Liver/pancreas/gallbladder \200 Pruritis and, in more severe cases, jaundice, occurs in the presence of biliary obstruction . Upper abdominal pain, sometimes radiating to the inter- scapular region, occurs in pancre atitis. Malaise, nausea, and vomiting may accompany pain. Haematemesis may be severe and li fe-threatening in patients with portal hypertension and varices. \200 Esophagus \200 Dysphagia may be caused by dysmotility of the smooth (involuntary) muscle of the esophagus in SSc and by oesophageal strictures or webs (Sj gren \200\231s). Heartburn or central che st pain, often worse after eating or on bending/lying may occur in GORD. This is common in SSc and SLE (up to 10%), and may also arise from meg- aoesphagus in Marfan syndrome or EDS. Ischaemic heart disease must be excluded in patients with chest pain. Examination of the abdomen \200 \200 Distension/asymmetry suggests organomegaly or mass. Visible peristalsis with small intestin al dilatation is common in small bowel over-growth or obstruction. Telangectasiae (spider n aevi) on the chest and upper body (in a non-SSc patient) or caput medusae (rare) indicate c irrhosis. THE GUT AND HEPATOBILIARY DISEASE 86 Tenderness \200\223 guarding, rigidity and rebound tenderness \200\223 suggests a \200 \230surgical abdomen \200\231. Local tenderness suggests gastritis/peptic ulcer (LUQ), hepa titis or hepatic congestion or cholecystitis (RUQ), ileocolitis, or appendicitis (RLQ). PR examination in suspected appendicitis. Perineal ulcers in Beh et \200\231s or Crohn \200 \231s disease. Palpate liver, spleen and kidneys, and check for ascites (shifting dullness) in distended abdomen. Auscultate for tinkling bowel sounds that may suggest obstruction or pseudo-obstruction sounds in an ileus. Small bowel follow-through for characteristic \200\230hide- bound \200\231 appearance of s mall intestine in SSc or presence of diverticulae. CT chest, abdomen and pelvis \200\223 u sed to seek solid organ malignancy, lymphadenopathy in risk patients (e.g Sj gren \200\231 s syndrome, DM), and for pneumatosis cystoides intestinalis. CT, conventional angiography o f mesenteric arteries in suspected PAN or mesenteric ischaemia. MR enteroclysis ( \201 lli ng with contrast medium of small bowel) for suspected intussuception. MR angiography or 18F DG-PET for suspected large vessel vasculitides. Video capsule enteroscopy for mucosal abnor malities of the small intestine (telangiectasias, aphthae, ischaemic ulcers, lymphoma). Sma ll intestinal manometry for SSc or suspected intestinal dysmotility. \200 \200 Investigations Mouth \200 \200 \200 Iron studies in patients with angular cheilosis. Vitamin B12 and red cell folate in oral ul ceration WBC (especially neutrophil count) in patients with candidiasis. Orthopantomogram t o assess TMJ arthritis (usually requested by oral/maxillofacial surgeons). Minor salivary g land biopsy may enable a diagnosis of SS or MALT lymphoma associated with SS. Parotid biops y occasionally necessary to distinguish diabetic sialadenosis, sarcoid and SS. Large intestine \200 \200 FBC and iron studies if chronic GI bleed suspected. Colonoscopy for bleeding per rectum, wh ere ulceration or ischaemia suspected. CT colonography can be used to exclude signi \201 c ant lesions, where colonoscopy is hindered by stricture or high risk. Mesenteric angiograph y (invasive/CT/MR) in suspected ischaemia. Anorectal manometry for fecal incontinence. Rect al biopsy \200\223 for amyloid. Esophagus \200 \200 Oesophageal manometry in SSc, SLE, RA, DM, and PM. Video- \202 uoroscopy or \201 bre-opt ic endoscopic examination of swallow (FEES) in proximal impaired swallow. Barium swallow (S Sc, EDS) \200\223 use water soluble contrast if at risk of aspiration. OGD may reveal re \202 ux oesophagitis, peptic stricture, or Barrett \200\231s metaplasia associated with GOR D. 24-h pH studies with pH catheter or mucosal adherent capsule to assess acid re \202 ux. Nuclear scintigraphy can assess volume of re \202 ux in achlorhydric patients (other meth ods rely on pH drop). CXR \200\223 air under the diaphragm occurs following perforation of stomach, small or large bowel. \200 Liver/pancreas/gallbladder \200 LFTs \200\223 ALT/AST elevated in hepatocellular damage, whereas elevated bilirubin, alkal ine phosphatase and gamma GT indicated biliary obstruction. ALT/AST may be elevated in pati ents with myositis; alkaline phos- phatase and gamma GT are acute phase reactants, and an i soform of ALP is also released from bone. Elevated amylase re \202 ects acute pancreatitis (SS, PAN, and WG). Can be elevated with salivary disease (SS) or vomiting. Infectious hepa titis serology \200\223 for hepatitis A, B, C, EBV, CMV. Autoimmune hepatitis serology \200\223 anti-smooth muscle antibodies and anti-liver-kidney microsomal antibodies accompan y autoimmune hepatitis; anti-mitochondrial antibodies (and more speci \201 cally