QJM Advance Access originally published online on January 24, 2006
QJM 2006 99(2):69-79; doi:10.1093/qjmed/hcl005
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Review |
Neurological involvement in patients with rheumatic disease
From the 1Department of Rheumatology, Northwick Park Hospital, Middlesex and 2Department of Neurology, Charing Cross Hospital, London, UK
Address correspondence to Dr N. Sofat, Department of Rheumatology, Northwick Park Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK. email: n.sofat{at}imperial.ac.uk
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Summary |
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Top
Summary
IntroductionPatients with multi-system rheumatic conditions may have disease affecting the central and peripheral nervous systems. Early assessment is often helpful in averting the development of serious complications, which in some conditions can be prevented by the prompt institution of treatment. We review the spectrum of neurological disease in patients with a rheumatological diagnosis. The wide variety of associated neurological complications is discussed in the context of specific rheumatic conditions, varying from spinal cord involvement in rheumatoid arthritis, to neuropsychiatric involvement in systemic lupus erythematosus and neurological sequelae in vasculitic disorders. We discuss diagnostic criteria and recommended management options (where available), and describe the role of new tools such as functional brain imaging in the diagnosis and monitoring of disease. We also discuss the potential for development of neurological complications from the use of anti-rheumatic drugs.
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Introduction |
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Neurological involvement is associated with significant morbidity in patients with rheumatic diseases, and may indicate heightened disease activity. Although certain neurological complications such as entrapment neuropathies are common and well recognized,1 other associations are less well appreciated. The most prominent features of neurological involvement in rheumatic diseases include cerebral ischaemia, polyneuropathy and psychiatric symptoms. Neurological associations in rheumatic diseases should be distinguished from important differential diagnoses, including multiple sclerosis, infection and malignancy. The extent of disease involvement is shown in Table 1.
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Little information is available on the prevalence of neurological disease in patients with a rheumatological diagnosis. In one study, 100 consecutive patients attending a neurology service were screened.2 Of these, 11% had a rheumatic or autoimmune disorder directly related to their neurological diagnosis. The most common conditions were Sjögren's syndrome (3%) and the presence of lupus anticoagulant (3%). The spectrum of conditions included stroke, dementia, migraine and hemiparetic somatization. Assessment of serum autoantibodies can be helpful, as certain diagnoses are associated with recognized autoantibody profiles (Table 2).
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Since many of the conditions involved are relatively rare, management has been based largely on case-control studies and anecdotal information. More recent work using MRI (magnetic resonance imaging) and PET (positron emission tomography)3,4 shows that they may be useful in disease assessment. This review aims to identify factors that may assist the neurological evaluation of patients with rheumatological diagnoses.
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Rheumatoid arthritis |
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Rheumatoid arthritis (RA) is a chronic, progressive, systemic inflammatory disorder where joints are the primary target. A wide spectrum of neurological conditions occur in RA, including peripheral neuropathy, encephalopathy, myelopathy, vasculitis causing neuropathy and stroke, myositis and denervation atrophy.12,13 RA patients have more neurological symptoms and deficits, based on standardized scoring criteria, than do normal controls.14 Cord compression is one of the most important life-threatening neurological sequelae. It can result not only from atlantoaxial subluxation at the cervical spine, but also from rheumatoid nodules15,16 and epidural lipomatosis.17 The clinical features and management of cord compression are discussed in more detail below. More rarely, nerve palsies, including hypoglossal nerve paresis,18 optic neuritis19 and pachymeningitis,19 are also described.19
Cervical spine involvement
Cervical spine disease in RA can cause atlantoaxial subluxation, which can lead to cord compression, or more commonly, the persistence of a neurological deficit from spinal cord level C1/C2 downwards, with sensory and/or motor signs, that usually warrants surgical intervention. Atlantoaxial subluxation is most often seen in patients with longstanding disease. Early and extensive erosive disease in the peripheral joints also predicts the development of atlantoaxial subluxation.20 Studies have addressed the advantages of plain radiographs vs. MRI in assessing the severity of atlantoaxial subluxation.21,22 Detailed bony changes are seen and precise measurements best made with plain radiography,22 but MRI can show changes such as pannus causing cord compression.22 Intravenous corticosteroid therapy is sometimes used to treat acute cord compression,23 but patients with persisting neurological symptoms often undergo decompression and fusion.24 The timing of surgery in atlantoaxial subluxation is a debated subject, and patients should be monitored carefully to optimize the time of surgery.25 Post-operative assessment, with a simple walking test and stair-climbing assessment, can prove useful.26
