Emergency medicine clinics  of North America 2008;26(l):35-55.   2. Bal SK, et al. 10-minute consultation. Red eye.  BMJ 2005;331:438 (20 August), doi:10.1136/  bmj.331. 7514.438.   3. Chauhan R. "Keyboard Conjunctivitis". Annals  Internal Medicine 7 April 2006. http://  www. annals. org/cgi/eletters?lookup=by_  date&days=7#2899.   4. Feingold EK. The outbreak of conjunctivitis at  Dartmouth. N Engl J Med 2003;348(25):2577-8.  [PMID: 12815147],   5. Youssef OH, et al. Odontogenic orbital cellulitis.  Ophthal Plast Reconstr Surg. 2008;24(l):29-35.  [PMID: 18209637],   6. Hossain GA, et al. High resolution ultrasound of  ophthalmic patients in a tertiary hospital. Mymen-  singh Med J 2007;16(l):50-6. [PMID: 17344780:  Abstract],   7. Wuepper KD. "Red eye" as the presenting sign of  syphilis d'emblee. Calif Med 1967;107(6):518-20.  [PMID: 6078899],   8. Sankaridurg PR, et al. Gram-negative bacteria and  contact lens induced acute red eye. Indian J  Ophthalmol [serial online] 1996 [cited 2008 Sep 23];  44:29-32. Available from: http://www.ijo.in/  text.asp?1996/44/l/29/24602.   Sexual dysfunction , in either sex, is often the result  of a complicated interaction of biological,  psychological, and interpersonal difficulties  between sexual partners, and may be defined as a  consistent long-term inability to respond in a way  that characterize the normal sexual response cycle.   The normal sexual response cycle, as classified  by DSM-IV-TR system, comprises four phases:   4. Resolution— General relaxation and well  being; the anatomic structures involved in  sexual response return to a baseline state.  The DSM-IV-TR system specifies three criteria   which are essential during the process of  evaluation for sexual dysfunction. They are:    * Sexual dysfunction due to gender identity, homosexuality,  and paraphilias is not discussed.    3. Cannot be accounted by another Axis I (i.e.  clinical syndrome) disorder or substance  effect.   Based on these criteria, the common sexual  dysfunctions as classified by DSM-IV-TR may  be grouped as follows (Table 37.1):   - Retrograde ejaculation ( vide infra 44).  In women:- Frigidity (i.e. female sexual   Sexual dysfunction can be primary (meaning  lifelong or never normal before), secondary  (meaning acquired with normal function  before), selective (such as only with a particular    partner), generalized (due to complex, deep rooted  causes), or due to combined factors.   Since sexual dysfunction is quite common,  but not obvious, it is essential that physicians  assume a proactive role. Every effort should be  made to differentiate between psychogenic/  functional and organic sexual dysfunction,  assessed via standard questionnaires such as  the International Index of Erectile Function and  Female Sexual Function Index (see below). In an  obvious psychogenic case, expensive and time-  consuming investigations should be avoided.  However, if an organic cause is suspected to be  the basis of sexual dysfunction, every effort  should be made to discern that organic cause as  early as possible, and refer to the appropriate  specialist for further investigations and  management.   > Psychosexual problems (sexual perfor-  mance anxiety, prior sexual failure,  negative learning and attitude about sex)   > Psychosocial: Ignorance, poor relationship, poor  sexual drive, performance anxiety, prior sexual  failure, negative attitude   > Phimosis, hydrocele, episiotomy scarring, prostatectomy,  mastectomy (poor body image), oophorectomy,  colostomy, amputation   > Prescribed: Antihypertensives, antidepressants,  antipsychotics, mood regulators, antihistamines,  hypnotics, sedatives, hormones, anabolic steroids,  corticosteroids   • Sexual enactment factors (lack of penile/  vaginal stimulation, lubrication; unfavorable  sexual positions)   • Diabetes mellitus is a common cause of ED.  Present evidence supports ED as a significant  marker for diabetes, particularly in younger  patients. Men 45 years old or younger with  ED were more than twice as likely to have  diabetes mellitus as men without ED, and men  with ED 46 to 65 years old were likely to have  diabetes. Thus, markers of ED may represent  an early warning for the development of  diabetes, which is particularly important  considering many diabetic patients remain  undiagnosed for several years. Therefore,  fasting, two hour postprandial blood  glucose, and HbAlc estimation should be  obtained. 1 " 3   • Hyperlipidemia, along with hypertension and  diabetes mellitus, is a risk factor for metabolic  syndrome which often coexists with ED;  therefore its estimation is important. 4,5   • Elevated TSH with diminished FT4 values in  primary hypothyroidism, and subnormal/  undetected TSH levels with elevated T3 or T4  or both in thyrotoxicosis   • TFTs are also useful to discover subclinical  hyperthyroidism (T3, T4 normal, TSH und-  etected); and subclinical hypothy-roidism  (T4 normal, TSH raised) which may be  responsible for sexual dysfunction.   • Low levels in patients with diminished  libido, or any signs of diminished secondary  sexual characteristics, i.e. mild or otherwise  asymptomatic androgen deficiency, or  hypogonadism.   • If serum testosterone levels are low, serum  PRL should be measured.   High (>20 ng/ml) levels — either due to  hypothalamic-pituitary lesion (suppressing  GnRH) or drug induced— are observed in  patients with low libido, in women with  little or no history of menstruation, and  gynecomastia.   • Serum LH and FSH estimation helps to  differentiate the etiology of sexual dysfunction.    either due to testicular (Ley dig cell) failure or  hypothalamic-pituitary lesion.   > If LH and FSH are normal or low, and PRL  is also normal, then the diagnosis is  hypothalamic-pituitary lesion.   > If LH and FSH are high, and PRL is  normal, then the diagnosis is testicular  (Leydig cell) failure.   > If LH and FSH are low, but PRL is high,  pituitary adenoma needs to be ruled out.   • Penile erections during REM sleep support  psychogenic etiology, and eliminate signifi-  cant neurologic, vascular, or endocrine  causes of ED.   • To evaluate vascular function within the  penis, i.e. in the cavernous arteries, before  and after injection of a vasodilator such as  prostaglandin El, e.g. in Peyronie's disease.  Duplex US can also evaluate blood flow  velocities to the clitoris, labia, urethra, and  vagina.   • To detect sensory neuropathy in pudendal  nerve pathway, and in evaluating the  autonomic innervation of the clitoris due to  diabetes mellitus and alcoholism.   • In young men with arterial insufficiency as  the cause for their ED, and who are candidates  for reconstructive surgery.   • To assess testicle/epididymis size, enlarge-  ment, growth, congenital abnormality, and  adnexal, uterine lesions.   • As indicated in patients with pituitary adenoma  (hyperprolactinemia with normal LH, FSH).   • Detection of sexual dysfunction in a patient  or a couple depends upon asking appropriate  questions because many are reluctant to  initiate discussion of their sex lives. Further,  what is regarded as normal sexual function,  and therefore, what is thought to be impaired  or unsatisfactory sexual performance  depends in part on the expectations of the  couple concerned. For example, one couple  may regard it as normal that the woman is  regularly unable to achieve orgasm, whilst  another may seek treatment. It is also a fact  that many physicians have their own  inhibitions in taking detailed sexual history  from the patient. Some of the potential  barriers cited for reluctance to address sexual  health issues include: embarrassment, feeling  ill-equipped or inadequate training to elicit  sexual history, belief that sexual history is  not relevant to the chief complaint, and time  constraints . 6,7 Thus both patients and  physicians need to curtail their inhibitions,  and begin to take the first steps toward better  sexual communication   • Patients prefer to communicate their  symptoms related to sexual dysfunction in  the privacy of verbal communication with  their physician. A respectful, open-minded,  and relaxed approach is essential. Questions  should be asked in a matter-of-fact, yet    sensitive manner, avoiding jargon. A simple  way to do this is by simply asking, "how  are things going for you sexually?", or, "how  is your sex life? Is everything all right?"; this  type of inquiry should elicit a clear, quick,  and direct response such as "everything is  fine." Any other answer may suggest  potential sexual dysfunction in him or her  which should be followed up (with consent)  with specific questions to identify problems  associated with various phases of sexual  response cycle (see above). If the patient is  part of the couple, the couple should be  interviewed together   • It is not unusual for some patient to be  unaware of an association between their  medical problem and underlying sexual  dysfunction. For example, patients with  obesity, tension headache, chronic backache,  vaginal discharge, pelvic pain, etc. This is an  opportunity for the physician to recognize  such an association and tactfully include  inquiry about sexual dysfunction   • A two way approach may be adopted in  obtaining sexual dysfunction history: The  screening method and the in-depth approach.  If the sexual history seems unrelated to the  chief complaint, a few screening questions  will suffice. Questionnaires have been  developed to collect data regarding ED  (International Index of Erectile Function —  IIEF + and female sexual dysfunction (Female  Sexual Function Index— FSFI*) to assess the  severity and impact of therapy in such  patients which may be useful to understand  the nature and scope of the patient's  problem. If the complaints have direct  bearing to the chief complaints, a more    + Web site: <http://www.urologyspecialists.net/print/  iief.html >Accessed on 16-11-08  ^web site:<http://www.fsfiquestionnaire.com/FSFI%20  questionnaire2000.pdf >Accessed on 16-11-08   Loss of NPT— At the very beginning a  carefully taken sexual history helps to rule  out organic causes of sexual dysfunction,  especially treatable ones. An alerting sign is  a loss of male morning erection, i.e. loss of  NPT during REM sleep. A history of erection  that occurs noctumally, during masturbation,  or during foreplay, or with other sexual  partners eliminates significantly neurologic,  vascular, or endocrine cause of ED. For women  there can be a similar loss of nocturnal vaginal  lubrication   Hidden agenda — Although some patients  may present directly with a complaint of  sexual dysfunction, many will present with  unexpected add-on problem at the end of  consultation as hidden agenda or exit problem  or parting shot. The exit problem or parting shot  is usually the patient's main reason for  consultation. Examples wherein such situation  is commonly encountered are:   > Infertility, menopause, andropause.  Despite a seemingly indirect or 'by-the-way'  nature of such encounters, the issue must be  recognized and treated with considerable  importance   History — Includes age, mode of onset,  duration, libido (i.e. sex drive), situational  context, foreplay, fantasies, frequency,  erection, orgasm, ejaculation (normal,  premature, delayed, or absent), and pain felt  during intercourse    • Sexual history — Includes early experiences  (sexual abuse), sexual knowledge, attitude  towards sexuality, past sexual practices, current  sexual relationship, self-pleasuring practices and  fantasies, homosexual experiences, personal  body image, and any past negative sexual  experiences such as sexual assault, incest   • Stress — Current stress factors such as  interfamily problems with children, elders,  death, and extrafamilial factors such as stress  from occupation, legal, and financial matters  create problems in the sexual relationship   • Habits — Such as nicotine use, alcohol intake,  and illicit drug use should be documented   • Medication history — Important in all indivi-  duals with sexual dysfunction. The onset,  frequency, and duration of the sexual side  effects of drugs are variable, which can be  confirmed by 'drug holiday'   • Mental state examination— May be indicated  to exclude psychiatric disorders and to explore  guilt, shame, anger and other emotional  elements associated with sexual dysfunction   • Family history —Includes parental influences,  cultural and religious influences, family  violence, and relationship with siblings   • Vasculopathy has come to be recognized as  the most common cause of ED, which has  elevated ED's importance in the primary care  setting as a sentinel to underlying cardiovas-  cular disease. Identification of cardiovas-  cular risk factors should be a routine part of  the evaluation for ED, and is as important as  taking the patient's sexual, medication, and  psychosocial histories 9   • Define the problem— As it appears to each partner,  in their own words   • Sexual drive — Early morning or nocturnal penile  erection, sexual thoughts /feelings of sexual arousal,  masturbation, frequency of intercourse   • Reason for present consultation — To elicit history  of any recent adverse psychosocial developments,  biological factors such as newly diagnosed disease  or surgical intervention   ■ Gynecomastia in men (hepatic cirrhosis,  digoxin, spironolactone, testicular  tumor, hypogonadism, Klinefelter's  syndrome: vide infra 11).   • Avoid moral or religious judgement of  patient's behaviour. Respect patient's  reluctance to disclose all sexual and  relationship details, especially during the  initial discussion.   defined as failure of the testis to descend from  its intra-abdominal location into the scrotum.  The exact etiology of cryptorchidism is not  known. It usually presents at birth or by  preadolescence; however, it can present at any  age. In one-third of patients, the condition is  bilateral. Patients present with the condition  or the parents bring the child with nonpalpable  testis. Physical examination reveals a  nonpalpable testis in the scrotum. The most  common location of the cryptorchid testis is  in the inguinal canal (72%), followed by  prescrotal (20%) and abdominal (8%)  locations. US, CT, MRI, arteriography, and  laparoscopy are used for diagnosis. Testicular  malignancies occur in 10% of men with  cryptorchid testis. The primary treatment of  cryptorchid testis is orchiopexy.   Dyspareunia — Persistent or recurrent genital  pain, during or after sexual intercourse, in either  sex; much more common in women, and  uncommon in men (usually organic in men, e.g.  Peyronie disease).    Erectile dysfunction (ED) — Persistent or recurrent  partial or complete failure to attain or maintain  erection until completion of sexual activity. ED  becomes more common with age, but is not part of  the normal aging process. ED is a symptom of other  potentially serious medical conditions. It may  indicate incipient cardiovascular disease,  neurologic degeneration, hormonal imbalances,  psychological issues, and even marital problems.  Therefore, it's important to perform basic physical  and psychological evaluation of the patient and  evaluate the risk factors for any impending disease.   Persistent or recurrent inability to achieve or  maintain sufficient sexual excitement, expressed  as a lack of excitement or a lack of genital or other  somatic responses such as adequate lubrication-  swelling response of sexual excitement. It's  usually due to psychological conflicts; altered  hormonal balance (testosterone, estrogen,  prolactin, and thyroxin); may be associated with  depression or medication effect. However, a detail  history is essential to rule out inadequate,  focussed, sexual stimulation and duration of  sexual activity.   It is the persistent or recurrent deficiency (or  absence) of sexual fantasies or thoughts and/  or the lack of receptivity to sexual activity. It's  usually due to reaction to sexual dysfunction,  chronic illness, surgery, major depression,  chronic anxiety, and marital discord, hyper-  prolactinemia, or CNS depressants.   Klinefelter's syndrome— KS, 47, XXY and its  variants, is the most common chromosomal  aberration among men, associated with hypo-  gonadism (small testes, azoospermia/oligosp-  ermia), gynecomastia in late puberty, and  infertility. Sexual dysfunction symptoms include  erectile dysfunction, and subnormal libido. Other    symptoms include fatigue, weakness, osteopo-  rosis, language impairment, academic difficulty,  and psychiatric disorders involving anxiety,  depression, neurosis, and psychosis. Infertility  and gynecomastia are the two most common  symptoms that lead to diagnosis, but many  cases of KS remain undiagnosed because of  substantial variation in clinical presentation.  MRI brain findings indicate a reduction in left  temporal lobe gray matter, a finding that is  consistent with the verbal and language deficits  associated with KS. Chromosomal studies are  indicated in prepubertal males with low  testosterone and elevated FSH and LH levels to  assess for Klinefelter syndrome. A semen  analysis (as per the WHO guidelines) is  indicated if fertility is an issue.   Leriche syndrome — It is used to describe  chronic lower limb ischemia characterized by:  Intermittent claudication in the buttocks; pale,  cold legs; sexual impotence; and absent femoral  pulses. It is caused by aortoiliac obstruction  (e.g. saddle embolism at bifurcation of the aorta).  The vessels above and below may be relatively  normal.   Orgasmic dysfunction — It is also called inh-  ibited male/female orgasm or retarded ejacul-  ation of the male; wherein there is persistent or  recurrent delay in, or absence of orgasm  following a normal arousal phase during sexual  activity — the individual may be sexually  aroused but orgasm is impaired or absent.   Peyronie's disease ( synonyms : Penile fibrosis,  Induratio penis plastica)—A condition characterized  by hardening of the penis due to the formation  of fibrous plaques on the dorsolateral aspect of  the penis, usually involving the membrane  (tunica albuginea) surrounding the erectile  tissue (corpus cavernosum penis). This may  eventually cause a painful deformity of the shaft  or constriction of the urethra, or both, leading    to penile angulation or an hour-glass like  deformity with distal flaccidity. It usually  affects only the erect penis. Sexual intercourse  can become painfully difficult or impossible.  Genetic susceptibility is thought to play a  role. Penile X-ray and ultrasound can demon-  strate calcified and noncalcified plaques  respectively. Corpus cavemosography can help  to demonstrate cavernosus deformity and  vascular blockage.   Post-traumatic stress disorder (PTSD)— PTSD  is a psychological condition that is triggered  by experiencing or witnessing severe trauma  that constitutes a threat to the physical  integrity or life of the individual or of another  person; these events being extreme in nature,  not necessarily outside the normal range of  human experience, but such as to arouse  intense fear, helplessness or horror, e.g. natural  disasters, violent personal assaults, rape, war,  severe automobile accidents, or the diagnosis  of a life-threatening condition. Sexual assault  on women probably is the most important  cause of PTSD. Four categories of criteria are  needed to accurately diagnose PTSD.   > First, a traumatic event occurred in which  the person witnessed or experienced actual  or threatened death or serious injury, and  responded with intense fear, horror or  helplessness.   > Second, on exposure to memory cues, the  person has reexperiencing symptoms, such  as intrusive recollections, nightmares,  flashbacks or psychologic distress.   > Third, the patient avoids trauma-related  stimuli (avoid thoughts, feelings, conversa-  tions, places or people that arouse recollec-  tions of trauma), and feels emotionally numb.   > Fourth, the person has increased CNS  arousal, manifested by difficulty falling or  staying asleep, irritability or outburst of  anger, difficulty concentrating, hypervigi-  lance, and startle response.    The symptoms persist for at least one month  and significantly disturb the patient's social  or occupational functioning (or both). Acute  PTSD is diagnosed when the symptoms have  lasted for 1-3 months as against chronic PTSD,  where symptoms have lasted for more than 3  months. The importance of this distinction lies  in the fact that active treatment in acute PTSD  may reduce the high risk of developing chronic  PTSD. Although level of exposure to traumatic  stressor is directly related to the psychological  impact, other factors contribute to develo-  pment of PTSD. Thus history of previous panic  disorders, previous trauma, child abuse, drug  abuse, as well as socioeconomic and demo-  graphic factors and ethnicity, appear to be risk  factors for vulnerability to PTSD. 1 2 3 4 5 6 7 8 9 10 ' 11   Premature ejaculation (PE) — Persistent or  recurrent ejaculation with minimal sexual  stimulation before, on or shortly after penet-  ration and before the person wished it (taking  into account age, frequency, and situation); more  common in younger men and often resolves with  increasing experience.   Retrograde ejaculation— Sexual climax with-  out the release of semen from the penis; occurs  when the semen passes into the bladder rather  than along the urethra. It is common after  prostatectomy, neurologic disorder (Parkinson's  disease, lumbar or sacral damage), and some  antihypertensives (methyldopa).   Sex aversion disorder — Persistent or extreme  aversion to and avoidance of all (or almost all)  genital sexual contact with a sexual partner;  applies mostly to female sex with history of  sexual assault, severe negative self-esteem,  marital discord, and in women complaining of  gynecological symptoms, e.g. pelvic pain,  vaginal bleeding, and other sexual dysfunctions.   Vaginismus — Persistent or recurrent invol-  untary muscle constrictions of outer third of  vagina that prevents penile insertion and    intercourse (coitus), usually due to sexual trauma  (rape, childhood sexual abuse); or as a conseq-  uence of dyspareunia, e.g. childbirth, surgery,  gynecologic pathology, atrophic vaginitis; and  also due to strict religious upbringing; or psych-  ogenic factors.   Widower's syndrome: It refers to a male who  experiences erectile dysfunction (with a new sex  partner) secondary to guilt feelings relating to  his dead spouse.    1 . Davies KP, et al. Markers of erectile dysfunction.  Indian J Urol 2008;24:320-8.   2. Ma RC, et al. Erectile dysfunction predicts  coronary heart disease in type 2 diabetes. J Am  Coll Cardiol 2008;51(21):2045-50. [PMID:  18498959: Abstract],   3 . Koppikar N, et al. Recent advances in the treatment  of erectile dysfunction in patients with diabetes  mellitus. Endocr Pract 2003;9(l):52-63. [PMID:  12917094: Abstract],   4. Lee JH, et al. Erectile dysfunction as a coronary  artery disease risk equivalent. J Nucl Cardiol  2008;15(6):800-3. Epub 2008 Sep 12. [PMID:  18984455: Abstract],   5. Ponholzer A, et al. Is the metabolic syndrome a  risk factor for female sexual dysfunction in sexually  active women? Int J Impot Res 2008;20(l):100-4.  Epub 2007 Sep 20. [PMID: 17882275: Abstract],   6. Merrill JM, et al. Why doctors have difficulty  with sex histories. South Med J 1990;83(6):613-7.  [PMID: 2356491: Abstract].   7. Wimberly YH, et al. Sexual history-taking  among primary care physicians. J Natl Med  Assoc 2006; 98 (12): 1924-9. [PMID: 17225835:  Abstract],   8. Nusbaum MR, et al. The proactive sexual health  history. Am Fam Physician 2002;66(9):1705-12.  [PMID: 12449269: Free full text],   9. Miner MM, et al. Erectile dysfunction: A sentinal  marker for CVD in primary care. Cleveland clinic  J of Med. (74), S3, May 2007.   10. Dejonghe ES, et al. Women survivors of intimate  partner violence and posttraumatic stress  disorder: Prediction and prevention. J Postgrad  Med 2008;54:294-300.   11. Kishen R. Post- traumatic stress disorder in the  critically ill patients. Indian J Crit Care Med 2006;  10:163-6.   Eccrine sweat glands are distributed all over the  body surface, but are most dense on the forehead,  palms and soles, and in the axillae. They open  directly on the skin and their secretion, commonly  called as 'sweat' (perspiration), is regulated by the  body temperature center in the hypothalamus (the  sudomotor system which controls sweat output) via  the sympathetic cholinergic mediator. Any  fluctuations in the sudomotor autonomic activity,  consisting of frontal operculum/ hypothalamus,  brainstem, spinal cord, sympathetic chain ganglia,  peripheral nerve, or eccrine sweat glands may result  in sweating abnormalities.   Sweating (i.e. insensible loss) is necessary to  maintain body's normal thermoregulatory  mechanism, and fluid and electrolyte hemostasis.  