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 . However, attribution to lupus of non-speci \201 c neurological symptoms, in particular hea dache, remains controversial. Structural MR imaging is often normal. CSF lymphocytosis is p redictive of a poor prognosis. Test for anti-AQ4 in myelitis. CHAPTER 3 Organ involvement in rheumatological disease 93 Endocrinology collaboration to investigate hypothalamic and pituitary involvement may often helpful. Antiphospholipid syndrome (APLS) Stroke predisposition. Sustained elevation of antiphospho- lipid antibodies, and venous or arterial thrombosis constitute the syndrome; improving ima ging studies reveal microthrombi previously missed \200\223 diffusion weighted and structu ral MRI is suf \201 cient in the clinic and ward setting. Takayasu arteritis Carotid artery stenosis and subclavian steal syndrome are seen secondary to vessel occlusion. Arch angiography and 18FDG-PET are useful in investigation. Giant cel l arteritis Optic neuropathy and third nerve palsy. All patients require ophthalmological a ssessment. Systemic sclerosis Peripheral neuropathy including autonomic and, in particular, painful tr igeminal neuropathy predominates. Sj gren \200\231s syndrome Sensory polyneuropathy and polyganglionopathy are the most comm on manifestations, and in the majority of cases precedes the development of sicca symptoms and diagno- sis of SS. Use of tricyclics (which dry the mouth), hepatitis C, human T-lympho cyte virus type 1, HIV, and lymphoma must be excluded. It is becoming clear that the severe myelopathy seen occasionally in patients is due to neuro- myelitis optica and, hence, anti bodies to aquaporin-4 should be tested. Other CNS involvement is rare. Beh et \200\231s disease Vascular-related parenchymal involvement and thrombosis. In the T urkish Neuro-Beh et study group \200\231s experience (155 male, 45 females) brainstem invo lvement occurred in 51% \200\224 a common \201 rst presentation), followed by cord (14%) , then hemisphere. The UK experience is similar. A lymphocytic CSF predicts a recurrent cli nical course. Dural sinus thrombosis is also common and hard to diagnose unless specificall y considered (raised CSF opening pressure, acellular, MR venography). Peripheral neuropathy is rare, more commonly due to thalidomide therapy. Dermatomyositis, polymyositis and inclusion body myositis (IBM) IBM is the commonest and le ast understood. It is charac- terized by a slow steady progression. CK (lower levels seen i n IBM), EMG, and muscle biopsy are the mainstay of investigation. Primary angiitis of the CNS (PACNS) and benign angiopathy of the CNS These are rare, and sy mptoms can re \202 ect focal ischaemia in any part of the brain anatomy. Angiography (bead ing, segmental narrowing) and a tissue diagnosis should be pursued in combination. Sarcoidosis Cranial neuropathy VII and II are most common. Patients may have episodic menin geal symptoms and chronic m eningitis. Psychosis, epilepsy, neuropathy, and myopathy are re cognized. CSF examination, imaging (contrast- enhanced MR essential) and biopsy are the key investigations. Relapsing polychondritis A limbic encephalitis has been reported; exclude HSV encephalitis, check anti-VGKC antibodies. Table 3.12 Anatomical classi \201 cation of nervous system involvement in rheumatological disease Meninges Brain Brainstem Cranialerve Cord Root Nerve NMJ Muscle Thrombosis Rheumatoid arthritis Ankylosing spondylitis SLE APLS Systemic sclerosis Sj gren \200\231s syndrome DM, PM, IBM Takayasu arteritis GCA Wegener \200\231s granulomatosis Churg \200\223Strauss, MPA, PAN Beh et \200\231s disease 1 \232 angiitis CNS Sarcoidosis Relapsing polychondritis More common; - less common Abbreviations: APLS, antiphospholipid syndrome; CNS, central n ervous system; IBM, inclusion body myositis; GCA, giant cell or