Peripheral nerve involvement
Entrapment neuropathies—the archetypal form is carpal tunnel syndrome—are often diagnosed clinically. In cases with mixed signs and poorly defined regions of involvement, nerve conduction studies may be helpful.1 In one study, nerve conduction studies showed that 6% of subjects with RA had carpal tunnel syndrome and 18% had mononeuritis multiplex.27 Reduced sensation over the distribution of the affected nerve may be associated with muscle wasting and functional impairment. Nerve conduction studies show reduced amplitudes with relatively normal sensory and motor conduction velocity. EMG (electromyography) shows fibrillation potentials and positive sharp waves due to muscle denervation. Supportive treatment includes modification of activities and splints. In many cases, use of medical therapies such as corticosteroid injections in appropriate sites (e.g. the carpal tunnel), is indicated, along with optimal treatment of the underlying disease.28 Surgery is usually considered in cases where medical management has failed.29
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Systemic lupus erythematosus (SLE) |
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SLE is an autoimmune disease characterized by inflammation in many organ systems. Neurological manifestations of SLE are common.30,31 The commonest conditions are psychiatric disorders, dementia and seizures, although long tract signs, cranial nerve abnormalities and peripheral neuropathy also occur. Psychiatric symptoms are the commonest form of neurological involvement,30–32 but rarer associations such as peripheral nerve conduction abnormalities33 and transverse myelitis requiring urgent immunosuppressive therapy, also form part of a small but significant group.34 Epileptic seizures are an important feature of CNS lupus.35 In a study of 519 patients with SLE, 11.6% had epileptic seizures. Seizures occurred at the onset of SLE symptoms in 31.6% and after disease onset in 68.3%.35 All patients with recurrent seizures had antiphospholipid syndrome and inter-ictal EEG epileptic abnormalities.
Less than 5% of cases with cerebral lupus present with stroke as the first manifestation of SLE.36 Serological tests for DNA binding are usually positive, but titres may not match disease severity. Several underlying mechanisms may be responsible for stroke, including coagulopathy associated with lupus anticoagulant, small-vessel vasculitis, cardiac embolism from Libman-Sacks endocarditis and hypertension from renal involvement.
The aetiology of neuropsychiatric involvement in CNS lupus has been linked to retrovirus infection.37,38 Others have reported the involvement of autoantibodies39 or immune complexes40 in cerebral disease. Anti-ribosomal P antibodies are also described in association with neuropsychiatric SLE.7,8
Other conditions should be excluded during the investigation of neuropsychiatric involvement in SLE. These include infections (e.g. bacterial meningitis, viral encephalitis); medications (including psychotropic drugs, high dose corticosteroids and non-steroidal anti-inflammatory drugs); metabolic causes (e.g. CNS effects of uraemia); and other medical conditions (e.g. hypertensive encephalopathy and primary psychiatric disorders).
MRI remains the principal brain imaging method in SLE. In one study, 116 MRI scans performed on 85 patients with SLE were reviewed:41 60% showed high-signal lesions on T2-weighted images, which most frequently occurred in the frontal and parietal subcortical white matter. Functional brain imaging, including magnetic resonance spectroscopy and diffusion/perfusion weighted imaging, has been used to assess disease activity in SLE.42 A study using PET in SLE showed hypometabolism in at least one brain region in all patients with severe or mild CNS symptoms (100%), compared with patients without cerebral symptoms (40%).43
Treatment of neuropsychiatric SLE is determined by its manifestations. Many patients with severe involvement, such as transverse myelitis, receive corticosteroids or even cytotoxic agents such as cyclophosphamide. Patients may benefit from specific therapies, e.g. antipsychotic medications for psychosis, antidepressants for depression and anticoagulants for thromboembolic disease.44 Clinical disease is best monitored by assessing improvement of neurological signs along with measurement of inflammatory markers such as ESR. Although MRI may be helpful in making the diagnosis, lesions may not change in response to immunosuppressive treatment, and PET scanning may be more sensitive.45 Recent work suggests that EEG abnormalities may occur in SLE even in the absence of brain abnormalities on MRI, particularly in patients with antiphospholipid antibodies.46 EEG may therefore be useful in identifying patients who may benefit from anticoagulation.46
The overlap between SLE and the antiphospholipid syndrome is an important consideration. In some patients with SLE who also have antiphospholipid antibodies, their neurological disease may be attributable to the prothrombotic risk conferred by the presence of these antibodies. The development of strokes and migraine in patients with antiphospholipid antibodies may warrant treatment with anticoagulants, including aspirin, heparin or warfarin, with doses adjusted until the disease activity is stabilized.47
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Vasculitis |
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The vasculitides are characterized by multi-organ involvement, and disease presentation is often with significant constitutional symptoms.48–52 They are divided into groups as summarized in Table 3.