The amount of sweat produced or its response to  physiological stimuli of heat, emotion, or eating  varies greatly by different individuals under  various conditions, and therefore, it is difficult to  define sweating abnormality —normal, excessive,  or deficient— in an individual. 1 " 3    Excessive sweating, called as hyperhidrosis, is  sweating beyond what is necessary to maintain  normal thermoregulation. Clinically, it may be  defined as a condition where noticeable sweating  occurs under different conditions, where it would  not be normally expected to occur or occurs in  excess, 4 often causing occupational disability and  social embarrassment. Patients usually present  because of abnormal wetness, sweaty palms,  stained clothing, offensive odor, and change in  the pattern of sweating. Patients report that they  are even embarrassed to hold the hands of those  they love.   Hypohidrosis and anhydrosis is reduced or  complete absence of sweating respectively; the  individual is unable to deliver sweat to the skin  surface in the presence of appropriate stimuli.   The etiology of sweating abnormalities, i.e.  hyperhidrosis and hypohidrosis, can be primary  (idiopathic or essential) or secondary to a  number of diseases and drugs. It may also be  localized or generalized, although such a strict  categorization may not be always possible in a  clinical setting. Unilateral, transient (lasting 1 to  3 days) hyperhidrosis typically involving the  face and arm have also been documented. 3 ' 6    Whereas hyperhidrosis is usually benign,  anhidrosis may predispose to hyperthermia.  Either hyperhidrosis or anhidrosis may accompany  a more serious underlying disorder. Correct  diagnosis depends on determining the anatomical  pattern of sweating and localizing the lesion  within the autonomic nervous system . 7   Sweating abnormalities, especially hyperhi-  drosis, can interfere with employment and social  relationships, and cause immense anxiety to the  suffering individual. Therefore, it is being  recognized increasingly, and its treatment  modalities are gaining widespread attention.  However, in the majority of patients with hyper-  hidrosis, providing scientific explanation, and  reassurance that excess sweating is not the conse-  quence of pathological condition once medical  causes have been ruled out is crucial in their  symptomatic management.    t Thermal sweating is governed by the hypothalamus.  s Emotional sweating is governed by the cerebral cortex.   • Intrathoracic lesion (paroxysmal unilateral  hyperhidrosis due to cervical rib, apical  bronchial carcinoma)   • Neurologic diseases (hypothalamic lesions.  Harlequin syndrome: vide infra 11 , autonomic  dysfunction)   • Leukocytosis in bacterial infection, heat  stroke; abnormal WBCs in leukemia; malarial  parasites in malaria.   • Elevated FT4 with low TSH suggest underlying  hyperthyroidism or thyrotoxicosis; elevated  TSH suggests hypothyroidism.   • May reveal diabetes mellitus or hypoglycemia.  To confirm nocturnal hypoglycemia — in  diabetic patients suspected with nocturnal  sweating— blood glucose estimation around  early hours of the morning must be done.   • Elevated urea, creatinine and low sodium,  potassium in heat stroke.   • To rule out parenchymal lesions, tuber-  culosis, lymphoma, or a neoplasm.   • In enteric fever, endocarditis, sepsis, and in  infections due to immunodeficiency disease.   • Mapping out areas of excessive sweating, i.e.  for direct visualization of the affected areas,  may be done by the iodine starch test. The  affected area is sprayed with a mixture of 0.5  to 1 gram of iodine crystals and 500 gram of  soluble starch. Areas that produce sweat will  turn black.   • To screen patients suspected of carcinoid  tumor; very high excretion rates of 5-HIAA  occur in carcinoid syndrome.   • In patients with localized hyperhidrosis (e.g.  focal axillary hyperhidrosis), eccrine nevus,  eccrine angiomatous hemartoma, etc. biopsy  is indicated.   • In rare disorders such as idiopathic hyper-  hidrosis, MSA, etc. sudomotor testing such as  Quantitative Sudomotor Axon Reflex Test  (QSART), Silastic sweat imprint test, and Ther-  moregulatory Sweat Test (TST) may be  indicated. These tests have a high sensitivity and  specificity for delineating the postganglionic  sudomotor function and site of lesion.   • It is to be remembered that sweating varies  with age because sweat glands function  immaturely in infants and less active in  elderly patients. As a result, patients in these  age-groups may fail to display sweating  associated with its common causes.   • An important step in determining the cause  of sweating abnormality is whether it is  generalized or localized.   • Generalized hyperhidrosis is common in adults  and is usually secondary to severe physio-  logic stress (shock, pain); a metabolic  disorder (diabetes mellitus, hypoglycemia,  thyrotoxicosis, menopause, pheochromo-  cytoma); febrile illness, drug effect, or  malignancy. Therefore, it is essential to  investigate for the underlying disorder.   • Localized hyperhidrosis (palmoplantar, axillary,  craniofacial) is often primary (idiopathic) and  unlike generalized hyperhidrosis, usually  begins in adolescence, but it can begin in  childhood or even in infancy.   • In generalized hyperhidrosis sweating is  common during both waking and sleeping  hours; whereas in local hyperhidrosis sweat-  ing usually reduces at night time and disap-  pears during sleep.   • History with regards to severity, extent,  periodicity, duration, and its impact on the  daily activities of the individual are noted.    Excess sweating restricted to palms, soles,  and axillae may be indicative of a normal  response to everyday events, or if it is more  generalized, may suggest an underlying  medical disorder, commonly due to hyper-  thyroidism and menopause.   • If sweating occurs primarily at night  (Table 38.1), then inquiry into fever, cough,  expecto-ration, hemoptysis, weight loss, and  other symptoms of esophageal reflux  disorder and neoplasm should be sought.  Tuberculosis, HIV infection, esophageal  reflux, and menopause are known to be the  most frequently associated disorders with  night sweats, defined as "sweating at night  even when it isn't excessively hot in your  bedroom within the previous month". 10   • Paroxysms of sweating are common with  anxiety disorders, menopause, carcinoid  syndrome, and pheochromocytoma.   • A drug history is inquired with a check for  use of antipyretics, insulin, anticholinergics,  antihistamines, and alcohol.   • Physical examination — May include presence of  weight loss (diabetes mellitus, hyperthy-  roidism; tachycardia (panic attack, hyperthy-  roidism, and heat stroke); hypotension (syncope,  autonomic dysfunction); hypertension, facial  flushing (pheochromocytoma, carcinoid  syndrome); fever or defervescence.   • The patient is examined for signs of other  systemic disorders such as tuberculosis  (segmental collapse, pleural effusion),  hyperthyroidism (goiter, lid lag, exophthal-  mos, and ophthalmoplegia), lymphoma,  malignancy (regional lymphadenopathy,  splenomegaly), endocarditis (new or chang-  ing heart murmur), peripheral neuropathy  (paresthesias with sensory, motor, and  autonomic nerve dysfunction), and alcohol  abuse (icterus, hepatomegaly).   Antipyretics, insulin, antipsychotics,  antihistamines, drug withdrawal in  addicts— alcohol, heroin, opioids   • Hyperhidrosis in hypoglycemia, acute  coronary syndrome, and autonomic hyper-  reflexia (spinal cord injury); and hypohid-  rosis or anhidrosis in heat stroke indicate  medical crisis.   • Hyperhidrosis beginning later in life should  prompt a search for secondary causes such  as systemic diseases, adverse drug reactions,  or metabolic disorders.   • Older patients may not exhibit sweating  because of a decreased sweating mechanism;  hence they are at increased risk of developing  heatstroke in high temperature.   Frey syndrome— It is a known complication after  parotidectomy, and manifestations range from  erythema related to eating to copious gustatory  sweating. The cause is believed to be an aberrant  connection of the parasympathetic fibers to the  sweat gland of the overlying flap of skin.   Harlequin syndrome** — A term originally  reserved for patients with asymmetrical facial  flushing and sweating without ocular signs of  Horner's syndrome, is a rare autonomic  condition characterized by flushing and  sweating that occurs only on one side of the face  and may occur for no apparent reason or in  response to such things as heat and exercise.  Since unilateral facial flushing can also be the  first symptom of more serious conditions such  as malignancy or stroke, a thorough diagnostic  investigation is required to determine the  underlying etiology of the condition. Occa-  sionally, patients with Harlequin syndrome  display symptoms that are also seen in Adie's  syndrome (tonic pupils with hyporeflexia) or  Ross syndrome (tonic pupils with hypo-  reflexia and segmental anhidrosis). The groups  of symptoms seen in these syndromes,  however, indicate a wider spread of autonomic  deficits than those seen in pure Harlequin  syndrome, with involvement of other parts of  the nervous system. This point should be  considered when making the differential  diagnosis. The syndrome is usually of benign  nature and does not require treatment unless  neurovascular compression signs and  symptoms are present.    ** The term Harlequin syndrome is also used to describe  an autosomal recessive skin disorder that represents the  most severe form of congenital ichthyosis.    Nail Patella Syndrome (NPS) — It is inherited  as an autosomal dominant trait involving  organs of both ectodermal and mesodermal  origin. The diagnostic tetrad includes  fingernail dysplasia, absent or hypoplastic  patellae, the presence of posterior conical iliac  horns, and deformation or luxation (i.e.  hypoplasia) of the radial heads. Patients often  complain of palmoplantar hyperhidrosis.  Kidney disease and glaucoma are now  recognized as part of the syndrome. The most  serious complication associated with NPS is  nephropathy. The correct diagnosis is rarely  established during childhood because the nail  and patella abnormalities may not become  apparent until later in life.   1 . Green BG, et al. Individual differences in temperature  perception: Evidence of common processing of  sensation intensity of warmth and cold. Somatosens  Mot Res. 2007;24(l-2):71-84. [PMID: 17558924:  Abstract],    2. Aoki K, et al. The effect of diurnal variation on the  regional differences in sweating and skin blood  flow during exercise. Eur J Appl Physiol Occup  Physiol 1995;71(2-3):276-80. [PMID: 7588701:  Abstract],   3. Schestatsky P, et al. Skin autonomic reactivity to  thermoalgesic stimuli. Clin Auton Res 2007;  17(6):349-55. Epub 2007 Nov 29. [PMID: 18049833:  Abstract],   4. Sato K. Disorders of eccrine sweat gland. In:  Fitzpatrick TB, et al. Dermatology in General  medicine. 4th ed. 1993. P.40-53.   5. Labar, et al. Unilateral hyperhidrosis after cerebral  infarction. Neurology 1988;38:1679-82. [PMID:  3185901: Abstract],   6. Rousseaux M, et al. Late contralateral Hyperhidrosis  in Lateral Medullary Infarcts Stroke 27:991-5.  [PMID: 8623124: Free full text].   7. Cheshire WP, et al. Disorders of sweating. Semin  Neurol 2003;23(4):399-406. [PMID: 15088261:  Abstract] .   8. Dinadio V, et al. Anhidrosis in multiple system  atrophy: A preganglionic sudomotor dysfunction?.  Mov Disord 2008;23(6):885-8. [PMID: 18361470:  Abstract],   9. Gibbons, et al. QDIRT: Quantitative direct and  indirect test of sudomotor function Neurology 2008  70: 2299-2304. [PMID: 18541883: Abstract]."'   10. Mold JW, et al. Prevalence of night sweats in primary  care patients: An OKPRN and TAFP-Net coll-  aborative study. J Fam Pract 2002; 51:452-6.   Swelling of the legs is commonly due to systemic  edema state. Edema is the excessive accumulation  of fluid in the tissues (or serious sacs*) due to  increase in the volume of interstitial fluid (ISF),  i.e. increase in the extravascular portion of the  extracellular compartment. In an adult, the ISF  should expand by at least 2 liters + before the  abnormality is clinically recognized as pitting  edema, i.e. persistence of indentation of the skin  following pressure.   In response to gravity, dependent edema first  appears in the feet and ankles in an ambulatory  patient, commonly called pedal edema*. The  patient usually complains of swollen legs,  swelling of ankles towards evening around the  top of the boot, weight gain, enlarged abdominal  girth, and puffiness of the face, particularly in  the morning.   Although a variety of clinical conditions,  ranging from benign, e.g. dependent edema, to   + At least 15% increase in body weight is necessary to  demonstrate pitting edema.    potentially life-threatening condition, e.g. deep  venous thrombosis is associated with pedal  edema, diagnosis is simplified by determining  localization of edema, i.e. whether one or both  legs are involved, its onset— sudden or gradual,  presence of pain, and other signs and symptoms  of inflammation, and associated systemic  symptoms such as breathlessness, jaundice,  unexplained weight gain, sleep apnea, etc.   • Renal (nephrotic syndrome, i.e. NS; acute  glomerulonephritis; chronic renal failure)   • Venous disease (deep venous thrombosis, i.e.  DVT; superficial venous insufficiency:  varicosity, postsaphenous vain harvest)   • Idiopathic edema (i.e. cyclical edema in  women: vide infra 4 - 4 )   • Venous/lymphatic obstruction (i.e. secondary  lymphedema, e.g. due to abdominal or pelvic  mass, tumor, lymph node resection, irra-  diation)   • Hypercoagulability state (vide infra 4-i:  antiphospholipid syndrome, i.e. APS). 1 ' 2   • Iron deficiency anemia, megaloblastic anemia  may be seen in nutritional deficiency diseases.   • Heavy proteinuria (> 3.5 g/day) is most often  associated with NS.   • An elevated serum bilirubin level; abnormal  transaminases, and alkaline phosphatase;  and reduced albumin level are common  with hepatocellular and cirrhosis of the liver.   • Abnormal TSH values can point to either  hypothyroidism or hyperthyroidism.   • It is the preferred first line investigation for  the evaluation of patients with superficial  and deep venous thrombophlebitis and  venous insufficiency. It is easy to perform, less  expensive than most high-tech studies, can  be performed as a portable examination, and  with proper attention to technique, sensitivity  of this test is approximately 9 7%. 4, 5   • A positive plasma D-dimer test, in association  with Duplex US of lower limbs and HRCT of  lungs favor DVT and PE respectively. 6   • 3D-gadolinium-enhanced test may be  recommended in patients in whom DVT of  lower extremity (or occlusion of the large  systemic veins, e.g. occlusion of the superior  vena cava) is strongly suspected but US is  equivocal. The positive diagnosis and extent  of DVT can be easily detected and monitored  by this noninvasive MRV technique. 7 ' 8   • To detect secondary pressure effects from  abdominal/pelvic mass, including ascites   • CT/MRI of the abdomen is preferred to  diagnose retroperitoneal fibrosis (as a cause  of venous thrombosis, or DVT).   • To evaluate for thromboembolic etiology in  CHF and valvular heart disease   • An echocardiogram is recommended in  patients who are at risk for pulmonary  hypertension, and in patients over age 45  with leg edema of unclear etiology.   • Plasma homocysteine level, lupus anti-  coagulant, anticardiolipin antibodies, anti-beta  2 glycoprotein 1 antibodies, and a study of the    ” The standard investigation contrast venography is now  replaced by Duplex US; the former is in most cases; they  are expensive, invasive, and associated with a small but  real incidence of phlebitis.    erythrocytic aggregation would appear to be  of value in patients presenting recurrent with  arterial or venous thromboembolic events.    • The initial clinical approach is to distinguish  between unilateral and bilateral pedal  edema (Table 39.1).    • Duration— Acute onset (usually <72 hours)  is common with thrombophlebitis, DVT,  cellulitis, ruptured popliteal cyst, etc.  Gradual onset is common with systemic  cardiac, hepatic, and renal disorders; chronic  venous insufficiency, lymphatic and venous  obstruction, etc. Intermittent edema is a  common feature of idiopathic (cyclical)  edema that is common in obese women.    • Is the pedal edema pitting or non-pitting, i.e.  solid? (Table 39.2).    • Is it lipedema or lymphedema ? Lipedema (a form  of fat maldistribution with sparing of feet)  exclusively affects women and is a bilateral  and symmetrical deposition of fat in the  lower extremities, without involving the feet;  whereas in lymphedema the swelling starts  in the most distal part of the foot(marked  foot and toe involvement); this differentiates  the two conditions.   • History of recent limb immobilization or  confinement to bed following surgery,  pregnancy, or history of cancer favors the  diagnosis of DVT.   • Associated symptoms — Dyspnea on exertion,  orthopnea, or paroxysmal nocturnal dyspnea  suggests heart failure as the cause of leg  edema. Jaundice, palmar erythema, spider  angiomata, and hepatomegaly suggests  cirrhosis of the liver. Generalized edema and  swelling of the eyelids (peri-orbital) is  typical with NS. If the leg swelling is absent  or minimal after recumbency but develops as   • A common but under- recognized cause of leg  edema is pulmonary hypertension, which  is often associated with sleep apnea. Findings  that may increase suspicion of sleep apnea  include loud snoring or apnea noted by the  sleep partner, daytime somnolence, or a neck  circumference >17 inches.   • Is the patient taking any drugs that could  cause the edema? Among the drugs that  should be considered are corticosteroids;  hormones— progesterone, estrogen, andro-  gens; NSAIDs; antihypertensive drugs —  calcium channel blockers, vasodilators, beta-  adrenergic blockers; hypoglycemics —  pioglitazone, rosiglitazone; antidepressants —  trazodone, and chemotherapeutic agents.   • Morning and evening chart of patient's  weight— Patients should weigh themselves  nude and with an empty bladder before food  or fluids in the morning and at bedtime. A  mean weight gain >1 kg is consistent with  idiopathic edema. 10   • Physical examination— Lower limbs should  be examined in the erect and recumbent  positions for dilated superficial veins and  perforators.   • Homans' sign, if positive (pain on dorsiflexion  of the ankle), indicates DVT.   • Signs of systemic illness associated with  swelling of the legs include— Periorbital edema,  jaundice, spider angioma, peau d'orange skin,  gynecomastia, ascites, hepatomegaly, cardio-  megaly, distended neck veins, gallop rhythm,  tachycardia, lung crepitations, hypertension,  and lymphatic obstruction.   • Patients with unexplained acute lower limb  swelling should have duplex sonography   • Any painless unilateral leg swelling in  women over age 40 years needs detail  investigations to exclude intraabdominal  lymphatic and venous obstruction, especially  compressing gynecologic malignancy.   • Bilateral leg edema, in the absence of signs of  CHF, and without lung disease, may be a  useful marker for underlying pulmonary  hypertension and obstructive sleep apnea,  especially in obese patients. 11, 12   • Pedal edema in patients with unexplained  thrombosis is known to occur due to combined  thrombotic lesions of peripheral veins as well  as the arteries such as in hypercoagulability  state, e.g. lupus, APS, occult malignancy, etc.  It is of major importance to make this  diagnosis so that patients can be treated with  the most effective therapy for secondary  prevention.   Hypercoagulable states— It can be defined as a  group of inherited and/or acquired molecular  defects that are associated with a predisposition to  venous thrombotic events (including upper- and  lower-extremity DVT with or without PE, cerebral  vein thrombosis, and intraabdominal venous  thromboses); arterial thrombosis (including  myocardial infarction, stroke, acute limb ischemia,  and splanchnic ischemia); or both. Although most  inherited conditions appear to increase solely the risk  of venous thromboembolic events, some of the  acquired conditions have been associated with both  venous and arterial thrombosis (Table 39.3). The  best clue for the presence of hypercoagulability is    ** Venous thrombosis occurs mostly in the lower limbs,  with or without pulmonary embolism, and cerebral  ischemia and transient ischemic attacks, followed by  coronary ischemia are the most common arterial events.    a positive family history. Clinical suspicions occur  when patients are seen with unexpected venous  thromboembolic disease, recurrent thrombosis,  or thrombosis at unusual sites, such as the brain,  portal vein, or hepatic vein. In addition, this entity  should be considered in cases of unanticipated  arterial occlusive disease of the central nervous  system, extremities, mesenteric vessels, or cardiac  tree.   probably the most common of the hyper-  coagulable disorders, which has received  considerable attention from the medical  community because of its association with a  number of serious clinical disorders, including  arterial and venous thromboembolism, acute  ischemic encephalopathy, recurrent pregnancy    loss, thrombocytopenia, and livedo reticularis.  It can occur within the context of several  diseases, mainly autoimmune disorders, and is  then called secondary APS. However, it may also  be present without any recognizable disease,  or so-called primary APS. The syndrome occurs  most commonly in young to middle-aged adults;  however, it also can occur in children and the  elderly. This syndrome is the most common  cause of acquired thrombophilia, associated  with either venous or arterial thrombosis or  both. It is characterized by the presence of  antiphospholipid antibodies, recurrent arterial  and venous thrombosis, and spontaneous  abortion. Patients are often asymptomatic until  suffering from thrombotic events of this  syndrome such as DVT, pulmonary embolism,  CVA, myocardial infarction, cardiac valvular  dysfunction, and skin ulcers. In a rare patient  with APS, a potentially devastating syndrome  known as catastrophic APS ( Asherson's syndrome)  occurs, leading to massive venous thrombo-  embolism, thrombotic microangiopathy, and  multiple organ failure. According to the  International Consensus statement, at least one  clinical criterion (vascular thrombosis,  pregnancy complications) and one laboratory  criterion (lupus antioagulant, antipcardiolipin  antibodies) should be present for the diagnosis  of APS.   Idiopathic edema 14 — It includes entities such  as cyclical edema, periodic edema, and fluid  retention syndrome. It is an orthostatic edema  accompanied by excessive weight gain from  morning to evening that primarily affects  premenopausal women, most common in  their third and fourth decades. Although the  cause is not clear, a number of hormonal  abnormalities are postulated to be involved.  These include rennin-angiotensin-aldosterone  axis, vasopr-essin, atrial natriuretic factor,  dopamine, hypothalamic disorders, and    thyroid disorders. In addition, exaggerated  postural abnormalities, psychological or  emotional disturbance, eating disorders, and  abuse of diuretic or laxative are also associated  with the onset of edema. It may also be  associated with discomfort in the areas of fluid  accumulation (including symptoms of the  carpal tunnel syndrome, nonarticular rheuma-  tism, and headaches, sometimes with pseudo-  tumor cerebri). Key features are periodic  episodes of edema in women who have weight  changes not clearly related to the menstrual  cycle. The diagnosis is usually one of exclusion.    1. Triplett DA. Antiphospholipid antibodies and  thrombosis. A consequence, coincidence, or  cause? Arch Pathol Lab Med. 1993;117(l):78-88.  [PMID: 8418768: Abstract],   2. Brick RL. Antiphospholipid thrombosis syndromes.  Clin Appl Thromb Hemost. 2001;7(4):241-58.  [PMID: 11697705: Abstract],   3. Kronenberg F. Dyslipidemia and nephrotic  syndrome: Recent advances. J Ren Nutr  2005;15(2):195-203. [PMID: 15827892: Abstract],   4. Andrews EJ Jr, et al. Sonography for deep venous  thrombosis: Current and future applications.  Ultrasound Q. 2005;21(4):213-25. [PMID:  16344726: Abstract],   5 . Labropoulos N, et al. Thrombosis in unusual sites  of the lower extremity veins. J Vase Surg  2008;47(5): 1022-7. Epub 2008 Mar 21. [PMID:  18358674: Abstract],   6. Righini M, et al. D-Dimer for venous thrombo-  embolism diagnosis: 20 years later. J Thromb  Haemost 2008;6(7):1059-71. Epub 2008 Jul 1.  [PMID: 18419743: Abstract],   7 . Carpenter JP, et al. Magnetic resonance venography  for the detection of deep venous thrombosis:  Comparison with contrast venography and duplex  Doppler ultrasonography. J Vase Surg  1993;18(5):734-41. [PMID: 8230557: Abstract],   8. Laissy JP, et al. Assessment of deep venous  thrombosis in the lower limbs and pelvis: MR  venography versus duplex Doppler sonography.  AJR Am J Roentgenol 1996;167(4):971-5. [PMID:  8819396: Abstract],   9 . Tazi Z, et al. Value of an extensive biological study  in venous or arterial thromboses. Presse Med 1996;  25(ll):531-6. [PMID: 8731796: Abstract],   1 1 . Blankfield RP, et al. Bilateral leg edema, pulmonary  hypertension, and obstructive sleep apnea: A  cross-sectional study. J Fam Pract 2002;51(6):561-  4. [PMID:12100781: Abstract],   12. Blankfield RP, et al. Bilateral leg edema,  obesity, pulmonary hypertension, and obstruc-   13. Gezer S. Antiphospholipid syndrome. Dis Mon  2003;49(12):696-741 . [PMID: 14679358: Abstract],   14. Streeten DH. Idiopathic edema. Pathogenesis,  clinical features, and treatment. Endocrinol Metab  Clin North Am 1995;24(3):531-47. [PMID:  8575408: Abstract],   Syncope, commonly described as fainting, passing  out, or blackout, is defined as a symptom complex  that is composed of a sudden, and transient loss  of consciousness, associated with an inability  to maintain postural tone, followed by  spontaneous and complete recovery, without  medical intervention.   Syncope is distinct from vertigo, seizures,  coma, and states of altered consciousness.  Vertigo and dizziness do not result in loss of  consciousness or postural tone. Vertigo is also  associated with a sense of motion. Aura, violent  muscular spasms, sphincter disturbances,  disorientation, and gradual return to conscious-  ness suggest a seizure. +   Evaluation of a patient with syncope is often  problematic because episode usually occurs  outside hospital, and accurate historical  information (usually by an observer) is often  lacking or conflicting. Moreover, patients are    * i.e - 'without any neurologic deficit and without using  any electrical or chemical cardioversion'.   + Ref. Chapter 10: Convulsions, p. 63; and Chapter 47:  Vertigo, p. 323 for details.    often asymptomatic and no longer remember  the event when seen by a physician.   Often the cause of syncope is benign and  the condition is self-limiting; but, concerns  that well-appearing patients may be at risk  for potentially serious disorder* (e.g. acute  coronary syndrome, malignant dysrhythmia,  aortic dissection, and pulmonary embolism, as  well as neurologic emergencies, such as  subarachnoid hemorrhage) often leads to  extensive diagnostic evaluation or hospital  admission. However, many studies have  demonstrated low yield of nondirected  diagnostic testing . 1, 2 The pivotal role of the  physician, therefore, is to identify those  relatively few patients with life-threatening  processes, and the majority with benign  disorders needing risk stratification § , which will  help device an optimum evaluation and  management plan for each patient.    | It is said that, 'unless proved otherwise, syncope should  be considered as an aborted second death'.   ®Risk factors for adverse outcomes include: age >45 years,  structural heart disease, history of CAD, CHF, coexisting  other systemic disease, ECG with non-sinus rhythm, family  history of sudden death, and younger individual with  exertional syncope.   • Postural hypotension (medications: Alpha  blockers, nitrates, diuretics; diabetic autonomic  neuropathy, pronged bed rest; varicose veins)   • Cardiac arrhythmia (heart block; Stokes-  Adams-Morgagni syndrome: vide infra i-l;  WPW syndrome: vide infra 4-4-; sick sinus  syndrome: vide infra 4-i; SVT; VT; Torsade de  pointes: vide infra ii; drug induced long QT  syndrome, e.g. amiodarone, cisapride,  erythromycin, gatifloxacin, thioridazine)   • A 12-lead ECG should be ordered for all  patients with syncope. A rhythm strip    during syncope (if faceable) is very helpful  for any evidence of arrhythmia. (Table 40.1).  A normal ECG in a patient with syncope may  indicate good prognosis.   • Brugada syndrome (partial RBBB with elevated ST  segments in leads Vl-3 and peculiar downsloping  of the elevated ST segments + inverted T waves in  those leads)   • Arrhythmogenic right ventricular dysplasia (RBBB,  QRS complex > 110 msec in leads V 1-3, inverted T  wave or epsilon wave.   • Functional hypoglycemia may cause syncope  in susceptible individuals under stress. Drug  induced hypoglycemia is common in diabetics  on insulin or oral hypoglycemic agents (OHA),  which are often responsible for syncopal  episodes.   • Low Hb% (due to chronic blood loss, e.g. GI  bleeding).   • To assess hydration status; hypokalemia,  hyponatremia due to diuretic use; hypo-  kalemia or hyperkalemia can precipitate  arrhythmias.   • Evaluation of a select number of etiologies of  syncope may be aided by CXR. Pneumonia,    CHF, lung mass, effusion, and widened  mediastinum can all be seen if present, and  may guide therapy   • In elderly patients and in patients who are  debilitated, pneumonia may precipitate  syncope; pneumonia may occur in the absence  of symptoms and signs in this class of patients.   • Indicated in patients in whom syncope due  to cardiac origin is highly suspected, and those  who give a history of chest pain with syncope,  dyspnea with syncope, or exertional syncope.   • Indicated in patients with history of cardiac  syncope, or cardiac risk factors are suggestive  oflHD.   • Advised in syncopal patients who have an  evidence of CHF, structural cardiac disorder  (congenital or acquired), prosthetic valvular  dysfunction, cardiomyopathy, cardiac tumors,  pulmonary hypertension, or abnormal ECG  findings. Evaluation of left ventricular function  and ejection fraction is useful in the  management of such patients.   • Ambulatory Holter monitoring for 48 to 72  hours may be useful in patients with  episodic syncope potentially associated with  cardiac arrhythmias or silent ischemia.   • Indicated if clinically there is evidence of  carotid bruit or history suggestive of  vertebrobasilar insufficiency (diplopia,  hemiparesis).   • Useful in patients with evidence of seizure,  stroke disorder, new neurologic deficits, or  in patients with head trauma secondary to  syncope.   • Indicated especially in patients with  recurrent or severe disorder of syncope as  well as for high-risk patients (i.e. those at  risk for injury if they faint). Hemodynamic  response such as heart rate, blood pressure  response, and ECG evidence for asystole  associated with syncope are monitored. The  test is used when cardiac causes of syncope  have been reasonably excluded.   • An invasive procedure; may be indicated in  patients with abnormal ECG reveling  conduction abnormalities or arrhythmias;  also in patients with recurrent unexplained  syncope, with or without structural heart  disease, and with negative results on tilt-  table testing.   • These gadgets have up to two years worth of  ECG recording capability and storage of  cardiac rhythm. The device is programmed  to store in memory cardiac rhythm after  automatic or patient triggered activation,  which provides high degree of 'symptom-ecg'  correlation. This procedure is indicated only  in patients with chronic unexplained syncope  or in whom tilt-table test is negative.   • Indicated in selective patients in whom  seizure is suspected or complicates syncopal  attacks.   • Indicated in patients with major depression,  generalized anxiety disorder, panic, and  substance abuse disorders.   • History is crucial to establish whether the  patient did have an episode of transient loss of  consciousness, and under what circumstances  it occurred, e.g. prolonged standing, hearing  bad news, physical exercise, micturition, etc   • An eyewitness to the event can help determine  if seizure activity such as tonic-clonic muscle  spasms, sphincter incontinence, or confusion  after the spell was present. Presence of features  such as aura, abrupt loss of consciousness,  sensory hallucinations, Deja vu/jamais vu  experiences, confusional states, motor  automatism, prolonged amnesia, and history  of alcohol withdrawal, and head trauma  favor seizure attacks   • Specific red flag symptoms such as chest pain,  dyspnea, headache, and abdominal pain  associated with syncopal event should raise  concern about life-threatening causes, (Table  40.2); these should be excluded initially as  they require immediate diagnostic evaluation,  treatment, or hospital admission   • Other associated symptoms and clinical features  (e.g. cardiac, neurologic, abdominal, or  respiratory) may facilitate diagnosis of an  underlying disorder such as acute coronary  syndrome (ACS), seizure, GI hemorrhage, ectopic  pregnancy, or pulmonary embolism (Table 40.3)   • Age — Noncardiac causes tend to be more  common in young adults, while cardiac  syncope becomes increasingly more frequent  with advancing age. Syncopal episodes in  elderly patients are difficult to evaluate due to  multiple coexisting illness, medications, and  physiological impairment as a result of aging.  Advancing age heralds an increased frequency    • Chest pain, with or  without palpitations or  dyspnea; symptoms may  be present as a presyn-  copal prodrome, follow-  ing syncope, or both    • Severe headache or  new neurological deficits,  with prodromal symptoms  such as vertigo,  dysarthria, diplopia,    • Strenuous exertion just  before syncope, especi-  ally in young athletes  with a cardiac murmur    Myocardial ischemia or  infarctions, aortic dissec-  tions, dysrhythmias, or  pacemaker malfunction    GI acute bleeding, e.g.  ruptured abdominal aortic  aneurysm; or in the  pregnant patient, an ectopic  pregnancy or placental  abruption.   Cardiac outflow  obstruction due to aortic  stenosis, HOCM, mitral  stenosis, pulmonary  stenosis, pulmonary  embolus, left atrial  myxoma, or pericardial  tamponade.    of CAD, arrhythmia, vasomotor instability,  autonomic failure, polyneuropathy, and the use  of polypharmacy— all of which can contribute  to syncope. Besides, elder persons can present  with atypical symptoms complicating syncope  such as unexplained falls or lapses in memory.  Therefore, advanced age is an independent risk  factor for syncope   • Vasovagal syncope is the most common type of  syncope, often initiated by a stressful, painful,  or catastrophic experience. Premonitory  symptoms such as nausea, sweating, pallor,  palpitation, and a 'sense of doom' are usual   • Situational syncope, e.g. on prolonged standing  (postural syncope), while urinating (micturition  syncope), on coughing (tussive syncope) are also  common, especially in the elderly   Prodromal symptoms  of nausea, sweating,  lightheadedness, blurred  vision, preceding pain,  fever, unpleasant event   Lacerated tongue,  jerking limbs, confusion,  no memory of episode,  sense of deja or jamais vu   Sudden, transient loss  of consciousness without  prodrome, underlying  heart disease, palpitation    • Orthostatic hypotension, i.e. decline in blood  pressure greater than 20 mm Hg systolic, or  diastolic greater than 10 mm Hg, or both,  immediately upon rising from supine to  standing position is a common cause of  syncope, especially in the elderly, in diabetics,  or those with autonomic neuropathy    • In patients with no known structural heart  disease, a family history of unexplained  cardiac death increases the likelihood of  HOCM or congenital long QT syndrome   • Carotid sinus syncope typically occurs in  relationship to head and neck movements,  shaving, or wearing of tight collars around  the neck (carotid sinus hypersensitivity)   • Effort (postexertional) syncope typically  occurs in patients with aortic stenosis,  hypertrophic cardiomyopathy, pulmonary  hypertension, mitral stenosis, or CAD   • Cardiogenic syncope due to arrhythmia is  often sudden in onset with loss of  consciousness regardless of patient's posture;  chest pain may also occur if the patient has  IHD or aortic stenosis   • Syncope associated with brainstem dys-  function symptoms such as diplopia, ataxia,  or vertigo are features of TIA involving  vertebrobasilar system   • A comprehensive drug history is important  in assessing whether medications have  contributed to syncopal episode. Drugs  commonly implicated in syncope include the  following:   • Physical examination— Especially cardiac  examination for heart rate, rhythm (arrhy-  thmia); blood pressure (postural hypo-  tension, hypertension); carotid bruit (TIA);  presence of S 4 gallop, and crescendo-  decrescendo murmur (aortic stenosis); late  systolic murmur and nonejection click  which changes in quality and radiation   • The patient should have a detailed neurologic  examination, including baseline mental status,  evaluation for cranial nerve deficits, motor  deficits, deep tendon reflex lateralization, and  sensory deficits   • If the cause of the syncope is not readily  apparent after initial clinical evaluation,  then a decision has to be made whether  certain categories of 'syncope-prone-  patients' require admission to hospital.  Examples of such subset of patients  warranting hospitalization include:   > Elderly patients >60 years with no  apparent cause of the syncope   > Sudden syncope occurring in a non-erect  patient with no premonitory symptoms  or prodrome   > Sudden syncope in a patient with a family  history of syncope or sudden death   > Patient has overt evidence of structural  heart disease by history or examination   • Occasionally, syncope may be confused with  atonic seizure (i.e. 'drop attack', with sudden  loss of postural muscle tone, consciousness  briefly impaired, patient may collapse); EEG  is indicated for differentiation   • Carotid sinus massage (to terminate tach-  ycardias) should be attempted only under  closely monitored conditions (with  resuscitative equipment stand-by to manage  the rare episode of asystole). It should not be  attempted in patients if carotid bruit is  present or with h/o recent stroke, TIA, or MI   • Patients with recurrent syncope of undeter-  mined etiology (so called malignant vasovagal  syncope 3 ): who have no prodrome are at risk  for injury to themselves or to others.   Adams-Stokes attacks— The term refers to a brief  episode of cardiac arrest due to either asystole or  ventricular fibrillation. This characteristi-cally  occurs in patients with heart block in whom  either the ventricular pacemaker suddenly fails,  or in whom ventricular arrhythmias are  superimposed on the heart block. Prior to an  attack, patient may become pale; heart rhythm  experiences a temporary pause, and collapse may  follow. Normal periods of unconsciousness last  approximately thirty seconds; but if the attack  is prolonged, convulsions may occur. The return  of consciousness is accompanied by flushing as  blood flows once more through vessels dilated  by hypoxia.   Atrial myxomas— These are the most common  primary heart tumors, originating from the fossa  ovalis region of the atrial septum, usually  occupying the left atrium. About 90% are solitary  and occur sporadically. Approximately 10% are  familial, transmitted in an autosomal dominant  mode and can be part of several syndromes such  as Carney syndrome ( vide infra 11 ). Multiple  tumors occur in approximately 50% of familial  cases and are more frequently located in the  ventricle. Most myxomas are pedunculated with  variable composition— from dense fibrous tissue  with or without calcification to friable  myxomatous tissue with propensity for  peripheral embolization. The mobility of the  tumor depends upon the extent of its attachment  to the interatrial septum and the length of the  stalk. Symptoms are produced by mechanical  interference with cardiac function or  embolization, and range from nonspecific and  constitutional to sudden cardiac death. Clinical  features include positional syncope, i. e. dizziness  occurs as the patient changes position; dyspnea,  pedal edema (CHF); TIA, stroke, seizures  (cerebrovascular embolization); or features of  collagen vascular disease. In about 20% of cases.    myxoma may be asymptomatic and discovered  as an incidental finding. Signs and symptoms of  mitral stenosis, endocarditis, mitral  regurgitation, and collagen vascular disease can  simulate those of atrial myxoma. A high index of  suspicion aids in the diagnosis. Although  transesophageal echocar-diography is more  sensitive, 2-dimensional echocardiography is  usually adequate for diagnosis.   Basilar Migraine (BM) —Described by Bickerstaff  in 1961, BM is a rare variant of migraine which  frequently affects young women and girls,  consists of headache accompanied by dizziness,  ataxia, tinnitus, decreased hearing, nausea and  vomiting, dysarthria, diplopia, loss of balance,  bilateral paresthesias or paresis, altered  consciousness, syncope, and sometimes loss of  consciousness. Localized vertebrobasilar vaso-  constriction leading to transient posterior  circulation ischemia may contribute to the  symptomatology of the disorder. Complications  of basilar migraines include remote possibility  of a basilar artery infarction.   Carney Syndrome— Carney first described an  autosomal dominant multiple neoplasia  syndrome featuring cardiac, endocrine,  cutaneous, and neural tumors, as well as a  variety of pigmented lesions of the skin and  mucosae, which includes myxomas in breast,  skin, thyroid gland, or neural tissue; potty  pigmentation of skin and mucous membranes  such as lentigines (i.e. flat brown discoloration  of skin), pigmented nevi, or both; and endocrine  overactivity such as Cushing syndrome. This  syndrome belongs to a group of genetic  disorders, the lentiginoses, which include Peutz-  Jeghers, LEOPARD, and Laugier-Hunziker  syndromes. The most serious manifestation of  the Carney complex is cardiac myxomas.   Sick Sinus Syndrome (SSS) — It is also known  as Sinus Node Dysfunction (SND), or tachy-    brady syndrome. It consists of a broad range of  electro-physiological abnormalities, including  inappro-priate sinus bradycardia, sinus arrest,  sinus node exit block, chronic atrial fibrillation,  and bradycardia-tachycardia syndrome. The  disease is commonly observed in older patients  with a history of concomitant heart disease, but  may also be observed in any age group,  including adolescents and children. Its clinical  manifestations vary widely. In the early stages  of SSS, most patients are asymptomatic. As the  disease advances, however, patients often seek  medical attention for bradycardia-related  symptoms. Syncope, near-syncope, and  dizziness are the most frequently reported  complaints, followed by palpitations, angina,  or shortness of breath. Thromboembolic  complications are a frequent cause of morbidity  and mortality. Sudden cardiac death is possible  at any point during the disease. Pacemaker  placement is the cornerstone of treatment for  symptomatic SSS.   Torsade de Pointes— A malignant form of  polymorphic ventricular tachycardia that is  characterized by heart rate between 200 and  250 beats per minute, and QRS complexes with  changing amplitude and twisting of the points  ('turning of the points '). The term also describes  the syndrome of tachycardia with prolonged  ventricular repolarization, long QT intervals  exceeding 500 milliseconds or bradycardia.  Torsades de pointes may be self-limited or may  progress to ventricular fibrillation. The patient  usually has syncopal attacks without premo-  nition that lasts few seconds or seizures. It is  commonly due to electrolyte imbalance or long  QT drugs. There may also be history of conge-  nital deafness or family history of sudden death.   WPW (preexcitation) syndrome is the most  common accessory pathway SVT. WPW is  mainly idiopathic or congenital, although it is    more common among patients with hyper-  trophic or other forms of cardiomyopathy,  transposition of the great vessels, or Epstein's  anomaly. In classic (or manifest) WPW  syndrome, antegrade conduction occurs over  both the accessory pathway and the normal  conducting system during sinus rhythm. The  accessory pathway, being faster, depolarizes  some of the ventricle early, resulting in a short PR  interval and a slurred upstroke to the QRS  complex (delta wave). The delta wave prolongs  QRS duration to >0.1 sec, although the overall  configuration, apart from the delta wave, may  appear normal. Depending on the orientation of  the delta wave, a pseudoinfarction pattern Q-wave  may be present. Because the early depolarized  parts of the ventricle also repolarize early, the T-  wave vector may be abnormal. In concealed WPW  syndrome, the accessory pathway does not    conduct in an antegrade direction; consequently,  the above ECG abnormalities do not appear.  However, it conducts in a retrograde direction and  thus can participate in reentrant tachycardia.  Symptoms of WPW syndrome may include  palpitations, chest pain, dizziness, dyspnea, or  rarely sudden death.    1. American College of Emergency Physicians  Issues Guidelines for Treatment of Syncope. Ann  Emerg Med. 2007;49:431-444; and Barclay L.  Medscape News. April 30, 2007.   2. Brignole M, et al. Guidelines on management  (diagnosis and treatment) of syncope-update 2004.  Executive Summary. Eur heart J. 2004;25  (22):2054-72. [PMID: 15541843], Web site: http:/  /eurheartj. oxfordjournals.org/cgi/content/full/25/  22/2054. Accessed on 26-12-08.   3. Khan Gabriel M. Heart Disease Diagnosis and  Therapy-A Practical Approach. Chap. 15 Syncope,  p. 473. 2nd ed. Humana Press.   Abnormal cutaneous sensations such as tingling,  numbness, pricking, shooting, cutting, stabbing,  aching, burning, constricting, band-like, shock-  like, etc. are caused by altered sensory nerve  function. Such sensations which are perceived  by an individual (i.e. subjective), without an  apparent stimulus, excepting pain, are called  paresthesias. Dysesthesias denotes all types of  abnormal or unpleasant sensations, even painful  ones, whether a stimulus is present or not.   While paresthesias and dysesthesias are  subjective sensory phenomenon, other abnormal  objective sensory abnormalities found on  examination include hypoesthesia (decreased  sensation to light touch, pressure, warm or cold  stimuli), anesthesia (absent sensation to the same  stimuli plus pinprick), hyperesthesias (exaggerated  pain perception to touch), and allodynia (the  perception of a nonpainful stimulus as painful, even  excruciating).   This abnormal sensory dysfunction can result  from six principal mechanisms, namely: Wallerian  degeneration (e.g. from trauma or nerve infarction);  axonal degeneration, sometimes referred to as dying-  back phenomenon (e.g. metabolic diseases);    segmental demyelination (e.g. Guillain-Barre  syndrome); compression (e.g. carpel tunnel  syndrome); infarction (e.g. vasculitis); and  infiltration (e.g. malignancy).   These mechanisms lead to various sensory  symptoms and signs (as noted above) resulting  from lesions at almost any level of the nervous  system, including cortex (e.g. stroke syndromes),  thalamus (e.g. Dejerine-Roussy syndrome),  brainstem (e.g. lateral medullary syndrome, i.e.  Wallenberg's syndrome), spinal cord (e.g.  Brown-Sequard syndrome, syringomyelia),  nerve roots (radiculopathies, plexopathies), and  nerve trunks (neuropathies).   Peripheral nerve disorders are the most  common causes of paresthesias and dysesthesias  affecting a variety of peripheral nerve cells and  fibers, including motor, sensory, and autonomic  fibers. These are broadly referred to as peripheral  neuropathies (PNs).   Most PNs affect both A and C types of nerve  fibers to some extent. However, a single fiber type  may be predominantly affected in some disorders;  e.g. C-fibers, i.e. small-fiber neuropathy (SFN), in  diabetes mellitus, and alcoholism. As small fibers  subserve pain and autonomic functions, these  neuropathies usually present with pain and    temperature loss, painful dysesthesias, autonomic  dysfunction (anhydrosis, orthostatic hypotension,  gastroparesis), or a combination. These patients  will have normal motor function and deep tendon  reflexes.   The large fibers, i.e. A fibers are myelinated  motor fibers. These fibers are responsible for  motion control, proprioception and vibration.  The clinical presentation in patients with large-  fiber neuropathy (LFN) are impaired vibration,  gait instability, weakness, numbness, small  muscle wasting, absent tendon jerks, but  preservation of most cutaneous sensation.  Dysesthesias, if present at all, tend to be tingling  or segmental/band-like. Sensation for touch is  carried by both small and large nerve fibers.   