temporal arteritis; DM, der matomyositis; MPA, microscopic polyangiitis; PAN, polyarteriitis nodosa; PM, polymyositis; SLE, systemic lupus erythematosus. THE NERVOUS SYSTEM 94 Table 3.13 Neurological side-effects of drugs used for rheumatological disorders Side-effect Drugs Aseptic meningitis NSAIDS, trimethoprim, IVIG Idiopathic intracranial hypertension (IIH) Glucocorticoids (GCs), especially on withdrawal in children, danazol. PML Rituximab (rare reports, FDA warning 2006) Anti-TNFA Allopurinol (including withdrawal), ch lorambucil, cimetidine, ciclosporin, NSAIDs, methotrexate Demyelination Seizures Headache NSAIDs, especially at the start of treatment, notably indomethacin, ketoprofen, diclofenac; dipyridamole, ciclosporin, tacrolimus Psychosis, personality change Chloroquine, opiates, indomethacin, GCs Delirium, encephalopathy Cimetidine and chloroquine, methotrexate Mania GCs, ciclosporin Hallucinations Ciclosporin NSAIDs, GCs, methotrexate, ciclosporin, interferon-A. NSAIDs, cetirizine Depression Dizziness Parkinsonism Metoclopramide, prochlorperazine, chloroquine, cinnarizine, neuroleptics (particularly if c ombined with antidepressants), lithium, cyanide, carbon monoxide, other toxins. Chorea Cimetidine, metoclopramide, levodopa Tremor Cimetidine, ciclosporin, indomethacin, GCs, valproate, caffeine, levothyroxine, bronchodila tors Ibuprofen, indomethacin, D-penicillamine, anti-TNFA, amiodarone, isoniazid, ciclospori n Chloroquine, NSAIDs, salicylates, aminoglycoside antibiotics, furosemide, chemotherapy ag ents Optic neuropathy Ototoxicity Allopurinol, azathioprine, D-penicillamine, gold salts, salicylates Dysgeusia Muscle cramps Cimetidine, gold salts, D-penicillamine, statins Myasthenia D-penicillamine: chloroquine unmasks myasthenia Myopathies Cimetidine, chloroquine (painful), colchicine, steroids (chronic, painless), lovastatin Myositis D-penicillamine (painful), zidovudine (AZT). Rhabdomyolysis rarely with statins. Chloroquin e, colchicine, gold salts, D-penicillamine, chlorambucil, anti-TNFA, thalidomide, le \202 unomide, nitrofurantoin, metronidazole, NSAIDs, cimetidine, dapsone, amiodarone Peripheral neuropathy Adapted from 1.3.3 Neurological complications, Ferguson & Hollingworth (2004). Many drugs c an affect the levels of immunosuppressive drugs, in particular, ciclosporin and tacrolimus, for which trough levels can be checked. Anti fungal drugs, trimethoprim, erythromycin and the oral contraceptive device are the most common. The following table should not be consid ered complete, nor an indication that the drug will turn out to be the cause of the symptom s. Abbreviations: AZT, zidovudine; FDA, US Food and Drug Administration; IVIG, intravenous imm unoglobulin G; NSAID, non-steroidal anti-in \202 ammatory drug; PML, progressive multifoca l leukoencephalopathy; TNF, tumor necrosis factor. ANCA-associated vasculitis (AAV) including Wegener \200\231s granulomatosis (WG) Swanson \200\231s study of 324 consecutive patients with WG revealed 109 (34%) with neurological in volvement: mainly peripheral (mononeuritis multiplex) or cranial neuropathy. CNS involvemen t was less common. \200 There are three patterns: vasculitic, meningeal due to adjacent granulomatous disease, and isolated granulo- mata in the parenchyma or meninges. Stroke, seizures, and retro-orbital g ranuloma may be seen. Exclude hepatitis B and C. In PAN and CSS an epineurial necrotizing v asculitis is seen histologically in >50% cases of neuropathy, often a painful mononeuritis multiplex. Vasculitis is the rarest cause of peripheral neuropathy in RA (consider drugs an d overlap AICTD). \200 Figure 3.14 (A) A 59-year-old woman with Behcet \200\231s syndrome and a spastic paraparesi s who developed worsening leg weakness 2 weeks after starting In \202 iximab (3 mg/kg) T2 (left) and T1-weighted MR images. Reproduced with