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Takayasu's arteritis
Takayasu's arteritis is a large-vessel vasculitis of the aorta and its branches. CNS symptoms such as light-headedness, dizziness and visual disturbances are described.53 The absence of peripheral pulses, claudication symptoms, hypertension, age >40 years, raised ESR and imaging of the affected vessels are all criteria in making the diagnosis.53 Stroke due to vertebral/carotid ischaemia or embolism has been described,53 and fundoscopic findings of microaneurysms, venous dilatation and beading may also be found.54 PET and MRI have been used to identify vessel wall thickening and disease activity,55 and are less invasive than X-ray angiography. Active disease is usually treated with high-dose corticosteroids (typically 1 mg/kg/day prednisolone), with steroid-sparing agents (e.g. methotrexate) in the long term. Vascular bypass may be necessary if limb or organ ischaemia threatens surrounding tissue viability, but can be associated with reocclusion.54
Temporal arteritis
Temporal arteritis is a large-vessel vasculitis preferentially affecting the superficial temporal artery and other branches of the external carotid artery. Moderate to severe headache, particularly in the temporal region, is described by most patients.56 Diplopia, blurred vision or amaurosis fugax may precede the development of sudden unilateral blindness. Overall, up to 40% of patients experience visual loss,57 and the most common cause is ischaemic optic neuropathy.58 Diagnosis is aided by high ESR and/or CRP, as well as a temporal artery biopsy that shows a mononuclear cell infiltrate with intimal hyperplasia and occasional giant cells in active disease. Non-invasive imaging including ultrasound has been used to show concentric wall thickening, often combined with stenoses, and PET can be used to observe vasculitis of large vessels >4 mm in diameter, although it is unsuitable for assessing the temporal arteries.59 Due to the risk of blindness, high-dose corticosteroid (usually 40–60 mg/day) should be initiated if clinical suspicion is high. With appropriate treatment, the chance of subsequent blindness is <20%.57 Once signs and symptoms have stabilized (usually within 1 month) and acute-phase reactant levels have declined, the prednisolone dose can be reduced (5–10 mg every 2–4 weeks) and subsequently more slowly (1 mg every 2–4 weeks when <10 mg/day). If weaning from corticosteroid therapy becomes problematic, steroid-sparing agents such as methotrexate may be required. Angioplasty or vascular bypass may be indicated if large-vessel involvement is producing claudication or other treatable complications.
Wegener's granulomatosis
Wegener's granulomatosis is a vasculitis associated primarily with pulmonary and renal involvement. In a large series of 324 patients, 33.6% had neurological involvement.60 The commonest features included peripheral neuropathies, cranial neuropathy, ophthalmoplegia, cerebrovascular events and seizures.60 Serum anti-neutrophil cytoplasmic antibodies (ANCA) and tissue biopsy to confirm granulomatous vasculitis are usually performed. Treatment is primarily of the underlying disease, often with immunosuppressive agents. Therapy typically includes high-dose corticosteroids (e.g. 1 mg/kg/day prednisolone) in conjunction with cyclophosphamide at doses of 1–2 mg/kg/day.61 Intermittent ‘pulsed’ intravenous cyclophosphamide does not appear to be as efficacious as daily oral dosing. Depending on the site of occurrence, peripheral neuropathies may require supportive therapy with splints and physiotherapy.
Polyarteritis nodosa (PAN)
PAN is a form of systemic necrotizing vasculitis that usually presents with some kind of neurological disturbance. The neurological conditions found include mononeuritis multiplex and symmetrical polyneuropathy.62 Distal sensorimotor polyneuropathy and late CNS involvement leading to encephalopathy also occur.63 A high index of suspicion for the diagnosis of PAN is required, since serological tests showing elevated inflammatory markers are rather non-specific. Biopsy of cutaneous lesions or a nerve may be required for a firm diagnosis to be made. PAN is associated with high morbidity. Untreated, mortality is >90%, but with corticosteroids it decreases to 50%.63 Treatment with corticosteroids (typically 1 mg/kg/day prednisolone) usually results in a better chance of long-term survival. Addition of cytotoxic agents such as cyclophosphamide and azathioprine may be required to achieve remission.