Although the diverse etiologies can make the  diagnosis of PNs quite challenging, a systematic  approach that classifies PNs on the basis of  clinical features, taking into account the mode of  onset (i.e. acute or chronic), type of peripheral  nerve fiber that may be involved (i.e. sensory,  motor, or autonomic), distribution (area of  innervation of a nerve or central afferent system),  associated neurologic symptoms and signs; and  aided by specific laboratory evaluation and  electrodiagnostic (EDx) tools will help in the final  diagnosis of the disorder.    Table 41.2: Common causes of peripheral neuropathies  by distribution of involvement   radiculopathies (infection,  disc herniation,  spondylosis,  tumor) Meralgia  paresthetica (lateral  femoral cutaneous  neuropathy) Herpes   Chloramphenicol  Chloroquin  Dapsone  Ethambutol  Ethionamide  Isoniazid  Linezolid  Metronidazole  Nitrofurantoin  Lipid-lowering drugs  Statins   • In suspected trauma (e.g. Colies' fracture) or  peripheral nerve compression as in hematoma,  hypothyroidism, acromegaly.   • NCS predominantly attempts to distinguish  the type of PN— axonal from demyelinating  neuropathies. The former are characterized  by decreased amplitude and to a lesser extent  slowing on NCS; the latter show more marked  slowing of the nerve conduction velocity. The  most common type of axonal PN, a distal,  symmetric, and predominantly sensory type,  is called a dying-back neuropathy.   • As indicated in stroke; cervical, thoracic,  spinal compressive syndromes; thoracic  outlet syndrome; multiple sclerosis.   • MRI of the brachial plexus may show  evidence of infiltrating Pancoast lesion.   • Nerve biopsy, (sural nerve biopsy), may be  used to assist in the diagnosis of some  inflammatory, infectious, and metabolic  PNs. Nerve biopsy may help to establish the    pathologic basis of the polyneuropathy  when EDx studies cannot conclusively  distinguish an axonal from an acquired  segmental demyelinating disorder.   • In suspected nutritional deficiency or if CBC  shows macrocytic/dimorphic anemia.   • May be useful in the diagnosis of inflammatory  (e.g. Guillain-Barre synd-rome), infectious (e.g.  Lyme disease, HIV), and a variety of immune-  mediated PNs (e.g. vasculitic neuropathies).   • For multiple myeloma or osteosclerotic  myeloma (as seen in POEMS syndrome).   • Serum or urine drug / heavy metal screening  if toxic neuropathy suspected.   • For hereditary neuropathies or inherited  metabolic disorders affecting nerves;  Dejerine-Roussy syndrome, HMSA, type 1  (Charcot-Marie-Tooth disease), etc.   • In normal persons tingling and numbness  can occur transiently after sitting or sleeping    in awkward positions (sleeping with the  arms above the head or sitting with the legs  tightly crossed). This is due to sustained  pressure on the nerve. These paresthesias  causing temporary physiological paralysis  but not degeneration, followed by complete  and rapid recovery are called neurapraxia.   > Mononeuropathy— Characterized by a focal  abnormality of a single nerve and usually  results from local nerve trauma or  compression;   > Mononeuropathy multiplexes ( multifocal  neuropathy)— Characterized by asymmetric  abnormalities in more than one nerve  trunk, which may occur simultaneously  or over days to years; and   • Symptoms — Depend on the nerves  affected; may involve sensory, motor,  and/or autonomic systems.   > Sensory— Tingling and numbness (pares-  thesia); burning sensation (dysesthesia);  decreased sensation (hypoesthesia), loss of  sensation (anesthesia), exaggerated pain  perception (hyperesthesia), and stoking-  glove pattern.   > Motor— Mainly muscular weakness, muscle  cramping and fasciculation causing  difficulty with activities of daily living.  Distal muscles are affected initially, e.g.  weakness of dorsiflexion of the toes is  common; diminished ankle reflex is often  an early sign. Proximal muscles are  involved later, except for inflammatory  neuropathies such as PAN and SLE.   > Autonomic— Abnormal (i.e. absent or  excessive) sweating is an early symptom;  postural hypotension, constipation,  diarrhea, erectile dysfunction, and urinary  retention occur only with advanced  autonomic involvement.    • The most common causes of PNs are  diabetes and alcoholism. In the absence of  these two risk factors, obtain additional  historical information, including history of  trauma (compression/entrapment neuro-  pathies), recent viral illness (Guillain-Barre  syndrome), drug and toxin exposure (Table  41.2), occupation (exposure to industrial  agents, pesticides), special diets (nutritional  deficiencies), travel (Lyme disease), and risk  factors for AIDS   • History of cancer, collagen vascular disease  (vasculitis), hypothyroidism, and leprosy  can be associated with PNs   • A detailed family history should include  inquiries as to the presence of gait abnormality,  muscular dystrophy, hammer toe, high arches,  etc. to rule out inherited disorders such as  Charcot-Marie-Tooth Disease (CMT)   • Onset— Generally gradual over months to  years as in diabetes, alcoholism, renal failure,  vasculitis, malignancy, etc. Causes of acute  onset PNs include trauma, ischemic  neuropathies, compartment syndromes,  Guillain-Barre syndrome, porphyria, and  Lyme disease   • Distribution (Tables 41.4 and 41.5) — Since  sensory nerves innervate particular regions  (dermatome)* of the body, correlating the  symptoms to areas of its supply is an  important method to identify the nerves  involved. Lor instance, the median nerve  innervates the thumb, the first two fingers,  half of the ring finger, and the part of the hand  to which they connect, i.e. C6-C7 dermatome.  The ulnar nerve innervates the other half of  the ring finger, the little finger, and the  remainder of the hand, i.e. C8 dermatome.    ’’'Generally sensory loss does not occur in the entire  corresponding dermatome; there is commonly a focus of  paresthesias, dysesthesias, etc. within a wider area of  impaired sensation in that dermatome.    More diffuse involvement of an entire limb  may be caused by involvement of the  brachial (C5 to Tl) or lumbosacral plexus  (LI to S3).   Most often, PNs produce symptoms that are  generalized and relatively symmetric,  conforming to a distal-to-proximal gradient  typical of stocking and glove distribution in  the hands and feet, e.g. diabetes mellitus  Unilateral involvement is seen in contralateral  disease of the brainstem, thalamus, or cortex,  e.g. stroke syndromes   Multiple sclerosis may cause symptoms in  several, widely separated areas  Physical examination is performed to  evaluate for possible systemic processes that  may be contributing to the neuropathic  process. Weight loss, fever, skin rash, icterus,  lymphadenopathy, arthropathy, organo-  megaly are significant signs for possible  systemic neurologic disorder  Palpable thickened and/or tender peripheral  nerves along with anesthetic skin patches  are typical of leprosy   Motor examination— Distal muscle groups  are affected initially. Loss of muscle power  progresses from distal to proximal. Deep  tendon reflxes are diminished or absent  Sensory examination— Which sensory tests  (i.e. pain, touch, temperature, and vibration)  to include in the physical examination  depends on the clinical setting  For patients with sensory complaints, testing  for all the above four sensory modalities is  necessary to uncover sensory dissociation, i.e.  preservation of touch and vibration  sensation, but loss of pain and temperature  sensation, which is an important clue to  incomplete spinal cord diseases such as in  syringomyelia, spinal stroke (i.e. infarction  of the anterior spinal artery), and Brown-  Sequard syndrome.    • For screening diabetic feet and limbs,  Semmes-Weinstein monofilament (5.07/10  gram) is recommended. The typical  distribution of paresthesia is distal and  symmetric, the feet being affected first in a  stocking distribution followed by the hands  in a glove distribution.   • The presence of Ti riel's sign is useful to localize a  nerve injury. The Tinel's sign refers to paresthesias  elicited by tapping along the course of a nerve.   • Clinically LFNs can be distinguished from  SFNs during sensory testing — Loss of  vibration and proprioception indicates  LFNs, while loss of pain and temperature  sensation is due to SFNs. Loss of sensation  for light touch may be due to LBNs or SFNs.   • Autonomic examination— Blood pressure  measurement in supine and standing posture  to check for signs of postural hypotension.   • Fundoscopy and examination of cranial  nerves— It is important to detect optic pallor  due to drug toxicity, hereditary demyelinating  diseases, etc. Diabetes mellitus, leprosy,  sarcoidosis, malignant lymphomas, myelomas,  etc. are known to involve cranial nerves + (V,  VII, IX, X, and XII) besides causing PNs.   • Upper extremity paresthesias could be the sole  manifestation of coronary syndrome, especially  in individuals with cardiac risk factors.   • In older patients, PNs is not an uncommon  presentation of many chronic illnesses,  including neoplasms and inflammatory  processes such as systemic lupus erythe-    matosus. Eliciting a full history, though often  difficult in this population, is vital for  accurate diagnosis and treatment.   • Leprosy must always be considered in a patient  with a combination of skin and neural disorder.   • In the case of Guillain-Barre syndrome, the  intensity of neuropathy may affect the  muscles of respiration, necessitating the use  of ventilatory support.   • Paresthesias and dysesthesias involving multiple  cranial nerves palsies and radiculopathies,  although similar in presentation to PNs, should  alert one to the possibility of leptomeningeal  metastasis; nerve biopsy is strongly indicated in  etiologic diagnosis.   • An often dominating arm pain, which mainly  radiates into the ulnar region, is a sign of the  infiltration of the plexus and the C8 and Tl roots.  The possibility of Pancoast lesions, typically  caused by apical adenocarcinoma or squamous  cell carcinoma of the lung should be considered  not only in the presence of brachial plexopathy,  but also when C8 or Tl radiculopathy is found,  usually associated with ipsilateral Horner  syndrome, characterized by miosis with a  pupil that is slow to dilate, a mild (l-2mm)  ptosis, ipsilateral anhydrosis and apparent  enophthalmos.   • Although human rabies is rare cause of PNs,  clinicians and public health workers should  suspect rabies when a history of possible  animal contact is known or when unexplained  atypical progressive neuropathy or unusual  febrile encephalitis is observed. 1   1. Human Death Associated with Bat Rabies —  California, 2003 JAMA 2004;291(7):816-7.   Tinnitus is a common disorder with many  possible causes. It is defined as any sound or  noise in the ears or head not attributable to an  external sound. It may be ringing, hissing,  humming, and buzzing squealing, clicking, or  popping noises.   Tinnitus may be unilateral or bilateral;  transient or continuous. It may be acute— the  episode usually lasting for seconds to minutes,  but may persist for days to weeks; commonly  due to noise trauma, or drug effect. Chronic  tinnitus may persist for more than 6 months.   At the outset tinnitus should be differentiated  from auditory hallucinations in which a person hears  voices, various kinds of music or sounds, which  are generally considered to be a symptom of  psychiatric or neurological disorders.   > More common form and may have its  origin in the external ear, middle ear,  inner ear, VUIth nerve, or central nervous  system.    > Common subtypes include: Otologic,  neurologic, infectious , metabolic, drug-  related, and psychogenic.   > Also audible to the clinician (with the  help of a stethoscope placed over head  and neck structures near the patient's  ear).   > Frequently due to a vascular or neuro-  muscular condition: a tumor within the  head, neck, or brain; or a structural defect  in the ear, usually the inner ear.   The evaluation of a patient with tinnitus  includes history, ENT-status examination,  audiological and vestibular findings, imaging   * Pulsatile tinnitus is the type of ear noise that is perceived  as a rhythmic pulsing that often synchronizes in time with  the heartbeat. It can be experienced as a thumping sound.  It is sometimes referred to as vascular tinnitus because in  the majority of cases, it is related to disturbances in the  blood flow.    investigations and, if necessary, examination by  other specialists. Many medical and nonmedical  treatments exist, with varying degrees of success  and safety. Once the physician determines that  the patient does not have a life-threatening or  obviously treatable underlying condition, the  patient should be counseled, reassured that the  tinnitus is not a life-threatening disease, and  offered appropriate treatment. All patients with  tinnitus can benefit from patient education and  preventive measures, and oftentimes the  physician's reassurance and assistance with the  psychologic aftereffects of tinnitus can be the  therapy most valuable to the patient. 1,2   These may be considered under three groups,  namely: Otologic, nonotologic, and psychogenic.   • Ear infection (acute otitis externa; otitis  media: acute and chronic; labyrinthitis :  viral, herpes zoster— geniculate ganglion)   + Injury following pressure changes; includes injury to  the eustachian tube, ear drum, lung and stomach.   • Ototoxic drugs (aspirin, NSAIDs, quinine,  quinolones, loop diuretics, beta blockers,  aminoglycosides, antipsychotics, anti-  neoplastics, sedatives, narcotics).   • Noise induced permanent tinnitus 3 (i.e.  NIPT: in factory workers, auto mechanics,  airplane workers, rock musicians, military  personnel with frequent exposure to gunfire,  and those working around loud engines)   • Neoplastic disorders (acoustic neuroma,  glomus jugulare tumor: vide infra >LL).   • Atherosclerotic, vascular disorders (carotid  artery aneurysm, arteriovenous malfor-  mation, vascular tumors)    • Severe anemia, including pernicious anemia,  is rare causes of pulsatile tinnitus 4   • Polycythemia vera, indicated by markedly  elevated Hb% and hematocrit is known to  cause transient neurological symptoms such  as headache, tinnitus, dizziness, blurred  vision, and paresthesias   • Elevated ESR is usually noted in autoimmune  vestibulitis and neoplastic conditions.   • A complete audiogram with pure tone and speech  thresholds, speech discrimination, acoustic  reflexes, and impedence testing is performed  even if the patient is unaware of hearing loss.   • A formal audiogram establishes a base from  which to pursue more advanced diagnostic  testing.   • Tympanometry helps to identify previously  undetected middle ear effusions, changes in  tympanic membrane stiffness caused by a  patulous eusta chian tube, or myoclonus of the  stapedial muscle or the muscles of the palate.   • Urea, creatinine, electrolytes, lipids, VDRL,  FTA, ABS — if indicated by history and  examination.   • CT may be indicated for the assessment of  patients with conductive hearing loss and    sensorineural hearing loss or vestibular  disorders of the peripheral type. Most  neoplasms and anomalies are best seen on  bone algorithm CT studies.   • For patients with nonpulsatile tinnitus, MR  imaging is the study of choice to exclude a  vestibular schwannoma or other neoplasm  of the cerebellopontine angle cistern. For  asymmetric hearing loss or unilateral  tinnitus. Gadolinium-enhanced MRI of the  internal auditory canals is indicated to look  for an acoustic tumor, and it is the procedure  of choice for evaluating patients with  suspected temporal bone tumors.   • Often indicated if vascular pathology —  usually manifested as pulsatile tinnitus, e.g.  arteriovenous malformations, vascular  anomalies, and aneurysms of the carotid in  the ear is suspected.   • Of the mastoids and petrous bones, and skull  X-rays if associated with head injury.   • Helpful in diagnosing multiple sclerosis and  central nervous system syphilis.   • Occasional tinnitus can occur in individuals  with normal hearing, and most experience  it in silent surroundings. Phantom noises,  that mimic ringing in the ears associated    with tinnitus, can be experienced by people  with normal hearing in quiet situations,  according to a new research. 5   • Evaluation of tinnitus includes, besides  otoaudiological examination, an evaluation  of psychosocial wellbeing of the patient, with  special attention to signs of depression. 6   • Objective tinnitus is unusual, but it may indicate  glomus tumors, arteriovenous malformations,  carotid stenosis, aneurysms, anemia, a patent  eustachian tube, or myoclonus.   • If it is subjective, is it unilateral or bilateral?  In general, pulsatile tinnitus, unilateral  tinnitus, and tinnitus associated with other  unilateral otologic symptoms represent  potentially more serious underlying disease  than bilateral tinnitus. 7   • Episodic tinnitus suggests Meniere's disease.  Pulsatile tinnitus suggests a vascular origin.  Auscultation over the neck, periauricular area,  orbits, and mastoid should be performed.  Tinnitus of venous origin can be suppressed  by compression of the ipsilateral jugular vein.   • Acute tinnitus, which can last days or weeks,  may be caused by ear infection, medications,  head or neck injury, excessive sound  exposure, earwax, and changes in blood  pressure or metabolism. With appropriate  evaluation, such underlying conditions  usually can be identified and treated, often  with resultant resolution of tinnitus.   • Chronic tinnitus (persistence for 6 months  or more) can also result from these conditions  and is more likely to occur in people who  have hearing loss.   • Concurrent medical conditions to be  considered include diabetes, hypertension,  thyroid disorders, hyperlipidemia, infection,  anemia, B p or zinc deficiency. 8   • Ototoxic drugs should be used with  particular caution in patients who have risk  factors that predispose them to ototoxicity.    such as advanced or very young age, renal  or hepatic impairment, pregnancy, or  history of hearing loss, or excessive and loud  noise exposure.   • Ongoing audiologic monitoring for possible  ototoxicity may be helpful when prolonged  use of ototoxic agents is needed.   • Continued counseling about the risk of  hearing loss is warranted if the patient is  exposed to damaging sounds.   • Counselling, preferably including general  information leaflet, is the cornerstone in the  management of tinnitus in the vast majority  of patients. There is no cure for tinnitus in  the common sense of the word, especially in  chronic cases. Many learn to live with their  tinnitus when they are convinced of the non-  threatening nature of their problem. Patients  can obtain relief from the symptom with  assistance from clinicians who are familiar  with tinnitus management strategies.   • Tinnitus plus unilateral hearing loss should  increase suspicion for acoustic neuroma.   • The presence of other neurologic signs along  with vertigo and deafness would suggest  multiple sclerosis, advanced acoustic  neuroma, basilar artery occlusion or  insufficiency, brainstem tumors, and central  nervous system syphilis.   • The severity of tinnitus varies from  occasional awareness of a noise to an  unbearable sound that drives some persons  to contemplate suicide. 9 ' 10   Cogan's syndrome— It is a chronic inflammatory  disorder that most commonly affects young  adults. Clinical hallmarks are interstitial  keratitis and vestibuloauditory dysfunction.  Typical Cogan's syndrome consists of flares of  interstitial keratitis and sudden onset of Meniere-    like attacks (nausea, vomiting, tinnitus, and  vertigo and hearing loss). Life-threatening aortic  insufficiency develops in 10% of reported cases.  Atypical Cogan's syndrome (audiovestibular  dysfunction with other types of inflammatory  eye disease) is associated with vasculitis in 20%  of cases, and has a less favorable prognosis than  typical Cogan's syndrome.   Glomus Jugulare Tumor— A relatively rare,  usually benign neoplasm — a paraganglioma  arising from sympathetic or parasympathetic  paraganglia outside the adrenal gland —  originating in the chemoreceptor tissue of the  carotid body, glomus jugulare, glomus  tympanicum, and aortic bodies. Glomus tumors  are encapsulated, slowly growing, highly  vascular, and locally invasive tumors. Although  most paragangliomas are sporadic, they can be  familial. Glomus jugulare tumors occur  predominantly in women in the fifth and sixth  decades of life. The most common symptoms  are conductive hearing loss and pulsatile  tinnitus. Other aural signs and symptoms are  ear fullness, otorrhea, hemorrhage, bruit, and  the presence of a middle ear mass. Significant  ear pain is uncommon. Involvement of the inner  ear produces vertigo and sensorineural hearing  loss. Cranial nerve involvement produces  hoarseness and dysphagia. The presence of  jugular foramen syndrome (paresis of cranial  nerves IX-XI) is pathognomonic for this tumor,  but it usually follows one year after the initial  symptoms of hearing loss and pulsatile tinnitus.  Less commonly, glomus tumors produce facial    nerve palsy, hypoglossal nerve palsy, or Horner  syndrome. Because of the insidious onset of  symptoms, these tumors often go unnoticed,  and delay in diagnosis is frequent. Because of  the location and extent of involvement, glomus  jugulare tumors present a significant diagnostic  and management challenge.    1. Alieva M, et al. Tinnitus. Primary Care  1990; 17(2) :289-97. [PMID: 2196610],   2. Noel CA, et al. Tinnitus. Diagnosis and treatment  of this elusive symptom. Geriatrics 2003;58(2):28-  34. [PMID: 12596495],   3. Axelsson A, et al. Tinnitus induced by  occupational and leisure noise. Noise Health  2000;2(8):47-54. [PMID: 12689461],   4. Cochran JH Jr, et al. Tinnitus as a presenting  symptom in pernicious anemia. Ann Otol  Rhinol Laryngol 1979;88(2 Pt 1):297. [PMID:  443725],   5. American Academy of Otolaryngology, Head  and Neck Surgery (2008, January 4). Silence  May Lead To Phantom Noises Misinterpreted As  Tinnitus. ScienceDaily Retrieved September 21,  2008, from http://www.sciencedaily.com- /  releases/2008/0 1/0801 01093825.htm   6. Zoger, et al. Relationship between tinnitus severity  and psychiatric disorders. Psychosomatics 2006  47:282-8 [PMID: 16844885: Free full text],   7. Waldvogel D, et al. Pulsatile tinnitus — a review  of 84 patients. J Neurol 1998;245(3):137-42.  [PMID: 9553842],   8. Ochi K, et al. Zinc deficiency and tinnitus. Auris  Nasus Larynx 2003;30 Suppl:S25-8. [PMID:  12543156],   9. Frankenburg FR, et al. Tinnitus, psychosis, and  suicide. Arch Intern Med 1994;154(20):2371,  2375. [PMID: 7944860],   10. Lewis JE, et al. Tinnitus and suicide. Clin  Otolaryngol Allied Sci 1994;19(l):50-4. [PMID:  8174302: Abstract],   Tiredness is one of the most common and  difficult presenting symptom to assess. Being a  constitutional and nonspecific symptom, it may  be less well-defined and explained by patients  than symptoms associated with specific  functions. Regardless of the cause, individulas  may describe their sense of tiredness variously  as exhaustion, weakness, loss of interest, low  vitality, fatigue, or feeling tired all the time  (TATT) — too tired to participate in family chore,  work, or even leisure activities. It is often  accompanied by a strong desire to rest or sleep.   Tiredness, being a nonspecific symptom, is  multicausal, which can neither be quantified nor  can be diagnosed with laboratory or imaging  studies. Analyzing the symptom and reaching a  diagnosis demands considerable skill, since  tiredness may indicate the first subtle manifestation   "Tiredness, fatigue, and weakness, though used  interchangeably, convey different meanings. Tiredness is a  state of subjective feeling of listlessness or lethargy which  can occur at rest; whereas fatigue is an excessive tiredness  on mental or bodily activity, lack of energy, which occurs  in tasks requiring sustained effort. Weakness denotes a  demonstrable reduction or loss of the strength or force of  muscle contraction or power. Exhaustion is extreme fatigue,  a marked loss of strength.    of a serious and uncommon disease, 1 ' 2 or more  commonly a normal occurrence as a result of full  day's work, or sustained physical activity, or as a  result of multiple potentially modifiable factors,  which may be fully treated, or at least alleviated,  thus increasing the well-being of the individual as  well as potentially slowing the progression of  disability. 3 In many cases no diagnosis can be made,  leading the patient to repeat consultations, lab  work, and multiple diagnoses. 