y g o o r u e N l features Symptoms: Sudden (peaking within 365 hemodilution ( \200\234triple H therapy \200\235). In extreme cases, intra-arterial therapy may be required. Nimodipine (60 mg/4 h PO for 3 wks, or 1 mg/h IVI) is a Ca 2+ antagonist that improves outcome (give to all if BP allows). The defini- tive management of a cerebral aneurysm involves either surgical clipping of the aneurysm or intravascular coiling of the aneurysm lumen. The sooner the better, as rebleeding is a common mode of death in those wh o have had a subarachnoid hemorrhage. Rebleeding occurs in 30%, often in the first few days . Ultimate outcome is strongly correlated with the patient \200\231s neurologi- cal status on initial presentation. Many unruptured aneurysms are diagnosed incidentally on imaging st udies; management is discussed in Table 10.14. Table 10.13 Mortality in subarachnoid hemorrhage based on Hunt and Hess grading Grade I II III IV V Signs None Neck stiffness and cranial nerve palsies Drowsiness Drowsy with hemiplegia Prolo nged coma Mortality (%) 0 11 37 71 100 Almost all the mortality occurs in the first month. Of those who survive the first month, 9 0% survive a year or more. Table 10.14 Unruptured aneurysms The management of unruptured cerebral aneurysms is controversial, based on conflicting data series. In general, the risk of rupture is felt to be between 0.5 and 1.5% per year (thus, odds favor intervention in younger patients and expectant management in those with an othe rwise short life expectancy). There is some data to suggest that irregularly shaped, larger , and posterior circulation aneurysms have higher rupture rates. Careful consultation with a neurosurgeon and interventional neurora- diologist is warranted whenever unruptured aneur ysms are discovered, even incidentally. 366 y g o o r u e N Figure 10.6 l Blood from a ruptured aneurysm occupies the interhemispheric fissure ( top arrow ), a cresc entic intracerebral area presumably near the aneu- rysm ( next arrow down ), the basal cist erns ( third arrow down, right of midline ), the lateral ventricles (temporal horns, the tw o lateralmost arrows ), and the fourth ventricle ( bottom arrow ). CT images can be manipul ated to show only high-density structures such as bones and arteries containing contrast. H ere is a middle cerebral artery aneurysm. We thank Professor Peter Scally for these CT images and the commentaries on them. Intracranial venous thrombosis Isolated sagittal sinus thrombosis (47% of patients) Present ation: Headache, vomiting, seizures, papilledema (one cause of intracranial hyper- tension and is in the differential diagnosis of pseudotumor cerebri/IIH). If venous infarction or b leeding supervenes, focal neurologic deficit will be seen (e.g., hemiplegia). Sagittal sinu s thrombosis is usually accompanied by thrombosis of other sinuses; e.g., lateral (transver se) sinus thrombosis (35%, with VI and VII cranial nerve palsies, field defect, ear pain), cavernous sinus thrombosis (see below), sigmoid sinus thrombosis (cerebellar signs, lower c ranial nerve palsies), inferior petrosal sinus (V and VI cranial nerve palsies \200\224 Gra denigo \200\231s syndrome). Cortical vein thrombosis This may cause venous infarcts ( foc al signs), encephalopathy, seizures, and headache (including thunderclap). It usually occur s with concurrent sinus thrombosis, but may be an isolated event. Venous angiomas \200\224o therwise benign, dilated vascular structures \200\224may be predisposed to thrombosis. Pred isposing factors In 30%, no cause is found. Hypercoagulable states, genetic and acquired, s uch as pregnancy and the postpartum period, are risks factors for cerebral vein thrombosis (Table 10.15). Differential diagnosis (See subarachnoid differential diagnosis list) Pseudo tumor cerebri/IIH, RCVS. 367 Table 10.15 Hypercoagulable states predisposing to cere- bral vein thrombosis Systemic Conditions : Dehydration, diabetes, neoplasms, heart failure, renal disease, infla mmatory conditions (Crohn \200\231s, ulcerative colitis, rheu- matological disorders, Beh et \200\231s), pregnancy/postpartum Infections : Meningitis, cerebral abscess, septicemia , fungal infections, severe sinusitis Drugs : Oral contraceptives, androgens, antifibrinoly tics Hematological : Activated protein C resistance (factor V Leiden), protein C or S defic iency (rare), prothrombin gene mutation (G20210A), hyperhomocysteinemia (e.g., from MTHFR m utation), antiphospholipid antibodies Post-craniotomy Evaluation Cerebral venous thrombosis is commonly missed at initial presentation, as the in itial \200\234dry \200\235 noncontrast head CT often appears normal, and the signs can be subtle on a routine noncontrast MRI (without MRV) as