Churg-Strauss angiitis
Churg-Strauss angiitis is a necrotizing vasculitis with prominent eosinophilic tissue infiltrates and granulomas affecting medium- and small-sized vessels. A mononeuropathy or polyneuropathy form part of the diagnostic criteria.64 Other neurological findings similar to PAN may occur,65 and treatment using corticosteroids is often implemented along similar lines after diagnosis has been confirmed on tissue biopsy. Survival is slightly better than in polyarteritis nodosa, with up to 90% of patients alive 1 year after the initial diagnosis.66
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Behçets syndrome |
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Behçets syndrome is a syndrome of recurrent, painful oral and genital lesions associated with uveitis and other forms of systemic inflammation. Neurological involvement is classified into: (i) inflammation of CNS tissue or (ii) vasculitis with a stroke-like presentation and sinus venous thrombosis.67 The latter form of involvement is less frequent.68 The wide variety of neurological findings that occur are headaches, ocular and other cranial nerve palsies, seizures, cerebrovascular insufficiency, brainstem syndrome leading to cerebellar ataxia and pseudobulbar palsy.69 Spinal cord disease, hemisphere lesions and meningoencephalitis also occur.69 Treatment of CNS lesions includes steroid pulse therapy (typically prednisolone 1 mg/kg/day) and long-term immunosuppression with steroid-sparing agents. Headaches can be treated with tricyclic antidepressants, valproic acid and topiramate.70
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Sjögren's syndrome |
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Sjögren's syndrome is a chronic autoimmune condition characterized by lymphocytic infiltration, particularly in the lacrimal and salivary glands, with consequent dry eyes and dry mouth. There is wide variation in reported neurological involvement in Sjögren's syndrome, possibly due to varying inclusion criteria.71 Associations include polyneuropathy, spinal cord involvement, motor neurone syndromes and most commonly, cognitive dysfunction.72,73 Where Sjögren's syndrome is complicated by cervical myelopathy or transverse myelitis, intravenous immunoglobulin therapy74 and interferon alpha75 have been used with some success.
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Idiopathic inflammatory myopathies |
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Myositis covers a range of conditions grouped together as idiopathic inflammatory myopathies. Diagnosis is important, since lack of treatment is associated with significant morbidity and mortality. The three main subgroups are dermatomyositis, polymyositis and inclusion body myositis.76 The main features of each form are illustrated in Table 4. The clinical features of proximal muscle weakness and fatigue are accompanied by laboratory findings of elevated creatine phosphokinases, alanine transferase and aspartate transaminase. A muscle biopsy from affected region(s) is usually required to confirm the diagnosis.77
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The idiopathic inflammatory myopathies may each present in isolation or with a connective tissue disorder, including SLE, RA, Sjögren's syndrome, and scleroderma. The mixed connective tissue disorders are most commonly associated with polymyositis.77 Treatment with corticosteroids (1 mg/kg/day), and in due course steroid-sparing agents, is the accepted treatment regimen, with regular monitoring of muscle strength.78 The use of intravenous immunoglobulin is recommended in the most refractory cases, with some success,79 and current trials are underway to assess the use of cytokine inhibitors in this disease.80
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Scleroderma |
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Scleroderma is a multisystem disease characterized by skin thickening and vascular disorders. The most commonly affected organs are the lung and kidney. Disease subsets are recognized, based on the extent of skin disease. Limited cutaneous disease involves fibrosis in the distal extremities and some areas of the face and neck. Limited disease is also known as CREST (calcinosis, Raynaud's, (o)esophageal dysmotility, sclerodactyly and telangiectasia). Diffuse disease includes patients with skin abnormalities extending to the proximal extremities (above the elbow and knee or trunk). Localized disease may occur such as patches of (morphoea) or band-like (linear scleroderma) skin thickening.