4 Therefore, it is  important for the physician to narrow down the  vast differential diagnosis with an emphatic,  structured approach, with an aim of cultivating a   • Systemic illness (anemia, hypothyroidism,  diabetes mellitus, obesity, COPD, dehy-  dration)   • Electrolyte/metabolic causes (hypercal-  cemia, sodium, potassium, periodic paralysis  syndrome: vide infra 44 -)   • To assess the type and severity of anemia—  generally IDA due to nutritional deficiency,  chronic disease, or chronic blood loss.   • Elevated in infection (TB, HIV) ; inflammation  (RA, PAN); and malignancy.   • Markedly elevated liver enzymes when the  liver is damaged by infections like hepatitis  or by toxins like alcohol and certain drugs   • In a jaundiced patient an elevated bilirubin  level is seen   • With chronic illnesses the albumin tends to  gradually fall to low levels.   • An elevated serum urea or creatinine with  dehydration or if the kidney function is  impaired   • A urine or serum beta HCG level in all women  of childbearing age may be indicated.   • In patients with history of TB, tobacco CHF,  smokers, and infection.   • TB, malaria, brucellosis, infective endocarditis,  hepatitis serology (HBsAg, HCV antibodies),  and viral markers (CMV, EBM).   • Should be considered in any patient whose  history of sexual risk factors and examination  is suggestive of the infection.   • Increased levels in polymyositis, dermato-  myositis, muscular dystrophy, drug-induced  myopathy (e.g. corticosteroids, statins,  gabapentin, colchicine, cyclosporin).   • The Tensilon test is best suited for examining  focal weakness of ocular or pharyngeal  muscles in suspected myasthenia gravis. If  the lid ptosis is a result of myasthenia gravis,  one will observe dramatic improvement in  the ptosis within 30-45 seconds after IV  Tensilon; lid ptosis typically will reappear 2-  3 minutes later. The Tensilon test is positive  in more than 90% of patients who have  myasthenia gravis.   • In patients suspected with leukemia,  lymphoma, lymphoproliferative disorders,  and neoplastic disease.   • Age and gender-related cancer screening - for  breast cancer, cervical cancer, endometrial  cancer, colorectal cancer, lung cancer, and  prostate cancer; or specific diagnostic methods  may be indicated in patients with obscure  cause of tiredness.   • The primary purpose of evaluating a patient  with tiredness is to identify its source or  contributing factors. Exhaustive, unfocussed  evaluations are not likely to be rewarding   • It is very useful to ask patients to define their  understanding of 'tiredness'. Characterizing  the patient's complaints in terms of onset,  associated symptoms, variability in symptoms,  stressors, precipitating and alleviating factors,  pre-existing medical conditions, and  medications can help in narrowing the  potential causes of tiredness and direct the  initial investigations   • Similarly, family issues, including children,  relatives, diverse, death, abuse, violence,  trauma, financial difficulties, and habits  should also be assessed    associated with family or social stressors, mood  disturbances, and associated with either  insomnia or early morning awakening  (depression) is more likely to be psychogenic. The  patient presents with multiple and non-specific  symptoms with a normal physical examination.   • Organic— Tiredness from organic causes is  acute in onset and shows a progressive  course; stressors are often absent; family  dynamics is sound and supportive. Sleep  disturbances may be present, but is often  related to the underlying disease process.  Tiredness is less in the morning and worsens  with activity. The patient presents with  associated symptoms (Table 43.1), and the  physical examination usually suggests  potential underlying cause   • A mixed category of tiredness is more  common which involves any of the above  entries occurring in combination. One  abnormality discovered may be treated and  resolved without changing the patient's  symptoms of tiredness (e.g. hypothyroidism  or malignancy with depression). A balanced  approach is essential to solve such problems   • In patients with tiredness, recognition of the  symptoms of sleep deprivation is essential,  as many such patients do not have a clear  awareness of their own sleepiness. Therefore,  a detailed ‘sleep history’ (Ref. Table 28.1, page  no. 192) is mandatory, because sleep disorders  are often associated with excessive daytime  sleepiness which can be misunderstood by  the individual as tired feeling 6, 7   • Physical examination— May reveal depressed  patient with characteristic sad facial expre-  ssion; skin pallor, petechiae, ecchymoses,  purpura (anemia, leukemia); skin pigmen-  tation (Addison's disease); lymphadenopathy  (infection, leukemia, metastasis ); hepatosp-  lenomegaly(infections, cirrhosis, malignancy,  leukemia); stigmata of alcohol or drug abuse  (gynecomastia, palmar erythema, needle  tracks, infected skin lesions); and thyromegaly   deficiency of iron, folic  acid, malabsorption  syndrome); CAD; cardiac  valvular disease, COPD;  thyrotoxicosis    (hypothyroidism, hyperthyroidism). Cardiac  and lung examination may reveal the presence  of S 3 gallop, wheezing, or rales suggesting a  cardiopulmonary etiology. A neurologic  examination may identify neuromuscular  disease as the cause (e.g. diplopia, ptosis.   • A person may present his symptoms of  tiredness as a hidden agenda or a ticket of entry.  i.e. to discuss symptoms related to some  personal beliefs, e.g. sexual dysfunction or HIV  infection, and psychological symptoms. Such  factors may be more important to the  individual than fatigue or tiredness itself.  Eliciting detail emphatic history usually  uncovers these hidden agendas which  reassures individual's help-seeking behavior. 8   • Avoid exhaustive, unfocussed work up; they  are not likely to be rewarding and in fact may  be counterproductive, reinforcing the  patient's belief in an existence of an insidious  unidentified medical illness.   • Chronic tiredness, lasting over six months, for  which diagnosis is elusive, should not be  confused with CFS; however, the criteria for  CFS may be considered for further evaluation.   • Chronic tiredness with depression or anxiety,  suicidal ideation, and psychomotor retardation  demands careful attention. 9   Burnout Syndrome— It is a popular term rather  than a scientific diagnosis denoting a severe state  of exhaustion and cynicism that occurs frequently  among individuals who do 'people-work' of some  kind. Heavy workload, long hours, prolonged  stress, poor coping mechanisms, low self-esteem  are all associated with burnout syndrome. Some  experts think the condition progresses through  stages— alarm (stress arousal), resistance (energy  conservation), and exhaustion. During the first  stage, the person is irritable, forgetful, anxious,  and unable to concentrate. Physical symptoms  may include hypertension, palpitations, bruxism,  insomnia, headaches, and GI problems. In the    energy conservation stage the person typically  tries to compensate for stress with behaviors like  procrastination, decreased sexual desire, social  withdrawal, cynicism, apathy, resentment, and  substance abuse. However, it's typically not until  the final exhaustion stage that the person realizes  that something is very wrong; symptoms include  sadness, extreme fatigue, severe headache, and  even suicidal ideation. Underlying depression or  anxiety is common in such people— especially if  there's suicidal ideation. A short-term psycho-  therapy or psychopharmacotherapy may be  indicated for stabilization, although taking a  simple break can cure some burnout.   Fibromyalgia— It is a poorly defined, complex,  chronic, and disabling disorder that causes  widespread pain and stiffness in the muscles,  tendons, and ligaments with multiple tender points  (■ trigger points ); most frequent in women aged 20-50.  Symptoms include generalized fatigue or tiredness,  reduced physical endurance, pain in specific areas  of the body, especially neck, shoulders, chest, back  (upper and lower), hips and thighs, insomnia or  poor sleep, sensations of numbness or swelling  (although swelling is not actually present), chronic  headaches, morning stiffness, worst on first arising,  along with unrefreshing sleep and fatigue. It is  commonly associated with conditions such as  depression, anxiety, viral infection, CFS, eating  disorders, physical or sexual abuse, IBS, tension  headache, migraine, and hypothyroidism. Physical  examination is normal except for trigger points ; there  are no specific tests for fibromyalgia; lab work up is  normal.   Myasthenia Gravis — It is an autoimmune condition  in which autoantibodies are developed against the  acetylcholine receptors of neuromuscular junctions.  The disease presents as fluctuating weakness and  fatigability of voluntary muscles. The muscles of  the eyes, head and neck are most commonly  affected. Diplopia or unilateral ptosis is the initial  symptoms in the majority. In severe cases, limb    and trunk muscles are involved and respiratory  function may be compromised. Myasthenia gravis  may be life-threatening when respiratory muscles  are affected (myasthenic crisis). Initial symptoms  may be subtle and only apparent at the end of the  day or when the patient is fatigued. Exacerbations  of myasthenia gravis may be precipitated by the  use of anesthesia, narcotics or sedatives. Other  autoimmune conditions, such as thyroid diseases  and rheumatoid arthritis, are more common in  myasthenia gravis patients and their families. The  diagnosis is confirmed by the Tensilon test,  electromyographic studies, and the finding of  elevated acetylcholine receptor antibodies.   Periodic Paralysis Syndrome— (Familial Periodic  Paralysis, Anderson-Tawil Syndrome) — It is a rare  inherited autosomal dominant condition that causes  occasional episodes of severe muscle weakness,  commonly associated with thyroid disorders.  Episodic bouts of severe weakness in the arms and  legs are the most prominent symptoms. Typically  these bouts occur during sleep, especially after  strenuous activity. Cold, stress, and alcohol may also  produce attacks. Other, less common, symptoms  may include weakness in the eyelids and face  muscles, muscle pain, arrhythmias, difficulty  breathing or swallowing. The two most common  types of periodic paralysis are hypokalemic and  hyperkalemic. Some specific features to the type of  periodic paralysis include:   > Attacks usually last between 4 to 24 hours,  but can last for several days.   > Attacks usually begin in adolescence, but  they can occur before age 10.   > Attacks are usually shorter (lasting 1-2  hours), more frequent, and less severe  than the hypokalemic form; breathing   > Between attacks, patients often expe-  rience muscle spasms or difficulty  relaxing their muscles, a condition known  as myotonia.   Giving oral glucose or glucose and subcutaneous  insulin may trigger a hypokalemic attack,  whereas giving potassium may trigger a  hyperkalemic attack. Because this primarily is  an inherited condition, the most important  aspect of diagnosis is obtaining a family history.   1. Renter EG, et al. Once tired, always tired?  Limitations in function over time of tired patients  in Dutch general practice. Eur J Gen Pract  2007;13(2):67-74.[ PMID: 17534742 : Abstract],   2. Avlund K, et al. Onset of mobility disability among  community-dwelling old men and women. The role  of tiredness in daily activities. Age Ageing. 2003;  32(6):579-84. [PMID: 14599997: Free full text],   3. Avlund K, et al. Factors underlying tiredness in  older adults. Aging Clin Exp Res 2007;19(l):16-25.  [PMID: 17332717: Abstract],   4. Gialamas A, et al. Investigating tiredness in  Australian general practice. Do pathology tests  help in diagnosis? Aust Fam Physician  2003;32(8):663-6. [PMID: 12973880: Abstract],   5. Ridsdale L, et al. Patients who consult with  tiredness: Frequency of consultation, perceived  causes of tiredness and its association with  psychological distress. Br J Gen Pract  1994;44(386):413-6. [PMID: 8790655: Free full text],   6. Guilleminault C, et al. Excessive daytime sleepiness: A  challenge for the practising neurologist. Brain  2001;124(Pt 8):1482-91. [PMID: 11459741: Free full text],   7. Black J, et al. Recent advances in the treatment and  management of excessive daytime sleepiness. CNS  Spectr 2007;12(2 Suppl 2):1-14; quiz 15. [PMID:  17277717: Free full article],   8. Ridsdale L, et al. Tiredness as a ticket of entry. The  role of patients' beliefs and psychological  symptoms in explaining frequent attendance.  General Practice Fatigue Group. Scand J Prim  Health Care 1999;17(2):72-4. [PMID: 10439488:  Abstract].   9. Norton PJ, et al. Suicidal ideation and anxiety  disorders: Elevated risk or artifact of comorbid  depression? J Behav Ther Exp Psychiatry 2008 Jan  18. [PMID: 18294614: Abstract]   In an adult, urinary frequency , i.e. the number of  voids per day varies considerably, depending on  factors such as age, gender, weather, intake of  fluids, food habits, voiding habits, cultural, and  social influences.   At the physiologic level, urination (also  known as micturition, voiding) is a reflex  mechanism (spinobulbo spinal reflex),  facilitated and inhibited by higher brain  centers (pontine micturition center), and  subject to voluntary facilitation and  inhibition. The normal bladder capacity in an  adult is approximately 500 ml, but it can be  voluntarily overridden until the content  reaches 600-800 ml, when the conscious urge  to void becomes difficult to ignore. However,  the micturition reflex can yet be voluntarily  inhibited until it is appropriate to begin  voiding (e.g. a toilet is reached). Any  condition which interferes with such  compliance of the bladder wall, diminished  bladder capacity, and increased irritability of  the bladder or urethra will lead to repeated    desire to micturate. Similarly, increase urine  output, i.e. polyuria, will result in increased  frequency of micturition.   Normally in an adult with an average fluid  intake, the act of micturition is initiated (as a  reflex) when the urine volume is about 300-  400 ml, and occurs 4 to 8 times during the day,  and none or once during the night. Urinary  frequency, strictly speaking, occurs when there  is increased need to urinate more often  without a concomitant increase in the volume  of urine. With no accepted reference range; 1 " 3  urinary frequency may be arbitrarily defined  as frequent urge to urinate without being able  to pass much urine; patients may complain that  they are is voiding more often than they used  to, but the total volume not exceeding 3L per  day. If the total volume is >3L, it is termed  polyuria. Two or more night time voids is  termed nocturia, and urinary urgency is sudden  compelling urge to urinate (patient has to  hurry to the toilet), often accompanied by  bladder pain.    It is critical to differentiate urinary frequency  from urinary incontinence’ , i.e. involuntary release  of urine or loss of bladder control. The four  common types of urinary incontinence include:  Stress incontinence— Characterized by urine  leakage associated with increased abdominal  pressure from laughing, sneezing, coughing,  climbing stairs, or other physical exertion.   Urge incontinence— A sudden, intense urge to  urinate, followed by an involuntary loss (i.e.  leaking) of urine. In urge incontinence, the  bladder is said to be overactive; it's contracting even  when it isn't full. Urge incontinence usually  entails urgency, frequency, or nocturia. These  symptoms are often referred to as the Over Active  Bladder syndrome (OAB).   Overflow incontinence —It is incomplete bladder  emptying, associated with frequent or constant  dribbling of urine, secondary to impaired  detrusor contractility or bladder outlet  obstruction.   Mixed incontinence — It is the coexistence of  stress and urge incontinence, characterized by  involuntary loss of urine associated with  urgency as well as exertion, cough, sneeze, or  any effort that increase intraabdominal  pressure.   These urinary symptoms, i.e. frequency,  urgency, incontinence, and nocturia are commonly  seen overlapping in patients with urologic and  systemic disorders. 4, 5 The prevalence increases  with age, and is more common in women. In the  elderly, it is very common in both sexes. However,  decisions concerning management depend on the  cause of the frequency and the degree of bother  that it causes the patient.    + According to the International Continence Society, urinary  incontinence is defined as a condition of involuntary urine  loss that is objectively demonstrable and is a social or  hygienic problem.   • Urinary tract infections (UTIs — cystitis, vaginitis,  urethritis, pyelonephritis, prostatitis)   • Neurogenic — spastic bladder (e.g. sacral  spinal cord lesion, trauma)    * Symptoms suggestive of cystitis and urethritis, usually in  post-menopausal women with atrophic vaginitis, and post-  coital sexual trauma.   • Microscopy® — leukocytes (10 or more  WBCs / cu. mm in fresh unspun mid-  stream urine sample), possible hematuria,  granular casts, and red-cell casts are  generally seen in UTIs.   • A conventional threshold count of >100,000  (i.e>10 5 ) bacteria/ml indicates active infection   • In symptomatic patients a count of 100 to  10,000 (i.e. 10 2 to 10 4 ) bacteria /ml is  recognized as an infection   • Count of <10,000 (i.e. 10 4 ) bacteria /ml in the  absence of therapy largely rules out  bacteriuria ++ but pathogenic organisms may  be present   • Count of 10,000 to 100,000/ml should be  repeated and cultured.   • The presence of bacteriuria of any degree (i.e.  any growth of pathogenic organisms) in  suprapubic aspirates or of >10 2 bacteria /ml  of urine obtained by catheterization is  virtually diagnostic of UTI.   • Peripheral blood eosinophilia may be an  initial manifestation of eosinophilic cystitis. 6  ( vide infra 11).   § Urine 'dipstick' test — both false-positive and false-  negative results are common.   • Especially diuretic induced hypokalemia is  important as it is responsible for the excess  mortality observed in patients with diuretic  treated essential hypertension and cardiac  abnormalities.   • Midstream clean-catch urine culture is  indicated only in relapse, reinfection, and  conventional therapy resistant UTIs, and in  those with predisposing conditions such as  complicated UTIs* **, diabetes mellitus, or  immunocompromised state.   • To detect renal size, calculus, obstruction,  mass lesion, and to measure postvoid urine  volume in BPH   • US of pelvis for prostate hypertrophy®® in  men, and lesions of uterus, ovaries in women.   • Dual-phase helical CT of kidney allows  different phases of excretion to be studied    (nephrographic phase compared to corti-  comedullary phase) and can define the extent  of the disease and identify significant  complications and obstruction   • Renal masses, bladder, and prostate tumors  and calculi, including lucent, low-density  calculi (e.g. uric acid stones) are well seen on  helical CT scan   • Limiting nonenhanced spiral CT (NECT) is  the preferred choice in patients who do not  have classical symptoms of renal colic; older  patients, and in those with a contraindi-  cation to the administration of intravenous  contrast media. 7   • Largely replaced by US and CT scanning, 8  but still plays a role in the diagnosis of  calculus disease.   • Indicated if cranial diabetes insipidus, e.g.  polyuria due to pituitary craniopharyn-  gioma is suspected   • To rule out spinal cord lesion from trauma,  tumors, or spina bifida.   • Indicated for patients with persistent  irritative voiding symptoms — frequency,  urgency, dysuria, or hematuria   • To diagnose bladder lesions such as cystitis,  stone, tumor, and urethral strictures.   • Ask the patient how many times a day he or  she voids, and how this compares to previous  pattern of voiding    • Toileting record — One of the most helpful  components of the history is the record kept  by the patient or caregiver during a 48- to  72-h period. The chart records the volume  and time of each void or incontinent episode.  A detail list of questionnaire and 24 hr  bladder diary is an extremely valuable tool  to differentiate various voiding symptoms 9   • Clarify whether frequent urination is associated  with excessive urination, or frequent attempts  to urinate with only reduced urine output; the  former indicates frequency with polyuria, e.g.  in diabetes mellitus, and the latter frequency  alone, e.g. in UTIs, BPH   • An approximate estimate of how much fluids  the patient is consuming in a day helps to  determine hydration status, detect excessive  thirst in diabetes mellitus and diabetes insipidus,  and also detect habitual overdrinking   • Caffeine intake, alcohol abuse, and diuretics cause  frequent urination. Some medications cause  nephrogenic diabetes insipidus, e.g. lithium,  leading to frequency and excess voiding   • Sexual history helps in assessing risk of  sexually acquired urethritis   • Past history of CNS infection such as  meningitis or hypothalamic-pituitary surgery  is the common cause of diabetes insipidus  resulting in polyuria and frequency   • Associated symptoms like fever, chills, loin  pain radiating to groin, dysuria, urgency,  terminal dribbling of urine, acute retention of  urine, etc. are pointers to UTIs, calculi, and BPH   • Morbid anxiety is a common cause of urinary  frequency; usually associated with other  genitourinary and sexual symptoms such a  dysuria, impotence, and frigidity. Other  symptoms of anxiety such as palpitation,  sweating, hyperventilation, dizziness, and  headache are also present   • Physical examination includes assessing state  of hydration, vital signs, abdominal palpation    for distended bladder due to retention or  urethral obstruction. In women, pelvic  examination, and in men digital rectal  examination should be performed. Abnormal  neurological findings such as deep tendon  hyperreflexia or absence of the bulbocaver-  nosus reflex suggest the possibility of  underlying neurologic lesion.   • UTI in male— In every male who has even  one episode of UTI, a careful search must be  made for possible cause; history of sexual  exposure may need direct inquiry   • In all women of childbearing age, exclude  pregnancy by doing a pregnancy test if a  period has been missed. The chances of an  unrecognized pregnancy presenting with  polyuria can thus be minimized   • Urinary tract TB is a common masquerade;  presenting in various systemic and genito-  urinary symptoms. Diagnosis depends on  constant awareness, especially in patients  with sterile pyuria   • In patients with irritative voiding symptoms  associated with neurologic signs such as  diplopia, blurred vision, paresthesia, consider  neurogenic bladder— multiple sclerosis is a  strong possibility   • Not all prostate hyperplasia is benign;  periodic prostate cancer screening is indicated  in select cases. Prostate cancer often is  asymptomatic despite extensive spread   • Interpret elevated prostate specific antigen  (PSA) with caution, as it may be elevated in  both BPH and prostate cancer.    predominantly with eosinophils, associated with  fibrosis with or without muscle necrosis. The  cause of EC remains unclear, although it has been  associated with various etiological factors, such  as allergy, bladder tumor, bladder trauma,  parasitic infections and chemotherapeutic  agents. EC is, probably, caused by the antigen-  antibody reaction. This leads to the production  of various immunoglobulins, which, in turn,  cause the activation of eosinophils and initiates the  inflammatory process. The most common  symptom complex consists of frequency,  hematuria, dysuria and suprapubic pain.  Cystoscopy and biopsy are the gold standard for  diagnosis. Additional laboratory evidence  supporting the diagnosis includes proteinuria,  microscopic hematuria and peripheral eosinophilia,  the last one occurring in few patients. There is no  curative treatment for this condition. Current  treatment modalities include transurethral resection  of the bladder lesion along with nonspecific  medical therapy, such as nonsteroidal  antiinflammatory agents or steroids. Because the  lesion tends to recur in spite of the above therapy,  long-term follow-up is mandatory '. 10 ' 11    1 . Latini JM, et al. Voiding frequency in a sample of  asymptomatic. American Men. J Urol  2004;172(3):980-4. [PMID: 15311017: Abstract],   2. van Haarst EP, et al. The 24-h frequency-volume  chart in adults reporting no voiding complaints:  Defining reference values and analyzing  variables. BJU Int 2004;93(9):1257-61. [PMID:  15180618: Abstract],   3. Fitzqerald MP, et al. Urinary habits among  asymptomatic women. Am J Obstet Gynecol  2002;187(5):1384-8. [PMID: 12439535: Abstract],   4. Clemens JQ, et al. Overlap of voiding symptoms,  storage symptoms and pain in men and women. J  Urol 2007;178(4 Pt l):1354-8. [PMID: 17706719:  Abstract] .   