well. Check that there are no signs of meningitis. Do an emergency MRI or CT scan. If CT is normal, proceed to LP, measuring the opening CSF pressure. If high, and the headache is persisting, but no subarachnoid bleed, s uspect cerebral vein thrombosis especially if presentation is acute or there are predisposi ng factors. Get further imaging. A contrast CT may show the \200\234empty delta \200\235 s ign, in which a transversely cut sinus shows a contrast filling defect (dark) in its triang ular cross section. Although angiography is the gold standard, MRV (best with contrast) and CTV (reconstruction of a carefully timed contrast CT) are being utilized as noninvasive sc reening tools with consid- erable success. Management Although there is a paucity of random ized trial data on the treatment of intracerebral venous thrombosis, the standard of care i s to anticoagulate with heparin, even in the setting of intracerebral hemorrhage . Manage \206\221 ICP and seizures as indicated. Catheter-based interventional radiographic procedur es may be successful in individual cases, but are not widely available or well studied. Cav ernous sinus thrombosis is a potentially grave condition typically resulting from the exten sion of nearby bacterial infection (e.g., meningitis, sinusitis, dental, orbital cellulitis ). It may present with cranial neuropathies (facial sensory disturbance and diplopia are co mmon; III, IV, V1, V2, VI, and sympathetics may be affected), chemosis (swollen conjunctiva ), exophthal- mos, and often obtundation. Dedicated imaging studies are diagnostic and, eve n with immediate antibiotic treatment, this septic thrombophlebitis is often fatal. Jugular vein thrombosis may occur as the result of central line placement, especially in criticall y ill patients or in the setting of other hypercoagulable issues. It may result in elevated ICP and may propagate intracranially. Septic jugular vein thrombosis (Lemierre \200\231s) may occur as the result of oral or pharyngeal infections, including peritonsillar pathology . Branch or central retinal vein occlusion presents with visual loss and dramatically abnor mal retinal exam, often with hemorrhage. Macular edema, ischemia, and complications due to neovascularization may result. 368 Subdural hematoma Consider this very treatable condition in all whose conscious level fluct uates and also in those having an \200\234 evolving stroke \200\235 \200\224especially if on anticoagulants. Bleeding is from bridging veins between cortex and venous sinuses (vulne r- able to deceleration injury), resulting in accumulating hematoma between dura and arachn oid. This gradually raises ICP, shifting midline structures away from the side of the clot and, if untreated, eventual tentorial hernia- tion and coning. Most subdurals are secondary to trauma but they can occur without. The trauma may have been so minor or have happened s o long ago that it is not recalled. The elderly are particularly susceptible, as brain atro phy makes bridging veins more vulnerable. Others at risk are those prone to falls (epilepti cs, alcoholics), those on long-term anticoagulation, and those with spinal fluid leaks. Sym ptoms Development of a subdural hemorrhage may be insidious so be alerted by a fluctuating level of consciousness (present in 35%). Typical complaints are of physical and intellectua l slowing, sleepiness, headache, personality change, and unsteadiness. Signs \206\221 ICP. Localizing neurological symptoms (e.g., unequal pupils, hemi- paresis) occur late and ofte n long after the injury (63 d average). CT Shows clot midline shift (but beware bilatera l isodense clots). Look for crescent-shaped collection of blood over one hemisphere. The si ckle-shape differentiates subdural blood from epidural hemorrhage. Differential Evolving st roke, cerebral tumor, dementia. Treatment Evacuation of symptomatic acute SDH via burr hole s usu- ally leads to full recovery. Minor cases can be managed with close observation. y g o o r u e N l Epidural hematoma Suspect this if, after head injury, conscious level falls or is slow to i mprove . Extradural bleeds are commonly due to a fractured temporal or parietal bone causin g laceration of the middle meningeal artery and vein, typically after trauma to a temple ju st lateral to the eye. Any tear in a dural venous sinus will also result in an extradural b leed. Blood accumulates between bone and dura. Symptoms and signs Look for a rapid deterior ation of consciousness after any head injury that initially produced no loss of consciousne ss or after initial drowsiness post-injury seems to have resolved. This \200\234lucid inte r- val \200\235 pattern is typical of epidural bleeds. It may last a few hours to a few