anti-pyru vate dehydro- genase antibodies) are associated with PBC. Serum IgG4 levels may be helpful in suspected autoimmune pancreatitis. HFE genotyping should be performed in individuals wit h elevated ferritin (without other elevated acute phase reactants) and transferrin saturati on >45%. USS abdomen \200\223 used to visualize liver, including biliary tree, gallbladder , and spleen; and Doppler ultrasound to interrogate portal and hepatic vein blood \202 ow . The view of pancreas is generally inadequate. Liver biopsy \200\223 generally performed under ultrasound guidance. Biopsy in suspected autoimmune hepatitis and to establish presen ce of cirrhosis. In haemochromatosis, biopsy liver if ferritin >1000 g/l. Note: Liver bio psy is not essential to con \201 rm the diagno- sis of PBC. Do NOT biopsy liver in suspect ed cases of amyloid. Stomach \200 \200 FBC and iron studies if chronic GI bleed suspected. Upper GI endoscopy in suspected gastric ulcer/cancer, biopsies for eosinophilic infiltration (CSS) and Helicobacter pylori (rapid urease test). Nuclear scintigraphic gastric emptying studies (solid and/ or liquid phase). Small intestine \200 Malabsorption screen (PTH, iron studies, vitamin B12, red cell folate, vitamins A and E, ma gnesium, phosphate, and calcium). Anti tissue-transglutaminase antibodies (85-95% sensitivi ty for celiac disease). Fecal pancreatic elastase is a measure of exocrine pancreatic dysfu nction. Albumin and immunoglobulins in suspected protein- losing enteropathy. Upper GI endo scopy for: suspected duodenal ulcer, coeliac disease, IBD affecting small bowel, with aspir ate and colony count for suspected bacterial over-growth and biopsies for coeliac disease, Giardia lamblia, and Whipple \200\231s bacillus. Glucose-hydrogen breath test for proximal small intestinal over-growth. CHAPTER 3 Organ involvement in rheumatological disease 87 Triple phase CT of the abdomen to examine pancreas and portal vasculature. Endoscopic ultra sound (EU) for visualization of upper GI mucosa where thickening is present on cross sectio nal modalities. EU gives good visualization of the pancreas (and for needle cytology of pan creatic masses). ERCP for suspected biliary and pancreatic ductal abnormalities. selective NSAIDs are associated with 50% risk of severe GI complications compared with non -selective NSAIDs. Risk of GI hemorrhage can be reduced by use of a proton pump inhibitor. Gastric antral vascular ectasia (GAVE): treat with argon beam ablation at endoscopy; look f or portal hypertension. Delayed gastric emptying can be improved with dom- peridone or eryt hromycin. Botulinum toxin injection into the pylorus can improve emptying in marginal cases . Treatment Mouth \200 Patients with any of the following risks for NSAID-associated GI disease should be prescrib ed a proton pump inhibitor: \200 \200 \200 \200 \200 Ulcers: review and alter medication, if likely precipiant. Routinely prescribe folic acid 5 mg weekly in patients treated with methotrexate and increase to 5 mg 5 times weekly if mou th ulcers occur. Prescribe benzydamine (Dif \202 am) mouthwash or salicylate gel for sympt omatic relief or topical glucocorticoid (e.g. betametasone tab- lets or triamcinolone paste applied 2 \200\2234 times daily) for short courses. Colchicine and, in severe, resistant c ases, anti-TNFA agents may be useful for mouth ulcers in Beh et \200\231s disease. Oral fi ssures: iron supplementation, if required. Prescribe nystatin ointment if fungal infection or short course of hydrocortisone cream for in \202 ammation. Xerostomia: arti \201 cial saliva is available as sprays (e.g. Glandosane, Saliva Orthana, Luborant), lozenges (Saliva Orthana) or gels (e.g. Oralbalance, BioXtra). Note that Luborant is a neutral pH and conta ins \202 uoride, and therefore may reduce dental caries. Muscarinic, cholinergic secretag ogues may be tried (see SS, p. 254 \200\223262). Candidiasis: if patient uses inhaled corti costeroids, review technique and post-inhaler mouth rinsing. Treat topically with nystatin pastilles suspension qds, micona- zole mouthwash or amphotericin lozenges qds. Systemic ant i-fungals may be required in resistant cases or in patients with xerostomia (see below). Te mporomandibular joint (TMJ) arthritis: refer to maxillofacial surgeon for assessment and po ssible TMJ glucocorticoid injection. High dose of NSAID. Prolonged use of NSAID. Age 65 years or over. History of peptic ulcer. Serious comorbidity (RA, CVD, renal/hepatic disease, diabetes mellitus, hypertension). Heav y smoker. Excessive alcohol ingestion. Helicobacter pylorii infection. \200 \200 Gastric masses: treatment depends on the nature of the mass, which is usually determined by biopsy. For malignant neoplasms liaise with oncology and for lym- phomas with hematology. Look for and eradicate Helicobacter pylori. Occasionally, masses re \202 ect underlying in \202 ammatory disorders and