5. Barry MJ, et al. Overlap of different urological  symptom complexes in a racially and ethnically  diverse, community-based population of men and  women. BJU Int 2008;101(1):45-51. [PMID:  17868419: Abstract],    6. Lin HH, et al. Blood eosinophilia, corticoadrenal  insufficiency and eosinophilic cystitis. Urol Int  2008;80(2):219-21. [PMID: 18362497: Abstract],   7. Mendelson RM, et al. Renal colic: A prospective  evaluation of non-enhanced spiral CT versus  intravenous pyelography. Australas Radiol 2003;  47(l):22-8. [PMID: 12581050: Abstract],   8. Wang JH, et al. Prospective comparison of unenhanced  spiral computed tomography and intravenous  urography in the evaluation of acute renal colic. J Chin  Med Assoc 2008;71(l):30-6. [PMID: 18218557: Abstract],    9. Web sites: http://misc.medscape.com/pi/editorial/  clinupdates/2008/12690/art-blaivas. fig2.pdf; http:/  /misc. medscape.com/pi/editorial/clinupdates/  2008/12690/art-blaivas. fig3.pdf. Accessed on  02.10.08.   10. Teegavarapu PS, et al. Eosinophilic cystitis and its  management. Int J Clin Pract 2005;59(3):356-60.  [PMID: 15857336: Abstract],   11. Itano NM, et al. Eosinophilic cystitis in adults. J  Urol 2001;165(3):805-7. [PMID: 11176473: Abstract],   Urticaria is a heterogeneous group of disorders  characterized by production of 'wheals', (also  called as 'hives'), i.e. itchy, transient, erythe-  matous, or pale, edematous swellings of the  superficial layers of the dermis which blanch on  pressure; each individual lesion is short-lived,  lasts for few minutes to several hours, seldom  more than 24 hours; episodes may recur daily  or several times each day for days, or years.  Wheals are rounded, oval, or ill-defined closely  placed lesions which may coalesce to form  various shapes and sizes from a few millimeters  to few centimeters. Any part of the body may be  affected, trunk being more commonly involved  than extremities or face.   Angioedema is a condition which involves  subcutaneous or submucosal tissue (rather than  the dermis), with sudden, diffuse, nontender  swelling of the involved parts, primarily of the   * Urticaria was described in 1772 by Heberden W. as "little  elevations upon the skin in the 'nettle' rash that often  appears involuntarily and seldom stays many hours in the  same place. There is nobody exempt from 'them' and by  far the greatest number experience any other evil from it  besides the intolerable anguish arising from the itching..."  (Heberden W. Of the Nettle Rash Transactions: College of  Physicians, London, 1772; 2; 173).    lips, periorbital areas, or genitalia. Occasionally  there may be swelling of the tongue or pharynx  which can be life-threatening, but the larynx is  virtually never involved. 1 The pruritus that  usually accompanies urticaria is conspicuously  absent in angioedema.   Urticaria and angioedema may coexist.  Angioedema accompanies urticaria in approxi-  mately 40% of patients, another 40% of patients  have hives alone, and about 20% of patients have  angioedema but not urticaria. 1   Acute — If the symptoms last less than 6 weeks;  etiological trigger is more likely to be identified  in acute urticaria such as drug reactions, and  food or contact allergies.   Recurrent acute urticaria — This is recurrent  episodes of urticaria, each episode lasting less  than six weeks.   Chronic — If there are recurrent episodes occurring  daily or almost daily for longer than six weeks.  The history itself can be regarded as the most  valuable diagnostic tool in identifying causes of  chronic urticaria; extensive laboratory studies    provide little information beyond that suggested  by the patient's history and physical examination.   From the patient perspective, chronic  urticaria affects as many dimensions of the  health-related quality-of-life as some life-  threatening diseases or well-recognized  disabling chronic skin disorders, such as  psoriasis or atopic dermatitis. Recent trials have  highlighted the serious disability of patients with  chronic urticaria, including loss of sleep and  energy, social isolation, altered emotional  reactions, and difficulties in aspects of daily  living. The disability is of the same order as that  experienced by patients with severe chronic  ischemic heart disease . 2, 3   • Infections (occult bacterial infection involving  sinuses, teeth, gums, gallbladder, chest,  genitourinary tract; mycoplasma, H. pylori  enteritis; viral infections: hepatitis A, B, and  C, infectious mononucleosis; fungal  infections: dermatophytosis, candidiasis)   • Ingestions (foods and food additives: eggs,  sea-food, nuts, metabisulfites, tartrazine, azo  dyes)   • Injections, i.e. drugs + (aspirin, penicillin,  sulfonamides, opiates, ACE-inhibitors, blood  products, herbal products)   • Contact urticaria (latex sensitivity, hair  bleaches, kumkum, cosmetics, lipsticks,  sunscreens, dental prosthesis, dental filling).   + Drugs taken as long as a month prior to the onset of  symptoms may induce urticaria.   • Pregnancy (Pruritic urticarial papules and  plaques of pregnancy, i.e. PUPPP ) 4   • Systemic disease (connective tissue diseases) :  Juvenile RA, SLE, vasculitis: vide infra 4 - 4 -;  endocrine disorders: Hashimoto's thyroiditis.  Graves' disease, diabetes mellitus; neoplasms:  lymphoma, leukemia, carcinoma, myeloma.  Sweet's syndrome: vide infra 4 - 4 -   • Skin diseases: Urticaria pigmentosa, i.e.  mastocytosis; dermatitis herpetiformis;  pemphigoid; amyloidosis   • Genetic: Autosomal dominant hereditary  angioedema, i.e. HAE: vide infra 4 - 4 -.   • WBC count may be elevated in systemic or  dermal infection; eosinophilia would prompt  a search for parasitic diseases, vasculitis, or  drug reactions.   • An elevated ESR suggests the possibility of  an underlying systemic disease.   • Proteinuria or hematuria may be due to either  a primary renal disease or secondary to  connective tissue disorder.   • To detect ova or cysts of helminthic or  protozoal infection.   • This may be performed as indicated by  patient's history; e.g. test for dermographism  by stroking patient's skin by a blunt, narrow  object (tongue blade); pressure urticaria by  application of pressure for defined time and  intensity; cold urticaria by ice cube test;  aquagenic urticaria by challenging with tap  water at various temperatures; solar urticaria  by exposure to defined wavelengths of light,  red cell protoporphyrin, fecal protoporphyrin,  and coproporphyrin.   • In patients with history of fever and sore  throat for streptococcal infection.   • LFTs for evidence of hepatocellular or  obstructive jaundice; urea, creatinine, and  electrolytes for renal disorders (pyeloneph-  ritis, glomerulonephritis, nephrotic syndrome,  renal failure); serum glucose for evidence of  diabetes mellitus, and serum calcium to screen  for malignancy.   • TFTs, including thyroid autoantibodies  (antithyroglobulin and antimicrosomal  antibodies) may be helpful, given the  association of chronic urticaria with  Hashimoto's disease, and Graves' disease.  Annual reassessment of TFTs in euthyroid  patients may be indicated who have elevated  antibody titers.   • IgM anti-HAV; IgM anti-HBc; HBsAg, i.e.  Hepatitis B surface antigen may be present    in acute infection or in patients who are  chronic carriers; anti-HCV; and H. pylori fecal  antigen test.   • To determine specific allergens responsible  for urticaria, anaphylaxis, or food reactions;  however, diagnosis of allergy to a specific  allergen cannot be made on the basis of  testing alone; it requires correlation of the test  results with the clinical history.   • IgE concentration by RAST and ELISA  method may be indicated in patients  suspected with allergy due to food, insect  bite, or latex allergy. Immunoassay is  appropriate for patients in whom skin testing  cannot be done (e.g. those who are unable to  discontinue use of interfering medications,  those who have severe dermatographism or  eczema, and those who have had a near-fatal  reaction to an allergen ). 5   • Indicated in all the patients with chronic  urticaria because a positive test is suggestive  but not diagnostic of an autoimmune basis  for the patient's chronic urticaria. Confir-  mation is needed by in vitro testing of the  patient's serum for the anti-FCeRIa or the  anti-IgE autoantibodies. In vitro 'the basophil  histamine release assay' is currently the gold  standard for detecting functional auto-  antibodies. However, it is available only at a  few research centers and cannot be performed  as a routine.   • Complement determinations are not indicated  for patients who have urticaria alone (since    the values are normal), nor need they be done  when angioedema accompanies chronic  urticaria, since patients with a hereditary or  acquired deficiency of Cl inhibitor do not  have hives. Only in patients who present with  angioedema alone, as in HAE, is  measurement of C4 indicated, followed by a  determination of the levels and function of  Cl esterase inhibitor, if C4 levels are below  normal.   • In patients with cold urticaria; presence of  cryoglobin suggests chronic hepatitis or  malignancy.   • May be indicated in patients with chronic  urticaria with features of connective tissue  disease such as Raynaud's phenomenon,  arthralgia, photo sensitivity, and rash.   • Helpful in patients with urticaria that persist  for more than 24 hours; chronic urticaria; or  urticaria associated with fever, arthralgia,  and elevated ESR suggesting urticarial  vasculitis.   • The diagnosis of urticaria is primarily  clinical; based on a good history, physical,  and systemic examination (Table 45.1)   • Small transient wheals;  with surrounding  flare; extends from neck to  thigh   • Urticaria develops 2-6 hr  after pressure, lasts for  12-72hr.; e.g. buttocks  (prolonged sitting); waist  (tight underclothes);  hands (in manual labor)   • Chronic urticaria,  frequently lasting >24 hr,  more painful than itchy,  associated with extracut-  aneous manifestations  such as fever, arthralgia,  nephritis, and leaving  areas of discoloration as  lesions resolve; may be  triggered by infection,  drugs, or malignant  disease; skin biopsy is  diagnostic   • Occurs with or without  urticaria; angioedema  without urticaria may  indicate a Cl-esterase  inhibitor deficiency, e.g.  HAE; commonly involves  the lips, eyelids, face,  extremities, and genitalia  in an asymmetr-ical  manner   • Cholinergic urticaria  (sweating due to anxiety,  strenuous work, hot bath,  alcohol)   • Maintaining daily diet diary and occurrence  of skin lesions for fixed duration (2 to 4 weeks),  including drugs ingested and activities may  be helpful in guiding the etiology. However,  it's to be noted that hypersensitivity reactions  can develop at any time despite years of  uneventful exposure   • Because of the effervescent (i.e. appearance  varying in minutes over hours) nature of the  urticaria, its features may be difficult to  evaluate on a particular occasion. However,  careful examination of the skin lesion is  important because special forms of urticaria  have special features, e.g. dermographism,  cold urticaria, cholinergic urticaria, etc   • A comprehensive physical examination of  skin, lymph nodes, eyes, joints, throat, neck,  ears, lungs, heart, and abdomen can uncover  important diagnostic clues that may help  diagnose comorbidities such as connective  tissue disorders, thyroid disease, and  lymphoreticular neoplasms   • The most common cause of acute urticaria is  drug reaction; however, up to 50% of cases  of acute urticaria a cause is not identified   • A chronic urticaria, frequently lasting more  than 24 hours, more painful than itchy,  associated with extracutaneous manifestations  such as fever, arthralgia, nephritis, COPD, and  leaving areas of discoloration as lesions resolve,  is suggestive of urticarial vasculitis   • Patients who have both urticaria and  angioedema tend to have more severe and  persistent disease than patients with only one  of the disorders   • Despite a complete examination and  extensive laboratory studies, a cause of  chronic urticaria is usually not identified.   • Since fatal reactions are known to occur with  challenging testes for foods or drugs, they are  indicate only in rare cases with compelling  reasons to confirm the causative allergen with  facilities available for monitoring the patient. 7 ' 8   • Any patient with tongue edema or edema of  the floor of the mouth and laryngeal edema  should be hospitalized for airway monitoring.   • Patients with chronic urticaria, suspected to be  due to urticarial vasculitis need to be fully  investigated for evidence of other autoimmune  connective tissue disease or other internal organ  involvement.   • Beware of most serious drug reactions such  as erythema multiforme (EM), Stevens-  Johnson syndrome (SJS), and toxic epidermal  necrolysis.   Hereditary Angioedema— HAE is an autosomal  dominant condition caused by a deficiency of the  plasma protein Cl inhibitor that afflicts 1 in 10,000  to 1 in 150,000 persons. HAE has been reported  in all races, and no sex predominance has been  found. It manifests as recurrent attacks of intense,  massive, localized edema without concomitant  pruritus, often resulting from one of several  known triggers such as trauma, surgery, dental  manipulation, or accidents. However, attacks can  occur in the absence of any identifiable initiating  event. The most commonly involved viscera are  the respiratory and gastrointestinal systems.  Involvement of the upper airways can result in  severe life-threatening symptoms, including the  risk of asphyxiation, unless appropriate  interventions are taken. This condition can be  differentiated from angioedema in that urticaria  does not occur, the lesions are not pruritic, and  the lesions are nonresponsive to antihistamines  and epinephrine. Historically, 2 types of HAE    have been described— an acquired form of this  disorder may also be observed, sometimes in  association with an underlying lymphoma. It is  important to consider this disorder in the  differential diagnosis of unexplained, episodic  cutaneous angioedema or abdominal pain.  Quantitative and functional analyses of Cl  esterase inhibitor and complement components  C4 and Clq should be performed when HAE is  suspected.   Sweet's syndrome (Acute febrile neutrophilic  dermatosis or acute neutrophilic dermatosis) —   Named after Dr Sweet from Plymouth, England,  who first described this condition in 1964, is a  reactive process to an internal condition such as  URTI, vaccination, pregnancy, IBD, RA, leukemia,  internal malignancy, and drugs, e.g. NSAIDs,  cotrimoxazole. It may also occur as a result of  external triggers such as needle prick, biopsy or  insect bite. In some patients they arise only in sun  exposed areas, but in others no underlying  condition is found. It is characterized by the  abrupt onset of tender, red-to-purple papules, and  nodules that coalesce to form plaques. The  plaques usually occur on the upper extremities,  face, or neck and are typically accompanied by  fever and peripheral neutrophilia. It most often  occurs in middle-aged women, but men, children  and the elderly may also be affected. Common  symptoms include high or moderate fever;  arthralgia; and one or more tender red papules  or plaques which enlarge and persist for several  weeks, they may have blisters, pustules or ulcers,  and sometimes they appear to clear in the center.  Sometimes other organs are affected including  bones, nervous system, kidneys, intestines, liver,  heart, lungs, muscles and spleen. Investigations  may reveal: raised ESR or CRP, indicating  systemic inflammatory disease; raised WBC count  (neutrophil leukocytosis); and numerous  neutrophil inflammatory cells on skin biopsy,  without leukocytoclastic activity. Sweet's lesions  resolve eventually without leaving a mark or scar.    with or without treatment. Sweet's syndrome  does not appear to be as rare as it seems though a  full blown classical picture may not be observed  in each case. Raised, erythematous and painful  plaques, particularly if they are asymmetrical,  especially in females, should arouse the suspicion  of this entity. This is more likely in patients who  have underlying malignancy.   Urticarial vasculitis— It is thought to be due to  immune complex mediated inflammation (i.e.  hypersensitivity vasculitis). Although the  prevalence of urticarial vasculitis is low, it is  nevertheless important to recognize because this  disease can be associated with other systemic  conditions (e.g. SLE, Henoch-Schonlein syndrome)  and is amenable to effective treatment. It is more  common in women than in men, and it usually  presents in the fourth decade of life. If skin lesions  have an urticarial appearance and last longer than  24 hours in the same location, urticarial vasculitis  should be considered. Typically these urticarial-  like lesions are:   • Less pruritic and more painful than observed  with true chronic urticaria   Angioedema may accompany urticarial  vasculitis. In addition, urticarial vasculitis may  be associated with systemic signs and symptoms  such as fever, arthralgia, arthritis, uveitis,  episcleritis, hematuria, wheezing, chest pain,  and diarrhea. Histopathologic findings include  swelling of endothelial cells, neutrophilic  perivascular infiltration, extravasation of  erythrocytes, leukocyto-clasis (nuclear dust), and  fibrinoid deposits around blood vessels.  Hemorrhage and edema of the dermis may also  occur. The clinical course is usually benign, on  average lasting 3 years. The prognosis varies,  depending on whether the diagnosis is  normocomplementemic urticarial vasculitis    syndrome (NUVS) or hypocomplementemic  urticarial vasculitis syndrome (HU VS). NUVS is  more benign than HUVS, but both disorders are  rarely fatal.    1 . Kaplan AP. Chronic Urticaria and Angioedema. N  Engl J Med 2002;346(3):175-90.   2. Greaves MW, Sabroe RA. ABC of Allergies. Allergy  and the skin. I-Urticaria. BMJ 1998;316:1147.   3. Grob JJ, et al. Urticaria and quality of life. Clin Rev  Allergy Immuno 2006;30(1):47-51. [PMID:  16461995: Abstract],    4. Brzoza Z, et al. Pruritic urticarial papules and  plaques of pregnancy. J Midwifery Womens Health  2007;52(1):44-8.[PMID: 17207750: Abstract]   5. Volcheck GW. Which diagnostic tests for common  allergies? Where to start when you face an allergy  puzzle. Postgrad Med 2001;109(5):71-85.   6. Yadav S, Upadhyay A, Bajaj AK. Chronic urticaria:  An overview. Indian J Dermatol 2006;51:171-7.   7. Wang Jet, et al.A. Food anaphylaxis. Clin Exp Allergy  2007;37(5):651-60. [PMID: 17456212: Abstract],   8. Rezvani M, et al. Anaphylactic reactions during  immunotherapy. Immunol Allergy Clin North  Am 2007;27(2):295-307. [PMID: 17493504:  Abstract],   Vaginal bleeding, as the term suggests, involves  bleeding from the vagina, which may happen  to a woman at any stage of her life. 1 " 3 There are  two types of vaginal bleeding. The normal vaginal  bleeding, with its characteristic features (Table  46.1), called as menstruation, which occurs with  the onset of ovulation beginning with menarche  (between 10-16 years of age), and ends with  menopause (between 45-55 years of age).    Abnormal vaginal bleeding (AVB) may be  defined as bleeding from the vagina due to a  disorder in the vagina or related reproductive  organ, particularly the uterus, and which may  occur in association with or independent from  menstruation. Thus, vaginal bleeding is  considered to be abnormal if it occurs:   • When there is a significant deviation from the  normal menstrual cycle, i.e. menstruation, and    • At a time when it is not expected, such as  before age 10 (precocious menstruation),  during pregnancy, or after menopause.   The following terms (Table 46.2) are used to  describe AVB related to the menstrual cycle, i.e.  abnormal uterine bleeding (AUB), on the basis of  its duration, amount, and frequency of the bleeding.   Prolonged (>5 days) or excessive  (>80 ml) menstrual bleeding at  regular intervals (21-35 days)   Irregular, frequent menstrual  bleeding that is not prolonged or  excessive (acyclic bleeding)   Regular menstrual bleeding at inter-  vals of less than 21 days (frequent  menses or shortened cycle)   Menstrual bleeding at intervals of  more than 35 days, but less than 90  days (infrequent menses)   No menstrual bleeding for 90 days  (3 usual cycle lengths) or longer   Menstrual bleeding (usually not  excessive) between otherwise regu-  lar menstrual cycles    Categorizing particular bleeding pattern as  defined above is one way of considering cases of  AUB. Although each category of menstrual  dysfunction has a particular list of causes,  necessary testing, and treatment; 'there is no  consistent relationship between abnormal  bleeding patterns and their causes'. 4 Since AVB  can present in many forms, pinpointing the cause  for bleeding abnormality can be challenging.  However, with the basic knowledge of menstrual  physiology, and a thorough approach, the  problem can be managed with confidence.   • Physiologic (ovulatory bleeding, i.e. midcycle  ovulation; hypothalamic-pituitary-ovarian  immaturity as in perimenarcheal age;  transition to premature ovarian failure as  in perimenopausal women)   • Complications of early pregnancy (abortion:  Threatened, incomplete, complete or mis-  sed)   • Pelvic inflammatory diseases (PIDs: STDs, TB  endometritis, salpingitis, cervicitis, vaginitis)   • Breakthrough bleeding (BTB) on oral / injec-  tables contraceptives, HRT   • Benign disorders (cervical or endometrial  polyps, cervical erosion, adenomyosis, endo-  metriosis)   • Complications of late pregnancy (placenta  previa, abruptio placenta, premature labor,  subinvolution of the placental site)   *DUB is a symptom complex that includes any condition  of AUB in the absence of pregnancy, neoplasm, infection,  and other pathology of the female genital tract as well as  other systemic cause of abnormal bleeding.   • Bleeding disorders (von Willebrand's dise-  ase, thrombocytopenia, leukemia, hemo-  philia, thalassemia)   • If premenopausal, urine (3-hCG; if ectopic  pregnancy is suspected serum (3-hCG-preg-  nancy test will be more definitive.   • Hemoglobin — Low Hb in chronic AUB;  however, a patient may have normal Hb and  hematocrit in spite of a heavy menstrual flow.  Excess menstruation may result in iron  deficiency, but iron deficiency anemia is a late  manifestation of excessive menstrual flow.  Therefore, a history of excessive menstrual  flow should not be discounted simply on the  basis of normal hemoglobin valve   • Diabetes mellitus is a risk factor for endo-  metrial carcinoma, and women with PCOS  have been recognized to have an increased  incidence of diabetes mellitus (and adverse  cardiovascular events which constitute  'metabolic syndrome').   • TSH, FT4, for possible thyroid dysfunction  in patients suspected with anovulatory  cycles.   • To detect uterine and ovarian abnormalities  (bicornate uterus, tumors, PCOS), hyda-  tidiform mole, and to establish the cause of  bleeding in pregnancy.   • Invaluable in the initial evaluation in women  at low risk for endometrial cancer. Adnexa,  ovaries, fibroids, and the endometrium for  its thickness (i.e. endometrial echo) can be  assessed to decide whether the patient  requires further evaluation with saline  infusion sonography (SIS) and hysteroscopy.  Normally the endometrial echo measures less    than 5 mm. Increased endometrial thickness  is associated with endometrial hyperplasia,  endometrial polyps, fibroids, and endome-  trial cancer. When the endometrial echo is  greater than 5 mm, or is indistinct or indeter-  minate, an enhanced view is required with  SIS or hysteroscopy. An endometrial echo of  less than 5 mm is associated with malignancy  in less than 0.5% of cases.   • To diagnose intracavitary lesions, endo-  metrial hyperplasia, and carcinoma. Current  indications for SIS include:   > Evaluation of an endometrium that is  thickened, irregular, immeasurable, or  poorly defined on conventional TVUS;   > The need to differentiate between sessile  and pedunculated masses of the endo-  metrium; and   • "SIS is a simple and elegant examination that  yields additional information over TVUS of  the uterus. Because the walls of the endo-  metrium are separated by SIS, they can be  evaluated individually. Focal abnormalities  are beautifully displayed by this technique.  This information can then be used to direct  the intervention. Biopsy of diffuse abnor-  malities can be performed with a blind  technique, whereas focal abnormalities are  best approached with a visually guided biopsy.  