day s before a bleed declares itself by a deteriorating level of consciousness caused by a risi ng ICP. Increasingly severe headache, vomiting, confusion, and seizures can follow, accompa nied by a hemiparesis with brisk reflexes and an upgoing plantar response. If bleeding cont inues, the ipsilateral pupil dilates and coma deepens, a bilateral spastic paraparesis deve lops, and breathing becomes deep and irregular. Death follows a period of coma and is due t o respiratory arrest. Bradycardia and raised BP are late signs. Tests CT reveals hematoma t hat is often lens-shaped (biconvex; the blood forms a more rounded shape because the tough dural attachments to the skull tend to keep it more localized). Skull x-ray may be normal o r show fracture lines crossing the course of the middle meningeal vessels. Skull fracture a fter trauma greatly increases the risk of an extradural hemorrhage and should lead to promp t CT. 369 Management Stabilize and transfer promptly (with skilled medical and nursing escorts) to a neurosurgical unit for clot evacuation. Care of the air- way in an unconscious patient and measures to reduce ICP often mandate intubation, hyperventilation and administration of IV mannitol or hyper- tonic saline. Meningitis Meningitis, an inflammation of the lining surrounding the brain, can be caused b y a variety of pathologies. Bacteria, viruses, fungi, mycobacteria, medications, and tumors can all cause acute meningitis. Depending on the etiology, the presentation will vary dram atically. Bacterial meningitis clas- sically causes fulminant illnesses with severe headach es, photophobia, and meningeal symptoms; viral and drug-related etiologies tend to have mil der symptoms; fungal and mycobacterial infections can be indolent; whereas meningeal carcin omatosis is often accompanied by radicular or cranial nerve findings. Other cases of asepti c meningitis are due to autoimmune or vasculitic diseases, such as systemic lupus erythemat osus, sarcoidosis, rheu- matoid arthritis, Wegener \200\231s/antineutrophil cytoplasmic ant ibody (ANCA)+, Beh et \200\231s, or Vogt-Koyanagi-Harada. The evaluation of suspected in fectious meningitis (fever, headache, stiff neck, nausea, photophobia) hinges on CSF sampli ng via LP. A significant body of research has investigated the necessity for obtaining CT p rior to LP in order to mitigate risk for iatrogenic herniation due to CSF withdrawal from t he thecal sac. There are conflicting priorities. An abundance of data indicate that antibio tic administration should be given as early as possible to improve outcome, but treatment p rior to LP may sterilize the CSF, thus rendering a specific microbiological diagnosis impos sible. Treatment delay, such as for obtaining CT scan, may worsen outcomes. Thus, the Infec tious Disease Society of America has formulated a consensus statement regard- ing managemen t of patients with suspected bacterial meningitis. If a patient is immunocompromised, has a CNS disease, develops a seizure during pre- sentation, or has papilledema, alteration of c onsciousness, or a focal neuro- logic deficit, then they should have blood cultures drawn, therapy initiated, and a head CT performed before the LP is performed. If all of those feat ures are absent, then the patient should have urgent blood cultures drawn, an urgent LP per formed, and empiric therapy initiated. Empiric therapy for bacterial meningitis includes IV dexamethasone and an antibiotic regimen based on the patient \200\231s age and risk factor s (Table 10.16). In the United States in 2012, an outbreak of severe and sometimes lethal f ungal meningitis occurred as the result of injection of contaminated ste- roid solution fro m a compounding drugstore for various spinal procedures; delay from the procedure to sympto m onset was many weeks. Once the CSF is obtained, it can be analyzed to determine whether i t is consistent with a bacterial, viral, fungal, mycobacterial, neoplastic, or drug-related etiology. This interpretation must include an assessment of the clinical situation as the patterns of CSF findings may not be classic. In general, bacterial meningitis is associated with higher CSFwhite blood cell (WBC) counts with a predominance of polymorphonuclear cell s, whereas viral and other meningitides have predominantly lymphocytes but can present earl y with neutrophils. The typical features of CSF in a variety of pathologies are summarized in Table 10.17. 