Polymyositis can be associated with scleroderma, as described above.77 Rare associations include intracerebral inflammation and the ‘en coup de sabre’81,82 variant of scleroderma. Brachial plexopathy83 and progressive brain atrophy84 attributed to underlying scleroderma are described. Such associations are notoriously difficult to treat. The degree of underlying disease determines the decision to institute high-dose cytotoxic therapy.85 In difficult cases, intravenous immunoglobulin is used, not only to treat the polymyositis, but also to help reduce collagen deposition from scleroderma.86
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Sarcoidosis |
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Sarcoidosis is a chronic inflammatory disease characterized by non-caseating granulomata at affected sites. Involvement of the nervous system occurs in a relatively small number of patients.87 In the CNS sarcoid, granulomas most often involve the meninges. The commonest findings are cranial nerve involvement, CNS parenchymal disease and demyelination. More rarely, features such as aseptic meningitis and peripheral neuropathy are found. CNS granulomas, symptomatic or asymptomatic, can be seen on T2-weighted MRI or contrast-enhanced CT.88 MRI and PET are being used to identify otherwise occult sites of inflammation that may be amenable to biopsy.88 Lumbar puncture is usually performed in cases of suspected neurosarcoid, although CSF findings are non-specific. Angiotensin-converting enzyme (ACE) levels may be increased, decreased or normal in the CSF. The mainstay of treatment remains corticosteroids, although other immunosuppressive agents, e.g. methotrexate, may be added for their steroid-sparing effect.89 More recently, anti-TNF therapy has been used in resistant cases of sarcoidosis, with some success.90
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Ankylosing spondylitis |
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Ankylosing spondylitis is an inflammatory arthropathy that affects predominantly the axial skeleton. It often begins in the sacroiliac joints and then ascends to involve the remaining spine. The main neurological complications in ankylosing spondylitis occur due to axial disease with spinal cord impingement at multiple levels. Surgical procedures in patients with atlanto-occipital disease, atlantoaxial subluxation and spinal stenosis have been performed for pain and neurological deficit.91,92 However, surgery is not without risk of permanent neurological damage. Suitable patients must therefore be identified and counselled carefully.
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Drug dosages for immunosuppressive therapies |
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Corticosteroids are often used at the time of acute disease flares or to control the disease process at its first presentation. For serious inflammatory disease, 1 mg/kg/day of prednisolone or equivalent may be used initially and titrated down according to response. Sudden withdrawal of corticosteroids is not recommended, and the dose is usually tapered down in divided doses, depending on disease response. Patients on corticosteroid therapy spread over some years usually require calcium and Vitamin D to prevent the development of osteoporosis.93 Where osteoporosis has been diagnosed, drugs such as bisphosphonates and lifestyle changes are also recommended to prevent further bone loss.93
Long-term disease control is often achieved with steroid-sparing agents. Methotrexate (usually from 10–30 mg/week), sulphasalazine (2–3 g per day in divided doses), hydroxychloroquine (up to 400 mg daily in divided doses) and azathioprine (1–2.5 mg/kg/day in divided doses) are amongst the drugs most commonly used in rheumatological practice to maintain disease remission.94 All require regular monitoring, in particular for bone marrow suppression and/or development of liver function abnormalities. Newer biological therapies have been licensed for patients who fail to respond to two or more of the more conventionally used disease-modifying therapies (DMARDs) or who have very aggressive disease. Treatments directed at the suppression of tumour necrosis factor cytokine activity include infliximab, etanercept and anakinra.94,95 The two treatments used in combination with methotrexate are infliximab (3–5 mg/kg i.v., repeated at 2 weeks, 6 weeks, then every 8 weeks) and adalimumab (40 mg taken alternate weekly). Both drugs are used in moderate to severe RA. Infliximab is also licensed for use in ankylosing spondylitis. Etanercept is licensed for the treatment of psoriatic arthritis and severe ankylosing spondylitis (25 mg twice weekly, subcutaneously).
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Immunosuppressive therapies for vasculitic diseases |
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The conditions described above illustrate the broad range of vasculitic diseases that have neurological manifestations. Immunosuppressive therapy is the main form of treatment, and the more widely used agents have been described where specific conditions are mentioned. However, newer agents such as mycophenolate mofetil, rituximab and tumour necrosis factor alpha inhibitors are being used to treat SLE,96 Takayasu's arteritis,96 Churg-Strauss syndrome,97 ANCA-positive vasculitis96 and Behçet's disease.98
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Anti-rheumatic drugs associated with neurological side-effects |
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A full drug history in patients with an existing rheumatological diagnosis is imperative, since a number of drugs used in the rheumatology clinic are associated with neurological side-effects (Table 5). Of particular concern are the reports of demyelinating disorders reported in patients taking cytokine inhibitors,99,100 although the risk of developing this side-effect appears low.
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Conclusions |
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Neurological involvement in rheumatic disease is associated with high morbidity and in some cases can be life-threatening. Early assessment and a high index of suspicion for recognized complications are essential in managing such patients. Although serious neurological complications in rheumatic disease appear to be rare, few studies have been conducted on their prevalence. Studies of larger cohorts of patients in multi-centre studies are required to assess the management of such patients more fully.
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