permission from Zandi & Coles, 2007). Treatment New biological therapies offer hope of true disease modi- \201 cation prior to damage accumulation. Neurosurgeons should be involved early in cases of compressive myelopa thy or neuropathy. CHAPTER 3 Organ involvement in rheumatological disease 95 steroid sparing agents, or appropriate biological therapy may be tried with caution. Systemic lupus erythematosus There is RCT evidence that cyclophosphamide is effective for s evere CNS disease. Otherwise pulse methylpredniso- lone, IVIG, or plasma exchange may give modest effect. rituximab shows the greatest promise in open-label studies, but awaits de \201 nitive trial, and mycophenylate is under evaluation. Stroke Stroke deserves a special mention given the high incidence in rheumatological patien ts, who as a group suffer from accelerated atherosclerosis. \200 Primary prevention by aggressive control of hypertension and serum lipids. Acute thrombolys is within 3 h of symptom onset with rt-plasminogen activator. Stroke units reduce risk of d eath or dependency in themselves. Neurorehabilitation is disappointingly underfunded and ma y require a proactive search. Anticoagulation for cerebral venous sinus thrombosis with low molecular weight heparin, followed by warfarin (duration controversial). Antiplatelet ther apy (low dose aspirin and dipyridamole \200\223 currently in trials against clopidogrel) \200\223 should be given immediately unless contra-indicated. The risks of bleed- ing must be taken into account in a patient taking NSAIDs. Anticoagulation for pre-existing atrial \201 brillation and changes to hypertension control generally delayed by 2 weeks \200\223 discuss with a specialist. Consider cardiover- sion in liaison with cardiology. Carotid en darterectomy for symptomatic carotid stenosis has most bene \201 t if done early (weeks af ter symptoms), and for older patients. Antiphospholipid syndrome (APLS) and stroke The evidence for APLS suggests prolonged warfar in therapy at a target INR of 2.0 \200\2233.0 in de \201 nite APLS patients with \201 rs t venous events (including cerebral venous sinus throm- bosis), >3.0 if recurrent or arteri al events (cerebral infarct). Patients with isolated positive APL antibodies and stroke sho uld be treated as for stroke (see below) unless the antibody persists. Sj gren \200\231s syndrome (see also p. 254) Unclear. Myelopathy should be treated aggress ively (in par- ticular if anti-AQ4 positive) \200\223 plasma exchange in the \201 rst in stance, then long-term azathioprine or mycophenylate, rituximab if refractory. Dermatomyositis (DM), polymyositis (PM), IBM The NIH approach for DM and PM is high dose in itial GCs (80 \200\223100 mg/day for 1 month, halved over 10 weeks to an alternate day regi me, then consider high dose azathioprine (3 mg/kg \200\223 check TMPT activity, monitor ly mphocytes), methotrexate, ciclosporin, or MMF. Therapy for IBM is dif \201 cult \200\223 add CoQ10 to steroids initially and an exercise program. For severe disease try IVIG. T cel l depletion, with alemtuzumab and anti-TNFA therapy is under evaluation. Sarcoidosis One ap proach is pulse methylprednisolone (1 g IV for 3 days) followed by 0.5 \200\2231 mg/kg pred nisolone (with methotrexate as the best sparing agent and long-term hydroxychloro- quine \201 rst line). Beyond cyclophosphamide, in \202 iximab is showing promise. Monitor with i maging, not CSF (remains lymphocytic). Bacterial meningitis Broad spectrum antibiotics should be administered imme- diately before LP- benzylpenicillin 2.4 g 4-hourly if not allergic and there is a typical meningococcal r ash, cefotax- ime 2 g 6-hourly if not. Add vancomycin for suspected S. pneumoniae until sen sitivities known and ampicillin 2 g 4-hourly to cover Listeria. If possible, without causin g delay, take blood cultures before the \201 rst dose. CT before LP to exclude mass effec t and look for suf \201 cient CSF space around the brainstem. Give dexamethasone with anti biot- ics, 10 mg 6-hourly IV for 4 days ( \201 rst dose with \201 rst anti- biotic dose) , as it has been shown to be bene \201 cial and safe even in areas endemic for MTB. Takayasu \200\231s arteritis Conventional bypass grafts for stenoses. GCs, azathioprine and mycophenylate are used; anti-TNFA therapy shows promise. Accelerated atherosclerosis needs management of conventional risk factors. Encephalitis Intravenous high dose acyclovir for presumed herpes simplex virus until CSF PC R known to be negative. Consider autoimmune or paraneoplastic encephalitis (send serum and CSF anti-VGKC, anti-NMDAR antibodies, screen for malignancy \200\223 small cell lung, germ line testis, breast, teratoma). Giant cell arteritis. High dose GCs with prednisolone 60 mg/day until normal- ization of ES R \200\223 may be 6 months to a year. Adjunctive aspirin 100 mg/day may reduce visual loss . \200\230Rescue \200\231 3 days 1 g IV methylprednisolone, if there are symptoms or signs of visual loss. Beh et \200\231s disease Controversial. GCs and thalidomide (precautions) are used, with a lemtuzumab (Campath-1H) reserved for resis- tant cases. Venous sinus thrombosis is usually treated with GCs and anticoagulation (heparin then short-term warfarin \200\223 duration c ontroversial). Headaches and facial pain Medication overuse headaches are very common and disabling, and c an worsen on cessation of the drug, e.g. opiate. Migraine is best treated with a drug to te rminate the acute event such as an NSAID, domperidone, or a triptan. Do not treat during au ra, or if hemiplegic migraine or any cardio/cerebrovascular disease \200\223 consider scre ening for a patent foramen ovale. If frequent and disabling, a regular night prophylactic a gent, such as a B-blocker or tricyclic may be used. Chronic daily headache, tension-type he ad- aches, trigeminal-autonomic cephalalgias may respond idiosyncratically to treatment. Tr igeminal neuralgia responds often dramatically to carbamazepine. ANCA-associated vasculitides (see p. 330 \200\223331) Heavy induction immunosuppression fol lowed by a main- tenance phase. The current best appears to still be initial high dose pred nisolone and cyclophosphamide, followed by azathioprine if tolerated. RA, relapsing polychondritis, systemic sclerosis (SSc) Extrapolation of extra-nervous syste m current best treat- ment suggests that high dose GCs, cyclophosphamide, THE NERVOUS SYSTEM 96 Resources Patient information and Internet sites Neuropsychiatric lupus case definitions. A vailable at: www.rheumatology.org/publications/ar/1999/ aprilappendix.asp British Hypertens ion Society. www.bhsoc.org Stroke Association UK. www.stroke.org Driving and Licensing auth ority (UK). www.dvla.gov.uk Cochrane Neurological Network. www.cochraneneuronet. org Trigem inal Neuralgia. www.tna-support.org Neuro-rheumatological trials. http://clinicaltrials. go v/ct2/results?term=nervous+and+rheumatology Neuropathic pain Local measures, nerve blocks, epidural injections, transcu- taneous electr ical nerve stimulation (TENS), cognitive coping strategies, and drugs all have their role. The best drugs are gabapentin, amitryptilline, pregabalin, venlafaxine, carbamazepine, and opiates. Specialist advice is best sought if no progress is made. Excessive daytime somnolence Modafenil is useful for truly excessive somnolence (but has ca rdiovascular and psychiatric side effects). Restless legs syndrome Dopamine agonists are the treatment of choice, but require a documen ted discussion as to the real side effects of impulsive behavior and gambling in particular and avoided if the patient feels susceptible. Valproate or gabapentin show effect \200 \223 as a second choice. ICD10 codes