370 y g o o r u e N Table 10.16 Bacterial meningitis organisms and empiric treatment l Predisposing factor Age <1 month Common organisms Empiric antibiotics Ampicillin plus Streptococcus agalac- tiae, Escherichia coli, Listeria mono-cytogenes, Klebsiella sp. cefotaxime or ampicillin plus an aminoglycoside Age 1 \200\22323 months Streptococcus pneumoniae, Vancomycin plus a third-generation cephalosporin Neisseria menin- gitides, S. agalactiae, Haemophilus influen- zae, E. coli N. meningitides, S. pneumoniae Age 2 \200\22350 yrs Vancomycin plus a third-generation cephalosporin Vancomycin plus Age >50 yrs S. pneumoniae, N. meningitides, L. monocytogenes, aerobic gram-negative bacilli ampicillin plus a third-generation cephalosporin Vancomycin plus a third-generation cephalo sporin Basilar skull fracture S. pneumoniae, H. influenzae, group A \222 - hemolytic streptococci Penetrating head Staphylococcus aureus, coagulase-negative staphylococci, aerobic gram-negative bacilli (inc luding Pseudomonas aeruginosa) Vancomycin plus trauma cefepime, vancomy- cin plus ceftazidime, or vancomycin plus meropenem Post neurosurgery Aerobic gram-negative Vancomycin plus 371 bacilli (including P. aeruginosa) , S. aureus, coagulase-negative staphylococci Coagulase-n egative staphylococci, S. aureus , aerobic gram-negative bacilli, Propionibacterium acnes cefepime, vancomy- cin plus ceftazidime, or vancomycin plus meropenem Vancomycin plus CSF shunt cefepime, vancomycin plus ceftazidime or vancomycin plus meropenem Table 10.17 CSF in meningitis Cell count Differential ++++ +++ +++ ++ + ++ Protein Glucose ++ Bacterial Viral Fungal Mycobacterial Neoplastic Drug related Polys Lymphocytes + Monocytes Variable Variable Variable Low Low to normal Low Low Very low Normal +++ +++ ++ + Encephalitis Whereas meningitis is caused by inflammation within the lining around the brai n (the meninges), encephalitis is caused by inflammation within the brain parenchyma. Encep halitis can be caused by both infectious and noninfec- tious etiologies, but classically th e term \200\234encephalitis \200\235 refers to infectious causes while the term \200\234c erebritis \200\235 is used to identify noninfectious inflam- matory processes within the br ain. Infectious causes of encephalitis include viral, bacterial, fungal, and myco- bacteria l pathogens, but viruses are by far the most common cause of acquired encephalitis worldwid e. The differential of viruses varies depending on geography, with arboviral pathogens (mos quito-borne viruses) changing dramatically from country to country. Within the United State s, the most common identifiable cause of nonepidemic encephalitis is herpes (HSV1), a devas tating illness that can lead to amnesia, seizures, and death. Typically, encephalitis prese nts with fever, photophobia, altered sensorium or behavior, and variable degrees of meninge al symptoms. In this setting, a patient should be initiated on IV acyclovir therapy for pos sible HSV encepha- litis while a LP is performed. Besides testing for cell count, protein, glucose, Gram stain, and bacterial culture, an HSV polymerase chain reaction (PCR) should b e sent. This highly sensitive and specific test is the gold standard for identifying patien ts with HSV encephalitis. Caution should be taken, however, due to the false-negative rate that occurs within the first 3 \200\2234 d of symptoms. In the appropriate clinical setting , when a high pretest probability occurs, a negative HSV PCR should not be an indication to stop acyclovir therapy, but rather a second LP should be performed and a second HSV PCR ob tained. West Nile arbovirus has emerged and spread in recent years throughout much of the w orld, with seasonal epidemics in the United States, and it may present with (meningo-) ence phalitis and/or a poliomyelitis-like picture of flaccid weakness. Fortunately, the vast maj ority of exposures result in mild or subclinical disease. Autoimmune encephalitis is increa singly being recognized as a cause of subacuate, non-infectious, progressive encephalitis. Limbic encephalitis pre- senting with personality changes, bizarre behavior, amnesia, and/o r difficult seizures is typical; cerebellar or other degenerative syndromes can be seen as well. Paraneoplastic as well as non-paraneoplastic associated antibodies have been identifi ed. Voltage gated potassium channel (VGKC) and anti-NMDA receptor antibodies are frequently implicated; anti-GAD, anti-AMPA recep- tor, and anti GABA receptor antibodies have also be en reported. Antibodies against other intracellular neuronal antigens may be markers rather than pathogenic. Search for and treatment of underlying malignancies (especially testicula r, breast, small cell lung, and ovarian) should be undertaken, and aggressive immunological treatments are often warranted. Commercial test panels are available for both serum and CS F analysis. 