are treated with increased systemic immunosuppression. Severe dysmotility or mega-esophagus may require additional routes of feeding into the stomach or intes- tine such as percutaneous endoscopically placed gastrostomy tube with extension of the enteral tube into the jejunum, or direct placement of a feeding tube into the jejunum i n cases of severe GORD. Small intestine Mucosal ulceration This can occur from underlying vasculitis and may respon d to immunosuppressive regimens including GCs, azathioprine, anti-TNFA agents, rituximab, o r Campath (Alemtuzumab). Esophagus \200 Oesophageal dysmotility: oesophagitis may be reduced with a proton pump inhibitor. Erythrom ycin or domperidone accelerate oesophageal clearance and gastric emptying. Aspiration: prac tical measures, such as raising the head of the bed may reduce nocturnal aspiration. Note: Fundiplication is absolutely contraindicated in patients with oesophageal dysmotility. Barr ett \200\231s metaplasia: treat with PPI. Surveillance for the development of oesophageal a denocarcinoma (according to local guidelines), treatment of high grade dysplasia or localiz ed lesions with radiofrequency ablation, mucosal resection, or oesophagectomy. Oesophageal varices: primary prophylaxis with B-blockers in cirrhosis. There \200\231s no evidence of b ene \201 t for primary prophylaxis in pre-hepatic portal hypertension. Variceal banding fo r secondary prophylaxis of bleeding. Oesophageal candidiasis: check WBC (in particular neut rophils). Treat with systemic anti-fungals (amphoter- icin, miconazole, \202 uconazole; N B use ketoconazole only in resistant cases and monitor LFTs carefully). Malabsorption Reversible disease should be treated by appropriate immunosuppression of chro nic in \202 ammatory disorders (refer to chapters on individual diseases) or by institutio n of a gluten-free diet in patients who have co-existing coeliac disease. \200 Whipple \200\231s disease may be treated with antibiotics; consultation with the Infectious Diseases Team is recommended. Patients with calcium malabsorption and secondary hyperparat hyroidism require high dose calcium supple- ments, although if there is severe osteomalacia particu- larly with fractures, bone pain and muscle disease (de \201 ciency range 25-OHD, high ALP, high PTH, and bone biopsy evidence) 1,25-dihydroxyvitamin D3 therapy should be c onsidered initially. Oral calcitriol is better absorbed than vitamin D3, will heal osteomal acia bone lesions and can be swapped to cholecalciferol after 3 months. The majority of 25- OHD replenishment, however, should be from UV on exposed skin surfaces. Stomach \200 Gastritis and gastric ulcers: minimize use of NSAIDs by optimal use of DMARDs and simple an algesia. COX-2 THE GUT AND HEPATOBILIARY DISEASE 88 Vitamin B12 may be supplemented by 3-monthly injections and folic acid by 5 mg daily. Creon can be prescribed for patients with exocrine pancreatic insuf \201 ciency (e.g. Sj gren \200\231s). In severe cases of malabsorption, parenteral nutrition is required. Acute surgical abdomen: appendicitis, toxic megacolon; see above. Constipation can be troub lesome in dysmotility conditions not complicated by bacterial over-growth and malabsorption , and may require a combination of bulk forming and stimulant laxative agents. Diarrhea due to dysmotility may be controlled with use of loperamide, as required. Megacolon and giant diverticulae may require surgical resection. Mucosal telangectasiae: bleeding point may be treated colonoscopically using argon beam electrocautery. Perineal ulcers: prescribe topica l GCs (e.g. triamci- nolone paste applied 2 \200\2234 times daily) for short courses). Colc hicine and anti-TNFA agents may be useful in Beh et \200\231s disease. A defunctioning sto ma may be required for severe perianal disease in Beh et \200\231s disease or for fecal in continence in SSc. Bacterial over-growth Low dose oral antibiotics (quinolone, tetracycline, B-lactam) should be cycled with antibiotic free periods between to limit the development of resistant organi sms \200 Low dose octreotide can stimulate restoration of the migrating motor complex in SSc. There is no evidence for bene \201 t of probiotic use in bacterial over-growth. Pseudo-obstruction Check and normalize electrolytes, rest bowel (patient nil by mouth), sup port with IV normal saline/5% dextrose, with appropriate potassium supplementation. A trial of 1 \200\2232 mg neostigmine if no contra-indications and with cardiac monitoring. Caecal decompression by percutane- ous endoscopically placed colostomy tube or colectomy may be r equired. Liver/pancreas/gallbladder Hepatitis Consider drugs (including herbal remedies or non- pres cription drugs) that could be causing the problem and stop where possible. Treatment with G Cs and immunosup- pressants may be required for auto-immune features. Note that immunosuppr essants, for which transaminitis