SIS requires minimal patient preparation, has  very few complications, and is well-tolerated  by patients. Given its advantages over other  techniques for uterine evaluation, SIS will    likely play an even larger role in pelvic imaging  in future" 5   • Further, three-dimensional saline infusion  sonography (3D SIS) is found to be valid and  reliable in women suspected of having  intrauterine abnormalities, and may indeed  have relevant clinical value in addition to  conventional SIS. 6   • Flexible hysteroscopy allows direct visuali-  zation of the endometrium and it can be used  for directed biopsy and removal of small  polyps.   • von Willebrand panel, including von Wille-  brand antigen and ristocetin cofactor assay,  and other tests for intrinsic qualitative  platelet disorders are indicated in adole-  scents and in patients with family history  of bleeding diathesis if a bleeding disorder is  highly suspected.   • In ovulatory cycles— preovulatory serum pro-  gesterone values are <1 ng/ml; and post-  ovulatory serum progesterone values are  >5 ng/ml   • In anovulatory cycles, serum progesterone  values never exceed 5 ng/ml.   • Ratio of LH: FSH >3 indicates PCOS; FSH  > 40 U/ml indicates imminent ovarian failure.   • Hyperprolactinemia needs to be ruled out  in women with anovular cycles.   • In women with hyperandrogenic symptoms  and signs - serum testosterone > 60 ng/dl  supports the diagnosis of PCOS   • If serum testosterone > 150 ng/dl, then 17-  hydroxyprogesterone estimation is indi-  cated to rule out functional adrenal or  ovarian neoplasm.   • High titers in trophoblastic disease like  hydatidiform mole (molar pregnancy) or  choriocarcinoma.   • To evaluate for adrenal or ovarian tumor in  women with hyperandrogenic symptoms  and signs with elevated serum testosterone  andDHEA-S.   • To detect adenoma; prolactinomas are the  most common hormone-secreting pituitary  adenomas.   • EMB is indicated in women older than 35  years of age who have AUB associated with  increased risk factors for endometrial  hyperplasia and endometrial cancer. Biopsy  is also indicated for patients aged 18 to 35  years with risk factors for endometrial  cancer. Risk factors include:   • Confirm source of vaginal bleeding— uterine  or extrauterine. It is not uncommon for a  woman to be unaware of the exact source of  an unexpected and AVB. She may just  complain that she has noticed blood on her  undergarments or on the tissue paper after  wiping external genitalia and that she cannot  find a reasonable explanation for such  abnormal bleeding — it being significantly  different from her previously established  pattern of menstrual flow. Therefore, the first  and foremost thing to do is to obtain careful  history to ascertain that the blood is flowing  from the vagina, and not from the rectum or  mixed with urine (i.e. associated with bowel  movements or urination), thus focusing on  genital etiologies, predominantly uterine  (AUB). Examination of stools for the presence  of blood (hematochezia) and urine (hematuria)    is helpful to differentiate between vaginal (i.e.  uterine) and extrauterine (i.e. gastrointestinal  or genitourinary) causes of AVB  Rule out or confirm pregnancy, if premeno-  pausal —Because bleeding can indicate a  complicated pregnancy, possible pregnancy  should always be considered in a woman of  child-bearing age. Spotting to minimal bleeding  may be normal, but any bleeding during  pregnancy needs to be evaluated. Heavy  bleeding before 12 weeks may indicate serious  problem, including abortion (threatened,  incomplete, and missed), molar pregnancy, or  ectopic pregnancy; and that occurring after 12  weeks may be due to placenta previa  In premenopausal women— is the bleeding  ovulatory or anovulatory? Normal ovulation  is necessary for regular menstrual cycle; a  distinction between ovulatory and anovula-  tory bleeding is critical because causes and  therapies are distinct (Tables 46.3 and 46.4)   All women with evidence of severe bleeding  on physical examination (e.g. pallor, hypo-  tension) should be fluid resuscitated and  emergently hospitalized.   Ovulation pain (mittelschmerz);  Premenstrual molimina (breast soreness,  bloating — fluid retention, weight gain,  and mood change), dysmenorrhea  (cramps, back pain)   Preovulatory cervical thin mucus  discharge is usually observed halfway  between menstrual cycles   Prolonged bleeding at irregular intervals  after not having a menstrual period for  several months; subjective symptoms  preceding the cycles are absent   DUB, hypothalamic dysfunction—  secondary to stress, depression, eating  disorders, obesity; adolescence; BTB;  endometrial hyperplasia   > Age of onset of bleeding, age of onset of puberty.  Though premenarchal bleeding may be  associated with precocious puberty, local  pathology, as well as adrenal and ovarian  tumors must be ruled out. In adolescence,  AUB is common in the first 2-3 years after  menarche due to many anovulatory cycles.    resulting in irregular, heavy menses and  probably dysmenorrhea. Once ovulation  and menstruation are regularly esta-  blished, the cycle follows a predictable  pattern (Table 46.1) and any deviation can  be considered as AUB.   > Menstrual history —The first day of last  menstrual period should be included in  all adult female patients, i.e. the date that  the menstrual flow began. Many patients  assume that occurrence of any bleeding  is a 'period'. Also, for many women,  monthly may mean once every calendar  month, so that a period on day 1 and day  27 of the same month, while normal, may  strike her as having periods twice a  month. Failure to make this distinction  can result in misleading information. A  menstrual calender + (over three or more  months) can be a very useful guide. The  quantity (the passage of 'clots' or inability  to control bleeding with tampons is  significant and indicates heavy bleeding),  duration, and frequency of bleeding* *  with respect to previous menstrual cycles  are recorded. Any significant deviation  from normal should be noted and  patient's cycles are categorized as in  Table 46.2.   > Postcoital bleeding (any bleeding after  intercourse or in association with  douching) is suggestive of cervical  dysplasia, or endocervical polyps.   > Postmenopausal bleeding (any bleeding  occurring in a postmenopausal woman  at least 1 year after cessation of cycles)  should be evaluated for endometrial  hyperplasia and carcinoma.   *It is not uncommon for women to change their sanitary  products frequently for hygienic reasons or because of  personal preference or concern for toxic shock syndrome  than because of heavy flow.    • Associated symptoms — Pain, discharge, fever,  nausea, vomiting, dysuria; symptoms of  hyperthyroidism (fatigue, weight loss,  sweating, palpitation); hypothyroidism  (fatigue, cold intolerance, constipation);  symptoms of hyperprolactinemia (headache,  nipple discharge, galactorrhea); symptoms  of virilization (excess hair growth); bleeding  diathesis (easy bruisability, petechiae, epi-  staxis, gingival bleeding); etc. should be  addressed   • Personal and family history— Marital status,  parity, infertility, epilepsy, and blood dys-  crasia. Smokers have higher incidence of  menstrual dysfunction   • Medications^ —Oral contraceptives, anticoa-  gulants antidepressants, antiepileptics, anti-  psychotics, opiates. Tamoxifen, and herbal  preparations (ginseng, ginkoba, soya supple-  ments)   • Physical examination — Evidence of puberty  (breast development, axillary and pubic  hair growth); virilization, hirsutism;  hypothyroidism (dry skin, coarse hair,  bradycardia, delayed reflexes); hypert-  hyroidism (sweating, weight loss, palpit-  ation); abdominal distension, tenderness,  hepatomegaly, splenomegaly; skin pete-  chiae; etc.   > Inspection of genitalia — Anatomy, dis-  charge, foreign body, evidence of trauma,  and source of bleeding— uterine or extra-  uterine.   ^Common medications, which increase the cytochrome  P450 enzymatic processes in the liver, may induce more  rapid metabolism of steroid hormones, thereby decreasing  their bioavailability and result in AUB that is secondary to  a relative insufficiency of estrogen or progesterone.    > Pap smear and biopsy of any lesion in  the genital tract.   • May be warranted to identify alternative  sources of bleeding such as rectal or urethral.   • In a woman of reproductive age, pregnancy  should always be ruled out despite a nega-  tive history of sexual activity   • AUB in a woman of reproductive age must  be considered a complication of pregnancy  until proved otherwise   • Vaginal bleeding in a postmenopausal  woman must be considered a malignancy  until proved otherwise   • Reevaluate patients diagnosed with hyper-  plasia with atypia for persistent or  worsening hyperplasia within 3-6 months of  treatment   • Vaginal bleeding that occurs before  pubertal development or normal menarche  should raise suspicion of nonendocrine  causes; rule out adrenal and ovarian tumor,  including rhabdomyosarcoma (sarcoma  botryoides)   • AUB during adolescence should be attri-  buted to a coagulation disorder until proven  otherwise   • AUB before menarche may warrant pelvic  examination under general anesthesia to  exclude focal lesions such as trauma, sexual  abuse or assault, and malignancy   • Any AVB/AUB should be investigated in  women taking Tamoxifen or Raloxifene  because the resulting side effects of these  drugs (indicated in breast cancer) include  an increase in the risk of endometrial cancer  and thrombosis.    1. Hill NC, et al. The etiology of vaginal bleeding  in children. A 20-year review. Br J Obstet  Gynaecol 1989;96(4):467-70. [PMID: 2751960:  Abstract],   2. Fishman A, et al. Vaginal bleeding in premenar-  chal girls: A review. Obstet Gynecol Surv 1991;  46(7):457-60. [PMID: 1876356: Abstract],   3 . Aribarg A, et al. Vaginal bleeding in young child-  ren. Southeast Asian J Trop Med Public Health  2003;34(1):208-12. [PMID: 12971537: Abs-tract],    4. Kilbourn CL, et al. Abnormal uterine bleeding:  diagnostic considerations, management options.  Postgrad Med 2001;109(l):137-50.   5. Berridge, Debra L, et al. Saline infusion sonohys-  terography: Technique, indications, and imaging  findings. J Ultrasound Med 2004;23:97-112.  [PMID: 14756358: Abstract],   6. de Kroon CD, et al. The clinical value of 3-dimen-  sional saline infusion sonography in addition to  2-dimensional saline infusion sonography in  women with abnormal uterine bleeding: Work in  progress. J Ultrasound Med 2004;23(11): 1433-  40. [PMID: 15498907: Abstract],   Vertigo can be defined as a hallucination of an  abnormal sensation of rotation or imbalance of either  the self or the surroundings (e.g. rotating, spinning,  tilting, and swaying). Patients may feel that they  are moving while the surroundings remain still  (subjective vertigo), or that the surroundings move  while they are stationary ( objective vertigo), or that  both they and the surroundings are in motion* It is  usually associated with headache, pallor, sweating,  nausea, vomiting, hyperventilation and imbalance.  The patient tends to keep his head immobile out of  fear of a fresh attack and is disinclined to walk,  especially in crowded surroundings.   In practice, however, it is unusual for patient  to complain of vertigo, i.e. the majority do not  present solely with true spinning vertigo — that  they are moving relative to the surroundings,  or that the surrounding is moving, and that the  symptoms are (or not) provoked by head move-  ments when they are at rest, sitting or lying  down. Most commonly patients complain of  symptoms suggestive of presyncopal episode,   * The distinction between subjective and objective vertigo  is probably of not much localizing value.    such as giddiness + , dizziness, fainting; or  symptoms of disequilibrium, such as inability  to maintain normal gait and normal posture  (Table 47.1). Therefore, the words that patients  use to describe their symptoms of 'vertigo' are  significant because a number of seemingly  synonymous terms often relate to distinct  physiological mechanisms.   The five sensory modalities which cons-  tantly monitor position and motion are: Vision,  vestibular end organs, proprioception, touch  and pressure, and cerebellum. Normally the  brain integrates the input from each of these  sensory modalities giving a comprehensive  image of position and motion in space. This  process enables us to maintain balance, move  about, and interact with other objects. However,  pathology affecting the central nervous system,  eyes, ears, locomotor system, and other systems  such as hemopoietic system, cardiovascular and  endocrine systems may all alter the delicate    + Giddiness is an unpleasant sensation of disturbed relation  to surrounding objects in space. Dizziness, however, is  an imprecise term, generally used collectively to describe  all types of equilibrium disorders, including giddiness,  light-headedness, imbalance, ataxia, vertigo, or minor  episodes of mental confusion.   "the ground tilts up  and down; like being  on a boat at sea".   Poor balance, but not  dizzy; "the problem is  in my legs".   Cerebellar lesion; brainstem lesion;  extrapyramidal disorder; bilateral  vestibular dysfunction; peripheral  neuropathy   Patient senses impending loss  of consciousness; often with  systemic symptoms— nausea,  diaphoresis, dimness of vision,  blackout; inciting event   "I am unsteady on my  feet"; "I am afraid I  will fall".   Often elderly people afflicted by  a variety of ills that summate to  impair the patient's ability to ambulate  unassisted; dramatically improved by  the use of a cane or the supporting  arm of a companion   Multiple concurrent problems; visual  impairment, deafness, peripheral  neuropathy, painful or disabling  orthopedic disorders, and  muscle weakness    balance of neural information resulting in  disequilibrium and vertigo. Hence, proper  understanding of etiopathology, i.e. central  (brain) or peripheral (inner ear, 8th cranial  nerve); coupled with systematic, efficient and  formal evaluation is required in order to provide  appropriate management and rehabilitation.   • Positional vertigo (vertebrobasilar ischemia,  cervical spine dysfunction, or benign paro-  xysmal positional vertigo, i.e. BPPV)   • Vascular (subarachnoid hemorrhage, verte-  brobasilar ischemia, brainstem infarct, cere-  bellar infract, lateral medullary syndrome,  i.e. PICA syndrome: vide infra i4-)    *This term usually refers to elderly persons who often  have altered sensory inputs or premature aging of the  vestibular nuclei.   • Neoplastic (acoustic neuroma, vide infraii,  tumors of brainstem, and floor of IVth ventri-  cle)   • Elevated WBC counts in infection. Elevated  hematocrit (polycythemia) predisposes to  CVA. Decreased Hb% in anemia.   • Pure tone audiogram, speech discriminating  testing, and tympanometry performed in all  patients with significant hearing loss or  tinnitus; valuable in differentiating labyrin-  thine rather than cerebral cortex or brain-  stem lesions as the cause of vertigo.   • Indicated in patients with head trauma to  identify fractures and CVA.   • Acoustic neuroma and other CP angle  tumors; acute vertigo with risk factors for   • Useful screening test in patients with sus-  pected central causes of vertigo. A normal  BSER safely excludes an acoustic neuroma.  If BSER is abnormal, an imaging procedure,  such as MRI, is indicated.   • To evaluate patency of the vessels and to  screen for evidence of plaque precipitating  TTAs.   • May be useful in demonstrating vertebral  foraminal encroachment, which sometimes  compromises arterial blood flow to the brainstem  and the peripheral auditory apparatus.   • Since classifying patient's complaints of vertigo  is made specifically on the basis of a careful  history, it is important to ask the patient to  describe symptoms in detail. It will then become  apparent whether the patient is suffering from  vertigo or other similar symptoms. Important  historical information include:   > The symptoms in the patient's own  words (is it vertigo or something else?)   > Is vertigo due to urgent causes or non-  urgent causes?   > Hearing loss, imbalance, aural fullness,  tinnitus (as in Meniere's syndrome).   > Aggravating factors (as with head  movement, postural change, travel,  noise, exercise).   > Recent head trauma or viral upper  respiratory infections (as in perilymph  fistula, vestibular neuronitis).   > Past history of similar attacks or risk  factors for atherosclerosis.   • Past medical history of aural infection,  head injury, diabetes, hypertension, CAD,  CVA, migraine, epilepsy , 1 or psychiatric  disorders are helpful in the diagnostic  evaluation   • All past and present medications should be  assessed with particular attention to  aminoglycoside antibiotics, anticonvul-  sants, antihypertensives, and high dose  salicylates   • Detection of nystagmus is critical because it is  the only objective sign of vertigo. Nystag-  mus can occur spontaneously or in response  to changes in eye or body position. Peripheral  vestibular disorders usually cause horizon-  tal or rotatory nystagmus, whereas brain-  stem disorders are reflected by vertical  nystagmus   • Vestibular testing. The most common and useful  test is the Barany or Dix-Hallpike maneuver. The  patient is asked to turn his head. A rapid  change in position from sitting to supine  (with head hanging over the edge of the  examination table) will produce active  rotatory nystagmus when head is turned so  that the affected ear is facing the floor. This  may be accompanied by nausea   • Weber's and Rinne's test help in differentiating  conductive loss from sensory neural hearing  loss. Conductive hearing loss is seen in cases  of otitis media and early stages of Meniere's  disease, while sensory neural hearing loss is  seen in ototoxicity and tumors of the audi-  tory nerve   • Cerebellar dysfunction can be evaluated  initially by observing the gait, Romberg test,  Fukuda test, dead finger-nose tesfi   • Cardiovascular examination with special  emphasis for orthostatic changes in BP,  carotid bruits, murmurs and arrhythmias  is helpful in selected cases   • Neurological examination includes evalua-  tion of cranial nerves, in particular fundoscopy    for papilledema or optic atrophy (II), ocular  movements (III, IV, and VI), corneal reflex  (V), and facial movements (VII)   • Onset and duration — Generally, central  vestibular disorders, i.e. central vertigo, are  characterized by gradual and insidious  onset of continuous imbalance, whereas a  peripheral vestibular disorder, i.e. peripheral  vertigo, is classically characterized by  sudden, short lived (of few hours) episodes  of vertigo (Table 47.2).    • Age — In young adults psychological causes  predominate, whereas vestibular disorders  do in the middle age. In the elderly,  cerebrovascular and cardiac disorders,  combined with multiple sensory deficits   Abnormal or absence of corneal reflex on the affected  side may be the first signs of CP angle tumors.    outweigh vestibular causes. Therefore, in  the elderly, it is more sensible to consider  vertigo (along with other conditions which  frequently accompany it) as part of a more  general syndrome"   • In an elderly sudden onset of severe vertigo,  headache, nausea and vomiting, usually  associated with other neurological symp-  toms, such as diplopia, dysphasia, hemi-  paresis — but without hearing loss or  tinnitus— is strongly suggestive of verte-  brobasilar insufficiency   • Sudden, episodic vertigo, associated with  progressive unilateral hearing loss and  tinnitus, lasting from hours to days is  suggestive of Meniere's disease   • Vertigo precipitated by positional factors,  i.e. vertigo on arising from supine to sitting  or standing position; vertigo with sudden  neck movements, accompanied by nystag-  mus, but without hearing loss, is suggestive  of cervical spine dysfunction, vascular  ischemia, or BPPV   • Mild vertigo (vague sensation of motion)  with prominent tinnitus, progressive  unilateral sensorineural hearing loss, and  loss of corneal reflex strongly suggests  cerebellopontine angle tumor — usually  acoustic neuroma   • Vertigo with multiple neurological signs  and symptoms, such as blurring or loss of  vision, diplopia, dysarthria, paresthesia,  and ataxia is suggestive of multiple sclerosis  (vide infra 4 - 4 -)   • Vertigo that is increased by a loud noise  (Tullio phenomenon, i.e. vestibular hyper-  sensitivity to sound) and Valsalva maneuver  suggests perilymphatic fistula   • Organic vertigo is accompanied by nystag-  mus; a psychogenic etiology is almost cer-  tain when nystagmus is absent during a  vertiginous episode.   • In elderly age group patients with risk factors  for stroke, possibility of vascular vertigo  should always be considered in both acute  prolonged vertigo and recurrent vertigo   • In a patient with acute vertigo, it is important  to distinguish vestibular neuronitis from an  inferior cerebellar infarction. A stroke involving  the inferior cerebellum can be a neurosurgical  emergency marked by cerebellar swelling  and brainstem compression. Patients with  cerebellar infarct are unable to stand or walk.  This is the main distinguishing feature from  vestibular neuronitis   • Majority of cerebellar infarct patients have a  cardiac source of embolism, requiring specific  cardiac evaluation and management.   Acoustic neuroma (AN) — It is also known as  vestibular schwannomas, and are nonmalignant  tumors of the 8th cranial nerve. Most commonly  they arise from the Schwann cell investment of  the vestibular portion of the vestibulocochlear  nerve. Less than 5% arise from the cochlear nerve.  As the tumor expands, it projects from the internal  auditory meatus into the cerebellopontine angle  and compresses the cerebellum and brainstem.  The 5th cranial nerve and later the 7th cranial  nerve are affected. AN occurs in two forms — a  sporadic form, and a form associated with an  inherited syndrome called neurofibromatosis  type II (NF2). About 95% of all cases are sporadic.  Clinical manifestations include hearing loss,  headache, vertigo, tinnitus, and facial pain.  Unilateral sensorineural hearing loss - sudden,  progressive, or fluctuating — is the most common  symptom present at the time of diagnosis. Vertigo,  dysequilibrium, headaches, facial numbness or  facial weakness are uncommon presenting  symptoms among patients with AN. A significant  number of patients with AN present atypically.    with none of the audiovestibular symptoms  classically associated with AN. Clinician  awareness of the atypical clinical symptoms may  lead to earlier detection of these lesions. 3 Further,  the natural history of AN is yet not totally known,  but most of them have the tendency to slow  growth, sometimes without any kind of  symptoms during the individuals entire time. 4  Considering ANs natural history, there is a  possibility for conservative treatment for  these tumors.   The definitive diagnostic test for patients with  ANs is gadolinium-enhanced MRI. Gadolinium  contrast is critical because nonenhanced MRI can  miss small tumors. If suspicion is high, and MRI is  contraindicated, air-contrast cisternography has  high sensitivity and can detect relatively small  intracanalicular tumors.   Meniere Disease — Meniere's syndrome is a  disease of the inner ear (resulting from non-  suppurative disease of the labyrinth) that is  characterized by attacks of severe vertigo,  tinnitus, fluctuating hearing loss, and ill-  described aural sensations of fullness with  spontaneous recovery in hours to days.  Meniere's disease usually develops between the  ages of thirty and fifty, and is slightly more  common in women than in men, and in 50% of  Meniere's patients become bilateral. The most  consistent pathological finding in Meniere's  syndrome is an increase in the volume of the  endolymphatic fluid and distension of the  canals, hence the term endolymphatic hydrops.  Although some specific causes such as bacterial,  viral, and syphilitic infections may lead to the  same pathological changes and symptoms, the  majority of cases are idiopathic. The prognosis  is for progressive reduction in hearing along  with increasing frequency of attacks. Some  patients stabilize with no subsequent attacks  of severe vertigo, but they are left with residual  hearing loss.    Multiple Sclerosis (MS)— An idiopathic inflamm-  atory demyelinating disease of the CNS, mainly  affecting young adults, and characterized by  destruction of myelin in the central nervous  system. Patients with MS commonly present with  an individual mix of neuropsychological  dysfunction, which tends to progress over years  to decades. Clinical manifestations include visual  loss, extraocular movement disorders, and  paresthesias, loss of sensation, weakness,  dysarthria, spasticity, ataxia, and bladder  dysfunction. The usual pattern is one of recurrent  attacks followed by partial recovery. The diagnosis  of MS is based on a classic presentation (i.e. optic  neuritis, transverse myelitis, internuclear  ophthalmoplegia, paresthesias), and on the  identification of other neurologic abnormalities,  which may be indicated by the patient's history  and examination. Typical findings on an MRI also  help to establish the diagnosis of MS. Patients  with atypical pre-sentations and/or a normal or  atypical MRI may require evoked potential  studies, to uncover subclinical neurologic  abnormalities, or cerebral spinal fluid (CSF)  analysis, which also serves to exclude treatable  disorders and document MS-like immune  activity in the CNS.   