372 Multiple sclerosis This typically relapsing/remitting disorder consists of plaques of demye lina- tion (and, as is increasingly apparent with pathological studies and newer imaging te chniques, axon loss and even destruction of gray matter) at sites throughout the CNS (but n ot peripheral nerves). Pathogenesis involves focal disruption of the blood \200\223brain ba rrier and associated autoimmune response, and myelin damage as well as neurodegenerative an d regenerative processes. Epidemiology MS affects 350,000 people in the United States, wit h a \231\200 : \231\202 ratio of 2:1. The peak age of onset is in the 20s and 30s, making MS one of the most common causes of disability in young adults. MS is more common in tempe rate climates, with some data suggesting an increased prevalence as you move farther away from the Equator, and with newer studies sug- gesting that early-l ife vitamin D deficiency may account for this link. There is also a strong genetic influenc e within MS, with monozygotic twins having a 30% concordance rate and dizygotic twins havin g a 5% concordance rate. Children of patients with MS have a 3 \200\2235% rate of MS, compa red to the background rate of 0.2% in Caucasian populations. Presentation is initially usua lly monosymptomatic due to a clinically isolated syndrome (cis) : Unilateral optic neuritis (pain on eye movement and rapid deterioration in central vision); numbness or tingling in the limbs; leg weak- ness or brainstem or cerebellar symptoms, such as diplopia or ataxia. Less often, there may be more than one symptom. Uhthoff \200\231s phenomenon, symp- toms wo rsening with heat (e.g., a hot bath) or exercise, may be present. Progression/prognosis: Ea rly on, relapses may be followed by remission/full recovery. With time, remissions are inco mplete, so disability accumulates. This form of relapsing remitting multiple sclerosis (RRM S) occurs in 80% of patients. Primary progressive MS is more relentless and seems to respon d poorly to therapy. Poor prognostic signs: Older males; motor signs at onset; many relapse s early on; many MRI lesions. Examination Look carefully for CNS deficits other than the pr esenting problem. Lhermitte \200\231s symptom (paresthesia/pain in the back or limbs on fle xing of the neck due to demyelination the cord) may be positive (also in cervical spondylos is or B 12 deficiency). Reduced perception of the color red in one eye or an afferent papil lary defect may indicate prior optic neuri- tis. Internuclear ophthalmoplegia (disconjugate movements due to reduced amplitude or velocity of adduction of one or both eyes, best note d on rapid side-to-side saccades to the extremes of gaze; additionally there is typically a bducting nystagmus) is characteristic of brainstem involvement in the dis- ease. When mild, patients may not report. Diagnosis This is clinical, requiring demonstration of lesions di sseminated in time and space, unattributable to other causes (Table 10.18). Isolated CNS de ficits are never diagnostic but may become so if a careful history reveals previous episode s (e.g., unexplained blindness for a week). Before the advent of MRI, making the diagnosis of clinically definite MS required more than one clinical episode. Utilizing MRI techniques , the diagnosis of clinically definite MS can be made after only one clinically apparent de myeli- nating event, based on subsequent appearance of other radiographic lesions. This abi lity is important due to data that suggest early immunomodulatory treatment can alter the c ourse of the disease. Additionally, patients with optic neuritis or other CIS with addition al characteristic imaging lesions at the time of presentation may benefit from disease-modi fying therapy without meeting formal criteria for definite disease. Differential diagnosis includes neuromyelitis optica (see below), CNS Sj gren \200\231s syndrome, acute dissemi nated encephalomyelitis (a monophasic but sometimes fulminate demyelinating condition), Sus ac \200\231s and other vas- culitis or autoimmune disorders affecting the CNS. Tests None i s pathognomonic; the quest for reliable serological and CSF biomarkers is ongoing. CSF: Typ ically, the CSF of patients with MS will show normal cell counts or a mild pleocytosis (up to 50 lymphocytes/ mm 3) , but, rarely there can be more profound elevations. A white blood cell count >50 cells/mm 3 should prompt consideration for alternate diagnoses. The protein level is usually normal or mildly elevated, rarely >100 mg/L. Evidence of inflammation res tricted to the CNS can be demonstrated by comparing CSF to serum, with IgG index and especi ally oligoclonal bands on electrophoresis showing utility. Although not specific for MS, th e pres- ence of two or more oligoclonal bands in the CSF that are not present in the serum can increase confidence in the diagnosis