is an ad- verse effect (e.g. methotrexate, azathioprine, m ycopheno- loate mofetil), often result in improvement of LFTs when used to treat autoimmune hepatitis. Close monitoring is required. Acute surgical abdomen Obstruction, small bowel infarction, mesenteric arterial rupture, pe rforation, appendicitis, toxic megacolon, chole- cystitis) \200\223 EMERGENCY: consult sur gical team. \200 Meanwhile, institute supportive measures (nil by mouth, IV \202 uids, IV opiate analgesia , and anti-emetic, IV hydro- cortisone for patients treated with GCs (for low/moderate pred nisolone doses, approximately double the daily GC dose for the perioperative period; TED st ockings). Anticipate peritonitis (blood cultures, antibiotics to cover seeding of peritonea l cavity with gut bacteria), hypovolaemic or septic shock (colloid; cross-match blood), and urgent laparotomy (FBC, Cr and electro- lytes, LFT, CRP, clotting, ECG, CXR). A diagnostic laparoscopy may clarify which patients can be managed expectantly and which require urgent laparotomy). The signs of peritonism may be masked by high dose GC use. Primary biliary cirrhosis Ursodeoxycholic acid should be prescribed at 13-15 mg/kg/day in 2 \200\2234 divided doses for patients with anti-mitochondrial antibodies and a cholestatic pattern of abnormal LFTs. methotrexate, azathioprine, ciclosporin A, and colchicine have al l been used to treat PBC, but meta-analyzes fail to show ef \201 cacy. Exocrine pancreatic insuf \201 ciency Look for reversible causes (rarely autoimmune pancre atitis) and replace with oral pancreatic enzyme replacement (100 000 \200\223200 000 lipase units per day, taken with meals, e.g. creon). Bioavailability improved by use of PPI. Mesenteric ischaemia In the presence of vasculitis, this generally requires surgical resect ion of the involved segment but it may respond to medical treatment with immunosuppression with careful monitoring to pre-empt perforation. Pancreatitis Can present as a surgical emergency. Assess severity using Glasgow score and e arly CT (Balthazar score). Involve specialist team (gastroenterology or surgery). \200 Nil by mouth, \202 uid resuscitation and supportive care for organ dysfunction in the \201 rst instance). Other conditions \200 Intussusception may lead to obstruction. Liaise with surgical team. Vasculitis: treatment o f the underlying condition with immunosuppression; see also p. 313. Amyloid: treatment of A A amyloid requires optimal management of the underlying in \202 ammatory condition. Avoid biopsies of sites where bleeding is dif \201 cult to control. Table 3.11 Glasgow Scoring system (severe acute pancreatitis de \201 ned by score of 3 or more) >55 years Age >15 \200\223 109/l WBC >10 mmol/l Glucose Large intestine \200 >600 IU/ml LDH Colitis responds to standard treatment with immuno- suppressant medications, such as 5ASA d erivatives, GCs, azathioprine, methotrexate, anti-TNFA agents, with additional biological t herapy in reserve for severe cases (Rituximab, Campath). >16 mmol/l Urea <32 Albumin <2.00 mmol/l Calcium (corrected) <8 kPa PO2 CHAPTER 3 Organ involvement in rheumatological disease 89 Other conditions \200 Gershwin ME, Mackay IR. The causes of primary biliary cirrhosis: convenient and inconvenien t truths. Hepatology 2008; 47: 737 \200\22345. Lindor K. Ursodeoxycholic acid for the treat ment of primary biliary Haemochromatosis: weekly venesection to maintain ferritin <50 g/l. Cirrhosis is irreversi ble. Wilson \200\231s disease: lifelong treatment with penicillamine 1 \200\2231.5 g daily; monitor urinary copper; liaise with hepatologist. Cholecystitis: may require acute cholecy stectomy or choecystotomy, and drainage in unwell individuals (see Acute surgical abdomen a bove). cirrhosis. NEJM 2007; 357: 1524 \200\2239. Mody GM, Cassim B. Rheumatologic manifestations of gastrointes- tinal disorders. Curr Opin Rheumatol 1998; 10: 67 \200\22372. Morgan SL, Baggott JE, et al. Supplementation with folic acid during methotrexate therapy f or rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 1994; 121 : 833 \200\22341. Nikou GC, Toumpanakis C, et al. Treatment of small intestinal disease in systemic sclerosis with octreotide: a prospective study in seven patients. J Clin Rheumatol 2007; 13: 119 \200\22323. Resources Assessment tools IBD scoring tools should not be used in enterocolitis associated with proven vasculitides as they are not validated in this setting and may be misleading. \200 Pagnoux C, Mahr A, et al. Presentation and outcome of gastrointes- tinal involvement in sys temic necrotizing vasculitides: analysis of 62 patients with polyarteritis nodosa, microsco pic polyangiitis, Wegener \200\231s granulomatosis, Churg \200\223Strauss syndrome, or rheu - matoid arthritis-associated vasculitis. Medicine 2005; 84: 115 \200\22328. Schneider T, M oos V, et al. Whipple \200\231s disease: new aspects of patho- PBC \200\223 LFTs