Multiple Sensory Deficit Syndrome — This  term usually refers to elderly persons who  often experience dizziness as a result of  altered sensory inputs or premature aging  of the vestibular nuclei. Visual impairment  (cata-racts), deafness (presbycusis),  decreased ability to feel their legs (peripheral  neuropathy), painful or disabling orthopedic  disorders, and muscle weakness collectively  alter the patient's perception of space,  fluidity of motion, and confidence in walking.    resulting in difficulty with activities of daily  living and even falls. Medication is usually  not helpful unless there is clear vertigo due  to inner ear dysfunction. However, Patients  can be helped by increasing their sensory  input by using a cane, not to support a weak  leg, but by dragging it along the ground,  which increases sensory input through the  arm where the cane is held. The individual  has a better sense of stability and 'where the  ground is', and many times can walk more  steadily and safely.   PICA (Posterior inferior cerebellar artery) Syn-  drome— The PICA syndrome, also known as  lateral medullary syndrome, or Wallenberg's syndrome,  is the most common brainstem stroke. It is  typified by vertigo, ipsilateral hemiataxia,  dysarthria, ptosis and miosis. Patients often  have Horner's syndrome (unilateral ptosis,  miosis and facial anhidrosis). There also may  be saccadic dysmetria (overshoot), saccadic  pulsion (pulling of the eye during vertical  saccades toward the side of lesion). Diagnosis is  generally via MRI. Prognosis is generally good  with full or near full recovery expected at  6 months.    1 . Neubauser H, et al. The interrelations of migraine,  vertigo, and migrainous vertigo. Neurology.  2001;56(4):436-41. [PMID: 11222783: Abstract],   2. Tinetti ME, et al. Dizziness among older adults:  A possible geriatric syndrome. Ann Intern Med  2000;337-44. [PMID: 10691583: Free full text],   3. Mackle T, et al. Atypical clinical presentations of  vestibular schwannomas. Otol Neurotol 2007;  28(4):526-8. [PMID: 17414179: Abstract],   4. Penido Nde O, et al. Vestibular Schwannoma:  Spontaneous tumor involution. Rev Bras Oto-  rhinolaryngology (Engl Ed) 2007;73(6):867-71.  [PMID: 18278239: Free full text].   As the world population ages, vision loss is  becoming a major public health problem.  Researchers for the Johns Hopkins Bloomberg  School of Public Health, and the London School  of Hygiene and Tropical Medicine found that,  without extra intervention, the global number  of blind individuals would increase from 44  million in 2000 to 76 million in 2020. 1 Therefore,  any type of vision loss, low vision, or visual  impairment (e.g. blurred vision, double vision,  night blindness, loss of central or peripheral  vision) is a symptom of great concern to everyone.   Vision loss means that a person's eyesight  cannot be corrected to normal level, making it  difficult or impossible to do daily tasks without  glasses, contact lenses, surgery, or other  assistance. This can lead to loss of independence  and reduced quality of life. This type of vision  loss does not include complete blindness, because  there is still some sight and it can sometimes be  improved with the use of visual aids.   "One who has impairment of visual functioning even  after treatment and/or standard refractory correction, and  has a visual acuity in the better eye of less than    6/18 to light perception, or a visual field of less than 10  degree from the point of fixation, but who uses, or  potentially able to use, vision for the planning or  execution of a task. " 2   However, to allow comparison with other  studies, the commonly used WHO classification  (Snellen) of low vision as: "best corrected visual  acuity < 6/18 to 3/60, and blindness as best  corrected visual acuity < 3/60 to NPL, i.e. no  perception of light" is generally used.   In order to facilitate the screening of visual  acuity by nonstandardized personnel, in the  absence of appropriate vision charts, the WHO  has now added, "inability to count fingers in  daylight at a distance of 3 meters", to indicate less  than 3/60 or its equivalent visual impairment. 3   Many causes of vision loss are very serious  medical conditions, requiring immediate or  urgent care, where delay can lead to loss of vision,  e.g. retinal detachment, or loss of life, e.g. occipital  stroke. Even transient blindness or loss of vision  cannot be ignored because it can result from  serious conditions such as TIA, hypertension,  diabetes mellitus, and epilepsy. Therefore, the key  to successful diagnosis lie in the history, age of the  patient, and the pattern of field loss, backed up by  an examination of the eye through a dilated pupil.    Chronic glaucoma; senile cataract  ARMD; retinal disease, e.g. diabetic  retinopathy, hypertensive retinopathy,  retinitis pigmentosa, choroidoretinitis  Optic neuropathies; optic nerve  compression, e.g. glioma, aneurysm  Chiasmal compression, e.g. pituitary  tumor, craniopharyngioma  Tumors; degenerative conditions   • Increased hematocrit, WBC and platelet cell  count in hypercoagulable states, e.g. retinal  vascular occlusions.   • Complications of cataract surgery (inflam-  mation, retinal detachment, posterior cap-  sular fibrosis).   • Toxic amblyopia (drugs/toxins - alcohol,  anticholinergic agents, amiodarone, cortico-  steroids, chloroquin, digoxin, ethambutol,  isoniazid, lithium, streptomycin, sildenafil,  and tobacco)    * In children common causes of visual failure are congenital  cataract, retinitis pigmentosa and retinoblastoma.   • PT, PPT, lupus anticoagulant. Factor V Leiden,  antithrombin III, protein C, protein S, etc. are  indicated in patients with hypercoagulable  states, e.g. retinal vascular occlusions.   • In severe hyperthyroidism extraocular  muscle entrapment (thyroid oculopathy)  may cause progressive loss of visual acuity  and visual field.   • Elevated in acute glaucoma; greater than  30 mm of Hg is highly suspicious.   • Helpful in detecting intraocular tumors,  orbital tumors, retinal detachment, vitreous  changes, thyroid oculopathy, and intraocular  foreign bodies.   • To assess carotid/vertebral circulation, and  stenosis in CVD and TIA.   • To exclude embolic source in valvular heart  disease, subacute bacterial endocarditis, and  atrial myxoma.   • Most useful in the diagnosis of retinitis  pigmentosa, optic nerve disease, and  occasionally in demyelinating disorders, e.g.  multiple sclerosis.   • Patients may not mention an eye complaint  during initial discussion; however, a  proactive approach (i.e. direct questions) to  uncover any serious eye condition needs to  be adopted during consultation, especially  in the elderly with comorbid diseases such  as diabetes and hypertension. Few simple  questions, e.g. — 'are you able to read  newsprint or see TV; are your glasses  adequate; are you being treated for any eye  disease; when you last consulted your  ophthalmologist' — will alert the physician  of an underlying disorder.   • The symptom of vision loss should be  investigated further by asking following  questions:   > Is the vision impaired all the time  (cataract, ARMD) or only at nights  (retinitis pigmentosa)   > Is the vision impaired only in part of  visual field? e.g. — can the patient see  objects directly in front of him but not  those to the left and right without moving  his head? This distinction between  central and peripheral visual loss is  useful. Central visual loss implies defective  retinal vision formation, e.g. macular  disease, optic neuropathy. Peripheral visual  loss is more subtle, especially when the  onset is gradual, and implies extrama-  cular retinal disease or a defect in the  visual pathway, e.g. hemianopia.   > Pain on eye movements — common in  optic neuritis, frequently precedes the  onset of visual loss;   > Flashing lights with eye movements and  floaters, i.e. photopsia — common in  retinal detachment    > Colored halos around lights, i.e.  whenever patient looks at white light, he  sees it as if white light is split into its  component colors, red being outermost,  seen in prodromal stage of angle closure  glaucoma, and cataract.   • Current medications : 4 Systemically administered  drugs produce a wide variety of adverse effects  on the visual system; e.g. amiodarone,  ethambutol, linezolid, sildenafil, long-term use  of glucocorticoids, phenothiazine, adrenergic  agents, certain [32-ad renergic agonists, and  anticholinergic agents.   • Associated disorders, e.g. tuberculosis,  diabetes mellitus, hypertension, hyperlipi-  demia, thyroid disease, autoimmune disease,  and malignancy.   • Past history of ocular disease or surgery, e.g.  orbital trauma, FB, corneal ulcer.   • Family history, e.g. developmental cataracts,  corneal dystrophies, retinitis pigmentosa,  Leber's hereditary neuropathy.   > Visual acuity for distance and near, with  and without glasses (Snellen chart) in all  instances (except in chemical trauma 4 ).   > Analysis of central visual field with an  Amsler grid (to locate macular blind spots  and areas of distortion and wavy lines)  used in daily self-monitoring for the  progression of macular degeneration.   > Fundus examination (ophthalmoscope)  with dilated pupil to assess the red reflex,  optic disk for papilledema, and retina for  presence of hemorrhage, cotton wool spots.    + In chemical exposure, the dictum is 'treat first, examine  later'; copious irrigation should be initiated before  attempting a visual acuity examination.   > Stenotic vascular disease (carotid or  vertebral artery atherosclerotic disease,  arteritis, dissection)   > Cardiac disease (hypertension, endo-  carditis, atrial myxoma, valvular dis-  orders)   • Documentation of the initial visual acuity  and visual field, and their subsequent  assessment can be important in a disability  or malpractice lawsuit.   • The presence of a cataract in relatively young  patient (e.g. juvenile diabetic cataract) is  unusual and shall prompt ophthalmic consult.   • Gradual vision loss associated with  progressive early morning headache is an  indication of intracranial neoplasm; urgent  referral is indicated.   • Prompt ophthalmic referral is prudent in all  intraocular hemorrhages, including subcon-    junctival bleeding, which can be ominous, e.g.  in patients with bleeding dyscrasias.    1 . Web site: http://www.jhsph.edu/publichealthnews/  press_releases/PR_2003/ Frick_Vision2020.html-  33.1KB. Accessed on 16-12-08.   2. Change of Definition of blindness. Web site: http:/  /www.who.int/blindness/Change %20 the % 20  Definition % 20 of % 20 Blindness.pdf. Accessed  on 25.09.08.   3. National Programme For Control of Blindness.  Web site: http://www.nihfw.org/ndc-nihfw/html/  Programmes/National Programme For Control of  Blindess.htm. Accessed on 25.09.08.   4. Li J, et al. Drug-induced ocular disorders. 2008;  31(2):127-41. [PMID: 18217789: Abstract],   Sudden vision loss (SVL) or acute visual loss is  an ophthalmic emergency requiring immediate  medical attention to avert permanent visual  impairment.   SVL means anything from instantaneously  to over the course of a week (Table 49.1). It can  be total, partial, transient, or permanent;  involving either one or both the eyes.   Patients with SVL present with variable  symptoms. Some patients describe it as a gray-black  curtain that moves up or down, fogging, blurring,  dimming vision, halos around lights, flashing lights,  and 'spider webs' in peripheral vision.   The physician's role is to recognize the signs  and symptoms of SVL, assess the vision rapidly,  obtain an immediate ophthalmic consult, and  stabilize the patient until the patient is seen by  an ophthalmologist.   • Nonarteritic anterior ischemic optic  neuropathy 1 (NAION: vide infra -li)   • Many causes of loss of vision (sudden and  gradual) have a vascular etiology and  generally affect older patients. In these cases  it is important to search for and treat  systemic hypertension, diabetes, cardiac,  and carotid disease   • In addition to historical notes explained in  the Chapter 48 'Vision Loss - Gradual', (p. 330),  the following physical examination should  be performed in rapid sequence   • As the patient's assessment of visual loss and  its severity is highly subjective, a quick  objective assessment of the vision should be  done after testing each eye separately with  a Snellen chart, whenever possible.   • There are 2 types: arteritic and nonarteritic. AAION is  an inflammatory vasculitis, and NAION is a diagnosis of  exclusion, which is made in the absence of provable  arteritis. NAION is more common than AAION due to  temporal arteritis. NAION is the most common acute optic  neuropathy and one of the most common causes of sudden  vision loss in the elderly.   > A quick assessment of the vision may be  done, testing each eye separately.   > If possible, assess acuity using a Snellen chart  at 3 meters instead of 6; if the patient sees the  top letter (6/60), it would be recorded as 3/60.   > If the acuity is less than 3/60, check if the  patient can count fingers (CF) at a distance  of one meter, or see hand movements (HM).   > If he cannot CF or see HM, check if he can  perceive a bright light (by shining the  bright light in each eye), and note  whether there is perception of light (PL)  or not (no PL or NPL).   > Checking the confrontation fields, with  HM in the four quadrants give an idea of  visual field loss.   > This test is performed to test for relative  afferent pupillary defect (RAPD) + , also called  as Marcus Gunn pupil.   > The test is performed by having the patient  look into the distance and then shining a  light into one eye, thus eliciting pupillary  constriction in that eye and consensual  constriction in the other eye. The light is  then quickly moved in front of the other  pupil, which normally should constrict  further. If this additional constriction does  not occur and the pupil dilates instead,  RAPD is present. The test is repeated several  times. The presence of RAPD requires  further evaluation by an ophthalmologist.    + RAPD is always unilateral. Since light in one pupil causes  both pupils to constrict, quickly switching from one eye  to the other will give a "relative" indication of the  functioning of each eye and optic nerve. If both eyes are  equally dysfunctional, no "relative" defect would be  found; hence 'bilateral' RAPD does not exist.    • Hysterical blindness or loss of vision — A  purely functional loss of vision can be  assumed when the orientation while  walking is intact, pupillary light reflex is  normal, and visual field is markedly  restricted or inconsistent on repeated  examination. If the patient indicates a  unilateral loss of vision, the examination  should be conducted in such a way that the  patient is unaware of which eye is being  tested or the actual size of the optotypes.   • In an elderly with SVL — Exclude temporal  arteritis that is typically associated with  high ESR; timely high-dose steroids will  avert permanent visual loss in the affected  eye and protects the other eye from the same  fate. This is one critical situation where a  physician takes immediate precedence over  an ophthalmologist   • Beware of atypical presentations, e.g.  nausea, vomiting, or abdominal pain, and / or  a seemingly innocuous red eye; AACG may  be missed    • Due care must also be taken not to diagnose  seemingly inappropriate behavior (due to  vision loss) as of psychogenic in origin   • Beware of acute presentation of vision loss  that is actually of chronic (gradual) onset,  but suddenly noticed by the patient.   Nonarteritic Anterior Ischemic Optic Neuropathy  (NAION) 3 ' 4 — It refers to an idiopathic ischemic  process of the anterior portion of the optic nerve.  The typical presentation is sudden and painless  visual loss with examination features of an optic  neuropathy. Among the various associated risk  factors are optic disk morphology (crowded disk),  advanced age, systemic arterial hypertension,  diabetes mellitus, hyperlipidemia, nocturnal  hypotension, hemoconcentration, hemodilution,  and hypercoagulable states. Since the introduction  of PDE-5 inhibitors for the management of erectile  dysfunction 10 years ago, there have been a number  of reports of patients developing, within hours of  PDE-5 inhibitor use, permanent visual loss due to  NAION. In some of the cases, visual loss recurred  upon rechallenge with the drug. However, as the  bulk of the evidence suggesting a relationship  between PDE-5 inhibitor use and NAION comes  from case reports and small series, it is difficult to  ascertain if a cause-effect relationship truly exists.  However, following a series of such case reports,  WHO and FDA have labelled the association  between use of PDE-5 inhibitors and risk of NAION  as 'possibly' causal. NAION has also been reported  in patients taking several other medications,  specifically sumatriptan, amiodarone, and nasal  decongestants.   Since NAION is not a disease entity but rather  the common pathogenetic pathway of a large  variety of diseases and conditions, and is often  the result of several interacting factors, there is    no 'standard therapy' for NAION. Careful  interdisciplinary work up in NAION frequently  reveals previously unrecognized diseases  requiring treatment according to internal  medicine standards.   1. Danesh-Meyer HV, et al. Erectile dysfunction  drugs and risk of anterior ischaemic optic  neuropathy: Casual or causal association? Br J   2. Brass SD, et al. Acute demyelinating optic  neuritis: A review. Front Biosci 2008;13:2376-  90. [PMID: 17981719: Abstract],   3 . Unsold R, et al. Anterior ischemic optic neuropathy:  Etiology, pathogenetic mechanisms and therapy.  Ophthalmologe. 2008;105(9):867-82. [PMID:  18810458: Abract],   4. Thurtell MJ, et al. Nonarteritic anterior ischemic  optic neuropathy with PDE-5 inhibitors for  erectile dysfunction. Int J Impot Res 2008 Jun 5.  [Epub ahead of print], [PMID:18528398: Abract],   Weakness of the limbs is one of the most common  complaints presented to the physician, which  may be part of any debilitating illness such as  systemic infection, malignancy, or psychiatric  disorder. In such cases there are usually pointers  to the cause of suspected disorder. But, when  limb weakness, i.e. true lack of strength is the  only principal complaint, it is more likely that  there is an underlying neuromuscular disease.   Since weakness of neuromuscular origin is  manifested by objective evidence of reduced  muscular strength, physically testing the strength  of an individual muscle or muscle group is an  important early step in the evaluation of  weakness. The following standardized physical  findings are followed in grading muscle strength  on the scale of 0 to 5 'out of five'.   Neuromuscular diseases that result in limb  weakness are best understood on the basis of  neuroanatomy of the motor pathways, which  consists of four integrated systems:    * Muscle must be tested in such a way that the examiner's  and the patient's strength are fairly evenly matched.   Variable muscle movement (i.e. flicker of  contraction possible), but no movement at the  joint   Normal muscle strength depends princi-  pally on normal functioning of a relay of the  above four systems, and any dysfunction at one  or more of these four levels, which includes  malfunction in the cerebral hemisphere, brain-  stem, spinal cord, nerve roots, peripheral nerves,  myoneural junctions, and within the muscle  itself can manifest in neuromuscular diseases.   • Hb may be reduced in chronic infection /  inflammahon; exacerbates muscular weakness.   • Ideally it should be done on every patient  with stroke as soon as possible. If the deficit is  secondary to hemorrhage, it will immedia-  tely be apparent (and such patients should  not be anticoagulated)   • It is important to correlate CT scan findings  with patient's neurologic examination;  patients with old or clinically silent infarcts  may be irrelevant to the acute situation.   • Spinal X-rays for fracture, infection, inflamma-  tion, degenerative, and metastatic lesions.   • May show lytic bone or mass lesion due to  bronchial cancer   • Markedly elevated, 10 to 200 times normal,  in muscular dystrophy, and inflammatory  myopathies   • In rheumatologic myopathy: If ANA is  positive, additional work up may include  rheumatoid factor (rheumatoid arthritis),  antidouble-stranded DNA or antiphospho-  lipid antibodies (lupus), or anticentromere  antibodies (scleroderma).   • In myasthenic patients, IV administration of  endrophonium, there is an obvious  improvement in strength of weak muscles  lasting for about 5 minutes.   • Estimation of urinary aminolaevulinic acid,  porphobilinogen, and porphyrin in patients  with porphyria.   • CT of the anterior mediastinum may be  indicated in patients suspected with  thymoma (neoplastic change) in myasthenic  patients with associated disorders   • A thymic shadow on CT scan may normally be  present through young adulthood, but  enlargement of the thymus in a patient > 40  years old is highly suspicious of thymoma. 1, 2   • Useful in obtaining more information about  lesions already seen on CT scans and in  diagnosing white matter lesions, e.g.  multiple sclerosis, and lesions in the posterior  fossa.   • Indicated to investigate abnormalities of  intracerebral vessels such as arterial (berry)  aneurysms or arteriovenous malformations,  or to delineate blood supply of tumors prior  to surgery.   US (Duplex Scanning) of Carotid and  Vertebral Arteries in the Neck   • Used as a screening tool to obtain information  about the degree of respective arterial  stenosis in patients with stroke.   • Immediate lumbar puncture is indicated in  suspected cases of CNS infection (without  evidence of increased intracranial pressure)   • When a CT scan is not available and  anticoagulants are anticipated; bloody or  xanthochromic CSF should be a contraindi-  cation to anticoagulation   • Gram's stain of CSF sediment will show  organisms in majority of untreated bacterial  meningitis cases. India ink preparation for  cryptococcus and AFB stains for TB bacilli  are usually positive   • CSF culture should include bacteria (aerobic and  anaerobic), TB, brucella, fungi, and viruses   • CSF for cryptococcal capsular antigen should  be done when fungal meningitis is suspected,  especially in those who are immuno-  compromised   • CSF for syphilis serology, e.g. venereal  disease research laboratory test (VDRL),  fluorescent treponemal antibody absorption  test (FTA-ABS)   • CSF IgG and measles antibody titers must be  obtained if subacute sclerosing panence-  phalitis (SSPE) is suspected   • PCR amplification of viral gene sequence can  be performed in patients suspected with viral  encephalitis and myelitis   • In various neuropathies to assess damage to  peripheral nerves, and to determine whether  the lesion is focal, diffuse, axonal, or  demyelinating.   • Used to investigate disorders of neuro-  muscular transmission such as myasthenia  gravis and myopathic disorders such as  muscular dystrophies.   • Confirms that the weakness is due to a  primary disorder of muscle and to distinguish  between various muscle diseases. Using MRI  to identify focal areas of muscle abnormality  can increase the diagnostic yield from muscle  biopsies.   • A thorough history is essential to distinguish  between primary (i.e. intrinsic) muscle  weakness from ambiguous terms such as  fatigue and asthenia (Table 50.1).   • Fatigue is a subjective feeling of weakness  characterized by an inability to perform a task  after multiple repetitions; in contrast, a  patient with primary muscle weakness is  unable to perform the first repetition of task.  Asthenia is a sense of exhaustion in the  absence of muscle weakness .   • The next step is assessment and localization  of muscle weakness which includes: 3    * Fatigue and asthenia can coexist with primary muscle  weakness which may lead to delay in the diagnosis of  muscle disease because weakness is misinterpreted as  fatigue/asthenia; specific screening tools may be essential  to differentiate them. 
DiagnosisInternalMedicineMadgaonkarC.S.SRG Diagnosis, Internal Medicine  - Madgaonkar, C. S. [SRG]_djvu.txt