in the right clinical setting. Delayed visual, aud itory, and somatosensory evoked potentials can y g o o r u e N l 373 provide information regarding previous demyelinating events that are not identified on clin ical exam. MRI is sensitive but not specific for plaque detec- tion and may exclude other c auses (e.g., cord compression). Correlation of MRI with clinical condition is poor. Some st udies have identified antibod- ies to myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) in patients with a single MS-like clinical lesion as being predictive o f conversion to clinically definite MS. It is likely that other disease markers will be ide ntified. Visual evoked potentials may show delayed peaks in prior optic neuritis. Optical c oherence tomography (OCT), a noninvasive retinal imaging modality, as well as specific MRI techniques, may serve as useful surrogate markers for disease activity, potentially guiding therapy before clinical evidence of relapse or progression. Treatment Methylprednisolone: 1 g/d for 3 \200\2235 d given IV shortens relapses, but does not alter the overall prognosi s, except in the case of initial optic neuritis. Repeated treatments with IV steroids can l ead to risk of avascular necrosis (osteonecrosis). Disease-modifying agents: After a slow s tart, development of new agents and new treatment regimens aimed at halting disease progres sion or otherwise protecting against damage are showing promise, with the welcome avail- ab ility of newer disease-modifying oral agents attracting great attention; there are few area s of neurological therapeutics making faster advances. Treatment of the disease has de fact o become a subspecialty in its own right. Interferon \222 (inf \222 -1b; inf \222 -1a): Trials show that these can reduce relapses by 30% in active RRMS. They also reduce lesion a ccumulation on MRI. Their power to diminish disability remains controversial, as does benef it in secondary and primary progressive MS. Side effects include flu-like symp- toms (low-g rade fevers, myalgias, fatigue), depression, and site reactions. Monitoring of liver functi ons tests is indicated. Development of antibodies against these agents has the potential to reduce efficacy. Glatiramer acetate: A copolymer comprising a random mix of four amino aci ds \200\224glutamate, lysine, alanine, and tyrosine. Some data suggest that glatiramer acet ate exerts its therapeutic effect by shifting a patient \200\231s immune system from predom inately a Th1 response to a more protective Th2 response. Side effects include site reactio ns and an idiosyncratic episode of flushing, palpi- tations, and chest pain that can last f or 20 min after injection. This response is not an allergy, and it is safe to continue trea tment. No blood tests need to be followed on this therapy. Oral agents have recently been d eveloped to great fanfare, but they, too, have serious risks beyond that of infection. Fing olimod, a sphingosine 1-phosphate receptor modulator, has won FDA approval, but carries maj or risks for dangerous bradycardia (potentially fatal), macular edema, reduced lung functio n, and other serious adverse effects mandating a specific risk evaluation and mitigation st rategy in the United States. Teriflunomide, a drug similar to one long used in rheuma- tolo gical disease, has recently been approved as well and carries lower risks of major complica tions. An oral psoriasis treatment, dimethyl fumar- ate, has shown significant activity aga inst the disease. Cladribine has been withdrawn from the U.S. and European markets due to s afety concerns (cancer) but is available in other countries. Where these newer agents fit i n the armamentarium is as yet uncertain (timing, mono- or polytherapy, etc.). IV immunologi cal agents can have rapid and dramatic benefit, but with significant risks \200\224 nataliz umab can lead to potentially devastating or even fatal progressive multifocal leukoencephal opathy from reactivation of latent JC virus in the brain; mitoxantrone has dose-limiting ca rdiotoxicity. Other, more aggressive immunosuppressant strategies may be employed in aggres - sive cases, sometimes combining multiple agents. Many newer monoclonal antibodies current ly utilized for other immunological and hematological diseases are being tested for activit y against MS. Symptomatic management 374 y g o o r u e N Table 10.18 2010 Revised McDonald criteria for diagnosing MS l Presentation \211 2 attacks; objective clinical evidence of \211 2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack \211 2 attacks; objective clinical evidence of 1 lesion Additional data needed None; clinical evidence will do (imaging evi- dence desirable; must be consistent with MS) Dissemination