generally adequate; Mayo risk score available online: www.mayoclinic.org /gi-rst/maymodel1. html; genesis and treatment. Lancet Infect Dis 2008; 8: 179 \200\22390. Silverstein SB, Rodgers GM. Parenteral Iron Therapy Options. Am J Hematol 2004: 76: 74 \200\2238. Patient organizations Beh et \200\231s Syndrome Society. www.behcets.org.uk Coeliac UK. ht tp://www.coeliac.co.uk/ National Association for Colitis and Crohn \200\231s Disease (NACC) . www.nacc.org.uk/content/home.asp Swinkels DW, Jorna AT, Raymakers RA. Synopsis of the Dutch multidisciplinary guideline for the diagnosis and treatment of hereditary haemochromotosis. Neth J Med 2007; 65: 452 \200 \2235. Twilt M, Schulten AJ, et al. Long-term follow-up of temporoman- dibular joint involvement i n juvenile idiopathic arthritis. Arthritis Rheum. 2008; 59: 546 \200\22352. See also: Spondylarthritis Vasculitis Drugs used in rheumatology SSc Sj gren \200\231s syn drome Viljammaa M, Kaukinen K, et al. Coeliac disease, autoimmune diseases and gluten exposure. S cand J Gastroenterol 2005; 40: 437 \200\22343. p. 209 p. 313 p. 529 p. 264 p. 254 Yazici H, Fresko I, Yurdakul S. Beh et \200\231s syndrome: disease manifesta- tions, manag ement, and advances in treatment. Nat Clin Pract Rheumatol. 2007; 3: 148 \200\22355. Yurdakul S, Mat C, et al. A double-blind trial of colchicine in Beh et \200\231s Further reading Ebert EC. Gastric and enteric involvement in progressive systemic syndrome. Arthritis Rheum 2001; 44: 2686 \200\22392. sclerosis. J Clin Gastroenterol. 2008; 42: 5 \200\22312. Gaston JSH. Cytokines in arthritis \200\223 the \200\230big numbers \200\231 take center stage. Rheumatology 2008; 47: 8 \200\22312. THE NERVOUS SYSTEM 90 The nervous system re \202 ecting excessive IFNA production and IFNA therapy for melanoma or hepatitis C reli ably causes a \200\230cognitive/ depressive lupus syndrome \200\231. Trials of anti-cytoki ne therapy, notably IL-6 and B cell activating factor are also underway. The cause of anti- TNFA therapy induced demyelination remains purely speculative (non-reduction of CNS TNF and /or increased peripheral T cell reactivity). Neurological symptoms occur frequently in outpatient and inpatient rheumatology consultatio n, with direct conse- quences of rheumatological disease, such as cervical cord compression in rheumatoid arthritis (RA), nervous system involvement in multisystem disease, and neuro logical mim- ics of rheumatological disease, such as early Parkinson \200\231s disease or m otor neuron disease. The immune system is a key player in both \201 elds and there may be coincidental neuroimmunological and rheumatological disease. Immu- nosuppressive and other therapies carry with them neuro- logical side effects, and similarly therapies for neurolo gical disorders may occasionally cause side effects that enter the rheumatologist \200\231s area. New biological therapies have brought about rapid change. History: the approach The history from the patient and, in most cases, a companion will giv e the most accurate clues to etiology, whereas the clinical examination will reveal locatio n(s) of involvement only. Thus, \200\230a telephone call is more useful than a tendon hamm er \200\231 (John Gar \201 eld). The interrogation of the \200\230funny turn \200\231 in particular requires aggressive cross-examination. Discard terms such as \200\230stroke \200\231 or \200\230migraine \200\231 given by the patient, unless with solid evidence, an d attempt to obtain an unbiased, objective temporal description of events. The tempo of sym ptom onset often provides the most useful part of the history, e.g. sudden (thunderclap), c reeping over days to weeks, step-wise, static. Infections involving the nervous system are over-represented in immunosup- pressed rheumatology patients, and often require sensitive s ocial- and sexual-history taking, as do the possibilities of drug abuse. Risk factors for nervous system involvement \200 \200 \200 \200 \200 \200 \200 Smoking. Hypertension. Hyperlipidaemia. Immunosuppression (infection, cancer). Anti-phospho lipid antibodies. Co-existent bone and joint disease. Psychiatric co-morbidity and social f actors. Etiology/pathophysiology: general issues The large genome wide association studies have inc reased our knowledge of the molecular mechanisms and path- ways behind rheumatological and neuro-immunological disease, and at the current rate new genes are appearing every few mont hs. Functional studies of these genes, mainly in animal models, are starting to ascertain t heir role in disease. The innate immune system (apoptosis and its clearance, toll-like-rece ptor activation) has resurfaced as a key component of pathogenesis. Speci \201 c aspects of the history should cover the pattern of weakness, headache syndrom e, bladder/bowel/sexual function \200\223 a new change should ring alarm bells for cord co mpression or cauda equina