Neurologic manifestations of rheumatoid arthritis

Neurologic manifestations of rheumatoid arthritis

Authors
Monica L Piecyk, MD
Peter H Schur, MD

Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: Mar 17, 2016.

INTRODUCTION — Rheumatoid arthritis (RA) is associated with various nonarticular manifestations, including severe neurologic abnormalities. A variety of pathogenic mechanisms are responsible:
●Rheumatoid synovitis and pannus may compress or invade adjacent structures (including the spinal cord and peripheral nerves), resulting in myelopathy, radiculopathy, and entrapment neuropathies.
●Rheumatoid vasculitis may cause ischemia, infarction, or bleeding; these may ultimately result in transient ischemic attacks (TIA), stroke, quadriplegia, or paraparesis. With peripheral nervous system involvement due to vasculitis, there may be multiple nerve dysfunction (mononeuritis multiplex) or a more indolent polyneuropathy. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)
The introduction of newer medications since the 1990s, along with more aggressive and effective strategies for the treatment of RA, appears to have reduced the frequency with which some of the neurologic manifestations of RA are observed.
Because both neurologic and muscular disorders may present with weakness, muscular diseases that occur in association with RA will also be reviewed here. Other nonarticular and non-neurologic problems associated with RA are also discussed elsewhere. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)
CENTRAL NERVOUS SYSTEM — Disorders of the central nervous system (CNS) due to rheumatoid arthritis (RA) include cervical myelopathy, vasculitis, rheumatoid nodules located within the CNS, meningitis, organic brain syndrome, and (rarely) progressive multifocal leukoencephalopathy. Stroke also occurs with increased frequency, but the basis for this association is not well understood.
Cervical myelopathy — Cervical myelopathy (cervical myeloradiculopathy) resulting from atlantoaxial subluxation, atlantoaxial impaction, and/or subaxial subluxation is discussed separately. (See "Cervical subluxation in rheumatoid arthritis".)
Central nervous system vasculitis — CNS vasculitis is rare in patients with RA, with the literature generally consisting of case reports of intracranial arteritis [1-8]. CNS lesions are also infrequent in patients with systemic rheumatoid vasculitis [8-10].
Clinical manifestations — Presenting manifestations of CNS vasculitis include seizures, dementia, cranial nerve palsies, strokes, encephalopathy, intracerebral or subarachnoid hemorrhage, and myelopathy.
Diagnosis — Brain biopsy is the most specific diagnostic test. Cerebral angiography and magnetic resonance angiogram also may be helpful but are less specific. However, some evidence suggests that magnetic resonance imaging (MRI) abnormalities among symptomatic patients with RA cannot be ascribed to vasculitis alone. One study, for example, evaluated the incidence of hyperintense white matter lesions with MRI, findings suggestive of vasculitis, in 33 asymptomatic patients with RA and 48 control individuals [11]. There was no significant difference in the number of such lesions between the two groups.
Treatment — Therapy of patients with RA and CNS vasculitis is similar to that for patients with isolated CNS vasculitis. This includes high-dose glucocorticoids and cytotoxic agents. (See "Primary angiitis of the central nervous system in adults".)
Rheumatoid nodules — Rheumatoid nodules have been reported rarely in the central nervous system [12,13]. Extradural nodules in the spinal canal may cause nerve root compression, spinal cord compression, and spinal stenosis [14,15].
Rheumatoid nodules of the cerebral leptomeninges and within the choroid plexus also have been described [6,16-19]. Neurologic signs and symptoms in these patients have not always correlated with the anatomic location of the nodules; in many cases, there was coexistent CNS pathology.
Most patients with CNS nodules have severe erosive joint disease, other extraarticular features, and high titer rheumatoid factors [14,17,19]. In reported cases, the diagnosis of CNS rheumatoid nodules was made pathologically, either at surgery or autopsy.
Surgical decompression should be performed if a rheumatoid nodule is compressing a vital structure.
Meningitis — Rheumatoid meningitis consists of an inflammatory infiltrate of the meninges without distinct rheumatoid nodules [12,20-23]. Most patients have longstanding seropositive disease. Symptoms may include altered mental status, fever, headaches, seizures, cranial nerve dysfunction, and hemiparesis or paraparesis. Elevated cerebrospinal fluid levels of protein are the most common abnormality, but pleocytosis and depressed glucose also are described. In several case reports, treatment with glucocorticoids resulted in improvement in neurologic symptoms [22,23].
Organic brain syndrome — Manifestations of organic brain syndrome (OBS), including confusion, memory loss, and seizures, have been described in six RA patients being treated with no or low-dose glucocorticoids [24]. However, it is unknown whether the OBS was actually due to RA. Four were treated with high-dose steroid therapy. All six patients, including those who were observed without therapy, improved within one week.