in space (DIS) , shown by: + MRI criteria; or await a further clinical attack implicating a different CNS site Dissemination in time (DIT) , shown by: Simultanous presen ce of asymptomatic 1 attack; objective clini- cal evidence of \211 2 lesions gadolinium-enhancing and nonenhancing lesions at any time; or a new T2 and/or gadolinium-en hancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or await a second clinical attack Dissemination in space and time , demonstrated 1 attack; objective clinical evidence of 1 lesion (clinically isolated syndrome) by: For DIS: + MRI; or await a second clinical attack implicating a different CNS site and For DIT: Simultanous presence of asymptom- atic gadolinium-enhancing and nonenhancing l esions at any time; or a new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irr espective of its timing with reference to a baseline scan; or await a second clinical attac k 375 Insidious neurological progression sugges- tive of MS (PPMS) 1 year of disease progression (retrospectively or prospectively determined) plus 2 of 3 of the following criteria: 1. Evidence for DIS in the brain based on \211 1 T2 lesions in th e MS-characteristic (periventricu- lar, juxtacortical, or infratentorial) regions 2. Eviden ce for DIS in the spinal cord based on \211 2 T2 lesions in the cord 3. Positive CSF (OCB s and/or elevated IgG index \212 \212 \212 If the criteria are fulfilled and there is no better explanation for the clini- cal present ation, the diagnosis is MS; if suspicious, but the criteria are not completely met, the dia gnosis is \200\234possible MS \200\235; if another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is \200\234not MS. \200 \231 \200\235 Attacks: These must last >24 h, be focal, patient-reported, or objectively ob served events typical of an acute inflammatory demyelinating event, without fever or infect ion. MRI abnormality: \211 1 T2 lesion in at least 2 of 4 MS-typical regions of the CNS ( periven- tricular, juxtacortical, infratentorial, or spinal cord) involves lifestyle and pharmacological therapies to treat fatigue, neurogenic/ spastic blad der, and tremor, as well as gait problems and other physical impairments. Fampridine (4-ami nopyridine) has been shown to improve impaired walking in patients with MS, but with risk f or seizure. Transverse myelitis Transverse myelitis is an inflammatory demyelinating disease restricted to the spinal cord. Patients present with acute to subacute onset of myelopathic symptoms. There are usually prominent motor, sensory, and bowel/bladder symptoms. This disease is us ually monophasic, but some patients experience recurrences. Risk factors for recurrence inc lude underlying autoimmune condi- tions such as Sj gren \200\231s or serology suggestive of an underlying condition (e.g., positive SSA/anti-Ro or SSB/anti-La antibodies). In the appropriate clinical set- ting of a acute/subacute myelopathy, imaging (MRI with gadolinium ) must be obtained to rule out compressive lesions, intrinsic masses, or vascular lesions, and a LP should be obtained to confirm evidence of inflammation (i.e., mild pleo- cytosis o r elevated IgG index). Absence of an enhancing lesion on MRI or pleo- cytosis within the CS F should prompt a search for an alternative diagnosis. Differential diagnosis Longitudinall y extensive transverse myelitis across multiple spinal levels can occur in Sj gren \200 \231s, lupus, sarcoidosis, or neuromy- elitis optica, whereas shorter segments are more typ ical for MS. An MRI of the brain should be obtained to evaluate the patient for possible MS . White matter lesions within the brain in association with a spinal cord demyelinat- ing e vent could indicate that the myelopathy is in fact the first symptom of MS. Other pathologi es that should be considered include neuromyelitis optica (see below), dural AV fistula, sa rcoidosis, spinal cord tumor, spinal cord infarct (venous and arterial), and compressive my elopathies. Treatment of transverse myelitis has two components, specific treatments to red uce the degree of inflammation and supportive care given to all patients with spinal cord p athology. Specifically for the transverse myelitis, high-dose IV steroids (1 g/d methylpred nisolone for 5 d) is the standard of care. For patients not improving on this therapy, plas mapheresis and/or pulse-dose cyclophosphamide is indicated. 