syndrome, and are emergen- cies. Impotence is an early sign of au tonomic failure, whereas failure of ejaculation points to the cord. Enquire about hallucina tions \200\223 visual or olfactory (often indicating organic brain disease); auditory or t actile, psychotic symptoms, depressive symptoms, attention and memory encoding vs retrieval (ask \200\230what is the worst thing that has happened to you as a result of your poor me mory? \200\231), and endocrine factors such as menstruation, shaving, and libido. Screen fo r sleep disturbance and excessive daytime somnolence, consider sleep apnoea. Novel antibodies directed towards cell-surface antigens are being identi \201 ed and are r e \201 ning characterization and classi \201 cation of disease, e.g. the AQ4 target in Ne uromyelitis optica and Sj gren \200\231s myelopathy is a water channel, the regional distr ibution of disease remains unclear. Voltage- gated potassium channel (VGKC) and N-methyl-D- aspartate receptor (NMDA) receptors are important for basic neu- ronal function and synapti c plasticity. Antibodies directed towards intracellular epitopes may still be pathogenic, i f found to cross react with extracellular antigens, e.g. a recent \201 nding has found th at ribosomal P antibodies in lupus can recognize a novel neuronal surface antigen. \200\230Funny turns \200\231 A witness account is mandatory. Focal and generalized seizure s are more prevalent in rheumatological disorders, in particular lupus. A full cardiovascul ar history is needed including posture during attacks (events lying down in a young person can suggest serious a cardiac cause such as Wolff \200\223Parkinson \200\223White). Medicol egally, such a loaded diagnostic label as epilepsy often requires a neurologist, particular ly in the young. Gene expression assays on lymphocytes are demon- strating new \200\230signatures \200\231 of disease activity that again may reclassify these disorders in the future and allow tailo red drug therapy. It is clear that T cells are also involved in driving in \202 ammation i n neurological tissue. Demyelination in multiple sclerosis may be driven predominantly by a recently-de \201 ned subset of CD4+ IL-17 secreting T cells (Th17), rather than the Th1 s ubset. The relevance of these cells in terms of importance in CNS rheumatological involveme nt, available biomarkers, and alternative thera- pies is unclear. The biology of B and T ce ll interaction, memory and regulatory cell \200\230sub-specialization \200\231, and hor- m onal and epigenetic modi \201 cation of tolerance, is a fertile research ground. Headaches and facial pain New headaches require full investigation. Facial pain is best div ided into that accompanied by cranial nerve symptoms and signs (a painful opthalmoplegia is often in \202 ammatory), neuralgias (lancinating), trigeminal autonomic cephalalgias, and pure facial pain (sinus/masticatory) \200\223 this narrows down a wide list of diagnostic possibilities, for which imaging is generally mandatory. Neuropathic pain Mononeuropathies and polyneuropathis can cause periph- eral neuropathic pa in. Spinal root/dorsal root ganglion, spinal cord, brainstem, thalamus, subcortical and cor tical lesions can cause central neuropathic pain. A painful mono- neuropathy suggests vascu litis. This symptom deserves full Cytokines from a wide range of immune cells are impor- tant in pathogenesis and therapy; fo r example, tissues from patients with SLE or Sj gren \200\231s exhibit an expression signa ture CHAPTER 3 Organ involvement in rheumatological disease 91 investigation for a cause, and differentiation from joint pain, osteomyelitis, and complex regional pain syndromes. endocrine, HIV and hepatitis, cryoglobulins, thrombophilia screen, coeliac antibodies are p articularly salient. New serum antibodies (it is helpful to send CSF also and store baselin e samples for future available tests in gray cases) include those against the \200\230cell surface antigens \200\231 \200\223 a growing list, best directed by phenotype \200\223 o nly those that currently change management (e.g. none for lupus) are listed: \200 Examination: key points The rheumatologist often has a dif \201 cult task due to the patie nt \200\231s frequent co-existing joint disease and pain. The key is to localize the lesion (s) having formulated a predic- tion to test on the basis of the history. One should ask if the \200\230hard \200\231 signs are suf \201 cient to generate a reasonable explanation and invoke \200\230soft \200\231 signs only towards the end. Involve neurology or neurosur gery teams early if there is doubt. Given the age of the patient, are two separate patholog ies likely, or will a unifying cause be most likely? A full systems examination is necessar y. Fundoscopy (raised intracranial pressure- tumor; thrombosis; emboli), autonomic assessme nt (history of erectile failure, postural BP, pupils, referral