www.who.int/classifications/apps/icd/ icd10online/ Neurorehabilitation A continence nurse should be involved early in cases of sphincter distu rbance with or without cord damage. Inter- mittent self-catheterization may be required if there is urinary residual or frequent infection. Consider referral to podiatry. Baclofen pu mps should be initiated by a specialist center. It is common sense and increasingly demonst rated in the literature, that keeping an active mind increases ability to function into old age. Exercises to increase \200\230cognitive reserve \200\231 include puzzles, voluntary work, engaging socially. Further reading Akman-Demir G, Serdaroglu P, Tasci B. Clinical patterns of neuro- logical i nvolvement in Beh et \200\231s disease: evaluation of 200 patients. The Neuro-Behcet Study Group. Brain 1999; 122:2171 \200\22382. Antel J, Birnbaum G, et al (eds). Clinical Neuroimmunology, 2nd edn. Oxford: Oxford University Press, 2005. Barile-Fabris L, Ariza-Andraca R, et al. Controlled clinical trial of IV cyclophosphamide v ersus IV methylprednisolone in severe neurological manifestations in systemic lupus erythem atosus. Ann Rheum Dis. 2005; 64: 620 \200\2235. Psychiatric co-morbidity and psychological therapy Pain, fatigue and stiffness are common. Cognitive behavioral therapy, if available should be preferred to or added to pharmacologic al therapy. Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: res ults of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 2000; 17: 60 \200\2236. Bertsias G, Ioannidis JP, et al. EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Cl inical Studies Including Therapeutics. Ann Rheum Dis 2008; 67: 195 \200\223205. Prognosis/natural history CNS disease in particular is associated with a marked raised mort ality, morbidity, and reduction in quality of life. A key message is that baseline CSF and histology secures a diagnosis, and often provides prognostic indicators prior to embarking on new path of therapy. Candalise L, Hughes R, et al. Evidence-based Neurology. Blackwell, Oxford, 2007. Dalakas MC. Immune-mediated mechanisms in inflammatory myopathies. In: Antel J, Birnbaum G, Hartung HP, Vincent A (eds). Clinical Neuroimmunology, 2nd edn. Oxford: Oxford University Press, 2005. Monitoring disease activity Serial clinical assessment, immune parameters (comple- ment, an tibodies), MR, and electrophysiology are standard. Serial angiography and CSF is used in pr imary angiitis of the CNS, but both are of no use in other conditions. There is much resear ch into predictors of \202 are after biological therapy, e.g. \202 ow cytometric detect ion of return of B cells after rituximab, serum B lymphocyte stimulator levels. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008; 7: 327 \200\22340. Drachman DA. Neurological complications of Wegener \200\231s granulo- matosis. Arch Neurol 1963; 8: 145 \200\22355. Ferguson IT, Hollingworth P. Neurological complications. In: Oxford Textbook of Rheumatolog y, 3rd edn. Oxford: Oxford University Press, 2004. Other issues Medicolegal pitfalls Commonly, failure to recognize treatable conditions that will otherwise result in permanent disability or death, or iatrogenic effects of treatment: life threatening arrhythmia presenting with \200\230funny turns \200\231, nerve entrapmen t, cord com- pression, cauda equina, conus medullaris, cerebral venous thrombosis, meningit is in the immunocompromised pa- tient, drug toxicity, Wilson \200\231s disease, failure to ascertain suicide risk, and failure to secure a diagnosis before heavy immunosuppression. Fujiki F, Tsuboi Y, Hashimoto K, et al. Non-herpetic limbic encephalitis associated with re lapsing polychondritis. J Neurol Neurosurg Psychiat 2004; 75: 1646 \200\2237. Hankey GJ. Clinical update: management of stroke. Lancet 2007; 369: 1330 \200\2232. Hattori N, Ichimura M, Nagamatsu M, et al. Clinicopathological features of Churg \200\223St rauss syndrome-associated neuropathy. Brain 1999; 122: 427 \200\22339. Kidd D, Steuer A, Denman AM, et al. 