376 Neuromyelitis optica (Devic \200\231s) Neuromyelitis optica (Devic \200\231s syndrome) is a demyelinating condition that is primarily restricted to the optic nerves and the spinal co rd. Clinically, it pres- ents as either an optic neuritis (diminished vision in one eye acc ompanied by pain with movement of that eye) or as an episode of transverse myelitis. Some p atients diagnosed as having transverse myelitis will actually go on to have the initial dia gnosis of Devic \200\231s syndrome after they have an episode of optic neuritis. MRI of the entire CNS with gadolinium is warranted to evaluate for evidence of MS. Patients with neur omyelitis optica (NMO) tend to progress more rap- idly than MS patients and do not respond to interferons or glatiramer acetate. A circulating IgG antibody to aquaporin 4 (anti-NMO) has been identified in a large number of NMO patients, suggesting a humoral etiology. Thus, these patients may respond best to plasmapheresis, IV immunoglobulin (IVIG), or immunosupp ressants with humoral activity. Immunomodulatory monoclonal antibody therapies are being te sted for potential disease-modifying effects, but none is yet part of a standard or approve d treatment regimen. Dementia The hallmark of dementia is impaired cognition with intact consciousness (unlike d elirium). Most causes are progressive and irreversible. The key is a good history: Ask spouse, relatives, or friends about progressively impaired cognition/memo ry. Get objective evidence. Histories usually go back months or years. There is worsening f orgetfulness, and normal tasks of daily living are done with increasing incompetence, such as going to the store several times in a day and then being baffled as to why there is a gr eat quantity of food in the kitchen. Sometimes the patient will exhibit personality change such as apathy, uncharacteristic rudeness, or literalness. For objective evi- dence, do tes ts of cognitive functioning. Epidemiology Rare <55 yrs. 5 \200\22310% prevalence >65 yrs. 2 0% prevalence >80 yrs, and 70% in those >100 yrs. y g o o r u e N l Common causes Alzheimer \200\231s disease (AD) ; see below . Vascular dementia: 25% of all dementias. It represents the cumulative effects of many small strokes. Look for evidence o f vascular pathology (hypertension, past strokes, focal CNS signs). Onset is sometimes sudd en, and deterioration is often stepwise (vs. slowly progressive). Lewy body dementia: Chara cterized by Lewy bodies in brainstem and neo- cortex, fluctuating cognitive loss, alertness , and attention; parkinsonism; detailed visual hallucinations; falls; loss of consciousness /syncope. It is the third most common dementia (15 \200\22325%) after AD and vascular cause s. Neuroleptics in these patients often cause neuropsychiatric symptoms. Parkinsonism is po orly responsive to levodopa. Frontotemporal dementia: Frontal and temporal atrophy without Alzheimer histology. Signs: Behavioral/personality change; early preservation of epi- sodic memory and spatial orientation; disinhibition; hyperorality, stereo- typed behavior, and e motional unconcern. Rarer causes: Alcohol/drug abuse, Huntington \200\231s, CJD, Parkinson \200\231s, corti- cobasal ganglionic degeneration, HIV, cryptococcosis, subacute sclerosing panencephalitis (SSPE), progressive leukoencephalopathy. Ameliorable causes Hypothyroidism , vitamin B 12 deficiency, thiamine deficiency (alcoholics),pellagra (B 3 /niacin deficienc y)syphilis, some cere- bral tumors (e.g., parasagittal meningioma), chronic subdural hemato ma, normal-pressure hydrocephalus (dilatation of ventricles without signs of \206\221 ICP, possibly due to obstructed CSF flow from subarachnoid space; CSF shunts help if patients r espond positively to high-volume LP; it is sug- gested by incontinence early-on and gait ap raxia), intracranial hypotension (rarely). Tests Before consigning a patient to the diagnos is of an irreversible demen- tia, make absolutely certain that no treatable cause of progre ssive mental status decline is missed, however unlikely. Assess for underlying or super- im posed delirium. Complete blood count, ESR, electrolytes, LFTs, ammonia level, TSH, B 12 , R PR/FTA, HIV, CT/MRI, and consider EEG. Treat depression if present. Nuclear imaging studies (single proton emission CT [SPECT), positron emission tomography [PET] with amyloid labeli ng) and spinal fluid sampling (A 42, tau, others) may be useful in specific instances to confirm a specific neurodegenerative etiology. 377 Alzheimer \200\231s disease This leading cause of dementia is currently having a huge impac t on our health care system, nursing home system, and society. As our population continues to live longer, a greater portion will suffer from this disease, requiring increasing atten tion from their children and families. Mean survival 7 \200\22310 yrs from onset. Suspect A lzheimer \200\231s in adults with enduring, acquired deficits of visual-spatial skill ( \200\234he gets lost easily \200\235), memory, and cognition; e.g., tested by mental test s cores + other neuropsychometric tests.