for tilt testing) and cognit ive testing are a physician \200\231s most common blind spots. Pattern of weak- ness, and e xaggerated or lost re \202 exes and sensory signs can distinguish cervical myelopathy from root compres- sion, cauda equina from conus medullaris, and L5 root compression from peron eal nerve palsy, but often investi- gation will be necessary. Anti-aquaporin 4 (AQ4; \200\230Nmo-Ig \200\231 refers to the immuno- histochemical pattern of binding) for cord and optic nerve in \202 ammation (neuromyelitis optica or Devic \200 \231s disease), e.g. longitudinally extensive transverse myelitis (LETM) \200\223 in Sj g ren \200\231s and lupus. Anti-VGKC for encephalitis, seizures, amnesia, psychosis often wit h hyponatraemia (exclude viral encephalitis). Anti-nicotinic AChR or voltage gated P/Q type calcium channel (AChR \200\223 Myasthenia gravis; VGCC \200\223 Lambert Eaton myasthenia , often associated with small cell lung cancer) for fatiguable weakness. Anti-NMDA for suba cute seizures, psychosis, encephalitis, encephalopathy, often associated with teratomata (u su- ally ovary; exclude viral encephalitis). Other paraneo- plastic encephalitides are more common: breast, germline testis, small cell lung. Anti-basal ganglia antibodies and anti-s treptolysin O titre (ASOT) for movement disorder after streptococcal infection [exclude ant iphospholipid (APL) antibodies]. A mini-mental state examination (MMSE) should be performed with any patient who complains ( or more likely their companion) of subjective \200\230memory problems \200\231 (a catch-al l lay term). A patient who cannot attend (spell WORLD backwards easily, subtract 7 serially from 100, encode an address) will not be able to remember informa- tion, but may have inta ct memory processes. The patient \200\231s pre-morbid best cognitive function should be tak en to account, as well as a collateral history of rate of decline. Formal neuropsychology o r neurological referral is the next step. Functional overlay (non-organic manifestations) m ust be assumed an elaboration of true organic disease until proved otherwise. Imaging \200 MR spine imaging. For cord compression or cauda equina an urgent neurosurgical opinion shou ld be obtained immediately \200\223 surgery before 48 h gives the best chance for preserva tion of sphincter function. MR spine ( biopsy) is also indicated for suspected disc herni ation or spinal in \202 ammation, tumors, discitis, and infective endocarditis. MR venogra phy (MRV; Figure 3.13) is useful in the inves- tigation of venous thrombosis, idiopathic in tracranial hypertension (no longer called \200\230benign \200\231 IH, given visual loss ma y be permanent). MR angiography (MRA) can provide useful clues without the requisite for fo rmal angiography, e.g. vertebral artery dissection. Principles of investigation Specialist tests should be sought to con \201 rm the examinati on or where joint deformity precludes accurate examination, but also to rule out important differential diagnoses, e.g. infection and cancer (such as lymphoma), hypertensive encephal opathy, pre-eclampsia, treatable metabolic conditions (e.g. Wilson \200\231s disease), and treatable surgical conditions (e.g. normal pressure hydrocephalus, disc disease, abscess). Special investigations should affect management: Infection Infective mimics are of the grea test concern in this patient group, many of whom have a dysregulated immune system or are i mmunosuppressed. Progressive multifocal leukoen- cephalopathy (PML) and nocardial infection are over- represented in rheumatology patients. For instance, does the patient with valve vegetation, antiphospholipid anti- bodies, and lupus markers, and microthrombi in the retin a and CNS have infective endocarditis or Libman Sacks endocarditis? Does the patient with W egener \200\231s treated with cyclophosphamide, who develops headaches and meningeal enhanc ement on MR, have meningeal granulo- mata or bacterial meningitis? MR imaging, blood cultur es, laboratory markers, spinal \202 uid analysis and tissue biopsy \200\223 should be vi gorously pursued. [See algorithm by Weiner (Warnartz 2003)]. Laboratory tests The list is b eyond the scope of this chapter. Metabolic tests (copper studies in the young with movement abnormalities), Figure 3.13 Straight sinus thrombosis (phase contrast MRV). THE NERVOUS SYSTEM 92 Diffusion weighted MR allows abnormalities in water diffusion to be picked up \200\223 rep resents neuronal swelling \200\223 used in standard clinical practice to detect early isch ae- mia or infarct. New or progressive cognitive impairment without focal neurology or acut e symptoms may be due to multiple small infarcts and emboli, which should be considered alo ng with infective endocarditis in such patients. 