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Rheumatoid arthritis Rheumatoid nodules The most common extra-articular manifestation of rh eumatoid arthritis (RA). \200 Subacute cutaneous lupus (SACLE) Diffuse erythematosus papules and scales or annular polycy clic (ring-like) erythema on neck, trunk, and arms. Exacerbated by UV light. 80% are positi ve for Ro/SS-A antibodies, 60% are ANA positive. 50% patients ful \201 l SLE ACR criteria usually on dermatological and serological grounds only. Transformation into SLE with modera te disease activity in 10 \200\22315 %. Treatment as for DLE. 90% of patients with rheumatoid nodules will be rheumatoid factor (RF) positive. Distributi on: extensor surfaces of the forearm, \201 ngers, occiput, back, and heel. Histology: gra nulomas with plasma cells, lymphocytes and histiocytes. Methotrexate-induced accelerated rh eumatoid nodulosis is well recognized and resolves with cessation of meth- otrexate. A simi lar phenomenon has been reported with etanercept. Lupus panniculitus/profundus Deep dermal and subcutaneous nodules with normal over- lying s kin (although characteristic lupus histology is found in overlying dermis). Heals with lipo atrophy. ANA positive 75%. Uncommonly transforms into SLE. Acute cutaneous lupus erythematosus (ACLE) Butter \202 y erythema. Diffuse erythema/maculo papular rash. Heals without scarring. Oral ulceration. Diffuse non- scarring alopecia. Phot osensitivity. Almost always ANA positive and 40 \200\22390% of patients are dsDNA positive. Often accompanies flare of systemic disease. Treatment: sunscreen, topical GCs, systemic S LE treatment. Rheumatoid cutaneous vasculitis Incidence of 2 \200\22310% in patients with RA, more common in males and RF positive patients. \200 Features in order of incidence are: cutaneous ulcers, purpura, nail-fold vasculopathy, non- speci \201 c nodular erythema, haemorrhagic blisters, livedo reticularis and erythema elev atum diutinum (red/purple nodules and plaques on extensor surfaces). Treatment is with gluc ocorticoids (GCs) and other immunosuppressants. The differential diagnosis of cutaneous ulc ers is large. Lower leg ulceration in a patient with RA is more likely to be due to venous ulceration. Dermatological advice should be sought before starting systemic treatment for c utaneous ulceration. Rare clinical sub-types Chilblain lupus erythematosus Peripheral painful nodules; 20% progr ess to SLE. \200 Neonatal cutaneous lupus Transient cutaneous lupus secondary to placental transfer of antib odies. Bullous lupus erythematosus Diffuse bullous lesions associated with active SLE. Granulomatous dermatitis This condition is rare, but usually associated with RA, although i t can be seen in other autoimmune connective tissue diseases (AICTDs). \200 Lupus erythematosus tumidus Urticarial plaques on sun exposed areas. Rowell syndrome. Erythema multiforme-like lesions. ANA positive \200\223 speckled pattern IF, anti-La antibodies and usually RF positive. The rash is erythematous to violaceous indurated linear cords (Rope sign). Rash is usually symmetrical extending from the axilla to the mid-back, but can occur anywhere. Antiphospholipid syndrome (APLS) Cutaneous \201 ndings in this condition have been descri bed with the following frequency: \200 Livedo reticularis 24%. \200 Leg ulcers 5.5%. \200 Pseudovasculitis 3.9%. \200 Cutaneous necrosis 2.1%. \200 Splinter hemorrhages 0. 