18FDG-PET can be useful in diagnosing and monitoring both GCA and Takayasu \200\231s arteritis. Diffusion tensor (tractography), MR s pectroscopy and functional MR are still chie \202 y research tools. Cerebral autosomal dominant arteriopathy with subcor- tical infarcts (CADASIL for NOTCH3 ge ne) is a differential of MS, APLS, CVAs. Neurological diagnoses to consider on seeing \200\230a new patient \200\231 in rheumatolog y A list of questions to cover blind-spots and an open mind are all that are required to pr ompt recognition. \200 Parkinson \200\231s disease can present with stiffness and rigidity, as can the rarer Stiff \200\223Person syndrome (mainly in para- axial muscles \200\223 con \201 rm with neuroph ysiology, check anti-GAD65 antibodies). Multiple sclerosis may have an MR scan like antipho s- pholipid syndrome, and patients may have positive ANA or a transient positive anti-cardi olipin. There is no his- topathological report of demyelination in lupus or APLS, but the c ases reported as \200\230lupoid sclerosis \200\231 in the early 1970s had false positive s yphilis serology, i.e. were probable APLS. Restless legs syndrome constitutes a predominant ly nocturnal urge to move the legs accompanied or caused by uncomfortable and unpleasant se nsations in the legs, relieved by movement. It is seen in 5 \200\22310% of the older popula tion, but with greater prevalence in RA, Sj gren \200\231s, scleroderma, and \201 bromya lgia in particular. CNS stimulant medication [methylphenidate (Ritalin), and dextroamphetam ine] may cause Raynaud \200\231s phenom- enon and livedo reticularis. Cerebrospinal \202 uid Check safe to lumbar puncture (LP) with CT brain if urgent. Measur e: \200 \200 Opening pressure. Microbiology: gram stain, cell count, culture and sensitivity, including prolonged culture for Nocardia, Zielh-Nielson stain and Mycobacterium tuberculosis (MTB) cu lture; PCR for and immunoglobulin against HSV, EBV, VZV, CMV, enterovirus. India Ink stain for Cryptococcus. Serology against Listeria, Aspergillus, Candida, Enterobacteriae, Pneumoc ystis jiroveci, Coccioides, and HTLV-1 antigens. Biochemistry: protein, glucose (with paire d blood glucose), LDH, ACE. Immunology: anti-neuronal antibodies (paired serum), oligoclona l bands (paired serum). Cytology: LP may need to be repeated several times. Includes lympho cyte phenotype. Neurological manifestations of rheumatological diseases A variety of central and peripheral neurological complications are associated with AICTD and vasculitides (Table 3.12) and dru gs used to treat rheumatological conditions are also associated with neurological adverse e ffects (Table 3.13). EEG, video telemetry, electromyography, nerve conduction tests \200 EEG: establishes encephalopathy, supporting, but not excluding a diagnosis of epilepsy, ide nti \201 es non-convulsive status epilepticus in coma. EMG: distinguishes muscle and nerve involvement. NCS: distinguishes axon vs myelin damage, small vs large \201 bre and local izing nerve damage. Rheumatoid arthritis (RA) Cervical myelopathy can present acutely or subacutely. Neuropathy is rare and usually due to entrapment or drugs. A \200\230pachymeningitis \200\231 is rar e, usually occurs in long standing disease (high RF) \200\223 consider with new headaches, cranial nerve palsies. \200 Visual perimetry and opthalmological assessment Request for suspected retinal vasculitis, o ptic neuropathy, endocarditis, CMV retinitis, temporal arteritis (age and ESR>50, abnormali ties of the temporal artery on examina- tion and histology; sometimes third nerve palsy) an d idiopathic intracranial hypertension (sometimes associated with sixth nerve palsy). Ankylosing spondylitis Spondylodiscitis including fracture may present with a sudden increa se in back pain. A neurosurgical opinion is required as repair may be warranted. Cauda equi na may occur insidiously and is less amenable to repair. Systemic lupus erythematosus (SLE) Lupus may cause diverse neurological features: \200 \200 \200 \200 \200 \200 Histopathology Combined nerve and muscle biopsy provides a greater yield than nerve alone. Skin biopsy is useful in assessing an isolated sensory neuropathy by measurement of intraep i- dermal nerve \201 bre density. Biopsy of non-dominant frontal lobe or obvious peripher al lesion in the brain/meninges should be ideally obtained in the workup of possible vascul itis or atypical infection \200\223 ask how secure is the diagnosis otherwise? Psychosis. Seizures. Encephalopathy. Depression. Myelitis Cognitive impairment (APL antibod ies conferring the greatest risk) Movement disorder, peripheral nerve disorder, associated Myasthenia gravis. Miscellaneous CXR, transthoracic, and transoesophageal echocardiography, tilt testing in an autonomic work up, cardiac CT or MR, 24h ECG, 12-lead ECG for Wolff \200\223Parkinson \200 \223White. Carotid ultrasound. Chest-abdomen-pelvis CT, 18FDG-PET and pelvic and testicular ultrasound in the search for occult malignancy. Sleep studies for obstructive sleep apnoea .