7%. Patients with a very similar cutaneous presentation without laboratory evidence of APLS may have Sneddon \200\231s syndrome. The pathogenesis of this disease is unclear and the r elationship to lupus/APLS is controversial. Cutaneous lupus erythematosus Cutaneous lupus erythematosus is not synonymous with cutaneou s manifestations of systemic lupus erythematosus (SLE). Distinct dermatological patterns of cutaneous lupus exist and the majority of patients with cutaneous lupus do not progress to SLE. Dermatological (American Rheuma- tology Association; ARA) criteria include malar rash , discoid rash, photosensitivity, and oral ulcers (see Plate 12). It is therefore possible to meet ARA criteria on dermato- logical signs only. However, some would argue that malar r ash and photosensitivity are one and the same. Histology and direct immuno \202 uorescence (IF) are often similar, but not identical in the different types of cutaneous lupus. Dermatomyositis Cutaneous features of dermatomyositis (DM) are charac- teristic and, in wel l developed cases, diagnostic. \200 Discoid lupus erythematous (DLE) Well-de \201 ned scaly plaques of variable size frequentl y in- volving the face. Scarring alopecia, atrophy, and pigmentary changes. Healing occurs with scarring. Can mimic rosacea. Exacerbated by UV light. Chilblain-like lesions often Classical cutaneous features include heliotrope rash (peri-ocular purple macular rash), eye lid oedema, photosensitivity, erythematosus papules over knuckles (Gottron \200\231s papule s), linear erythema over fingers, CHAPTER 3 Organ involvement in rheumatological disease 99 dilated/tortuous nail-fold capillaries, ragged cuticles, poikiloderma in a photosensitive d istribution, cutaneous calci \201 cation and erythema of extensor aspect of knees and elbo ws. Non-classical cutaneous features include exfolative dermatitis, gingival telangiectasia (juvenile DM), \202 agellate erythema, bullae, erythema nodosum, urticaria, psoarisi- fo rm plaques, livedo reticularis, and erythema multiforme. SACLE and DM cutaneous signs are o ften dif \201 cult to differentiate. DM often exhibits erythema on the upper eyelids and n asolabial folds, whereas SACLE does not. Cutaneous features precede myositis in 30% of case s. Amyopathic dermatomyositis (ADM) is being increas- ingly recognized as a presentation. P rogression to classical DM is not inevitable. Patients can have exclusively cuta- neous dis ease for over 5 years. A positive ANA is found in 63% of ADM patients, but only 3.5% have m yositis-speci \201 c autoantibodies (e.g. Jo-1, Mi-2). ADM is not a benign condition and i s associated with interstitial lung disease in 13% of cases. Cutaneous treatment includes s unscreen (UV exposure may exacerbate myositis), topical GCs/calcineurin inhibitors. Systemi c GCs and other immunosuppressants are often required. Cutaneous calcinosis Often digital calcinosis progresses to digital ulcers. A minority of p atients have sheets of cutaneous calcinosis over the trunk and limbs leading to extensive u lceration. Can be treated by a carbon dioxide laser and surgery. Localized scleroderma (morphea) Localized scleroderma is a skin-limited disease that rarely displays systemic involvement. It is included in this chapter as it is commonly mistaken f or SSc. \200 There is little evidence to support morphea as part of a spectrum of SSc. Morphea can be di stinguished from SSc by clinical signs and autoantibody pro \201 le. Individuals with morp hea rarely exhibit Raynaud \200\231s phe- nomenon and do not have nail-fold capillary chang es. Importantly morphea very rarely progresses to SSc. There are a number of recognized sub types of morphoea, brie \202 y reviewed below. \200 \200 Plaque morphea Plaques on trunk, face, and limbs. Well-de \201 ned erythematous indurated plaque with violaceous border. Resolves with atrophy and pigmentatory changes. Generalized morphea Feature of 13% of patients with morphea. Insidious onset and can progre ss to involve large surface area. This type of morphea is often mistaken for SSc. Not assoc iated with systemic complications.