Progressive multifocal leukoencephalopathy — The risk of progressive multifocal leukoencephalopathy (PML), which is associated with the polyoma JC virus, is increased in patients treated with rituximab for RA, but the absolute risk is very small. PML was reported in two patients with RA prior to the use of biologic disease-modifying antirheumatic drugs (DMARDs) [25]. A case was also reported in a patient with RA on rituximab and other immunosuppressive therapies, who was also treated for a malignancy [26]. There has been at least one case reported in association with use of adalimumab in RA [27]. There was one case of leukoencephalopathy in a RA patient treated with methotrexate [28]. In patients with RA treated with rituximab, at least four cases of PML have been reported to regulatory agencies [29]. The estimated absolute risk of PML is one case per 25,000 patients with RA treated with rituximab [30]. In an observational study using a nationwide inpatient sample database in the United States, the rate of PML in hospitalized patients with RA was estimated at 0.4 per 100,000 discharges, twice the rate in the background population [31]. (See "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis" and "Overview of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Hypogammaglobulinemia and infection'.)
Hyperviscosity syndrome — Hyperviscosity may cause symptoms similar to those seen in patients with Waldenström’s macroglobulinemia [32]. The clinical manifestations of hyperviscosity include headache, visual changes, vertigo, tinnitus, hearing loss, and cognitive dysfunction. This syndrome is discussed in more detail elsewhere. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)
Stroke — There is an increased risk of stroke in RA, especially ischemic stroke. A 2008 meta-analysis, involving 111,758 patients in 24 studies, found a significant increase in the risk of death from cerebrovascular accidents in patients with RA, compared with the general population (weighted-pooled summary estimate of standardized mortality ratios of 1.52, 95% CI 1.40-1.67) [33]. Significant heterogeneity, however, was found between the studies analyzed, and some studies have not shown stroke to be increased [34]. The following are examples of three large individual studies that have addressed the risk of stroke in RA:
●The magnitude of this effect was illustrated in a nested case-control analyses within a longitudinal data bank of 16,990 patients with RA compared with 5140 patients with noninflammatory rheumatic disease, 226 first strokes, of which 59 were ischemic, occurred in the RA patients (odds ratio 1.64 for all first strokes, 95% CI 1.16-2.30, and 2.66 for ischemic strokes, 95% CI 1.24-5.70) [35]. Risk factors for ischemic stroke included severity of RA, hypertension, myocardial infarction, and low-dose aspirin use, but not diabetes, smoking, exercise, or body mass index. Treatment with rofecoxib and possibly antecedent treatment with glucocorticoids were other possible risk factors.
●A significant increase in stroke was also noted in a population based study of 25,385 Canadian adults with RA, which evaluated the incidence of cardiovascular events (including myocardial infarction, stroke, or cardiovascular death) compared with age- and sex-matched controls [36]. The patients with RA had a small but significant absolute increase in stroke risk (2.4 per 1000 person-years, rate ratio 1.9, 95% CI 1.7-2.1). The absolute increase in cardiovascular events in RA patients was much greater in those over age 65.
●A nationwide Danish cohort study involving 18,247 patients with RA followed for a median of 4.8 years identified 718 strokes in patients with RA, representing a significant absolute increase in stroke risk compared with the general population (1.9 per 1000 person-years, with an adjusted incidence rate ratio of 1.32, 95% CI 1.22-1.42) [37]. This study also demonstrated an increased risk of atrial fibrillation in patients with RA, but the degree to which this contributed to stroke risk was not determined. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Atrial fibrillation'.)
Patients with RA also have an increased risk of coronary artery disease. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications".)
PERIPHERAL NERVOUS SYSTEM — Compression neuropathies are the most common neurologic manifestation of rheumatoid arthritis (RA). Sensory and motor dysfunction may also occur due to noncompressive neuropathies and myopathies.
Compression or entrapment neuropathy — Entrapment neuropathies are diagnosed in approximately one-half of RA patients with severe peripheral disease and subcutaneous nodules [38]. Joint deformities and inflamed synovium, ligaments, or tendon sheaths may compress peripheral nerves that are in close proximity to joints or bursae. There is no correlation between compression neuropathies and gender, duration of RA, functional class, the presence of other extraarticular disease, seropositivity, or the level of acute phase reactants [39].
Carpal tunnel syndrome — Carpal tunnel syndrome (CTS) is probably the most common neurologic manifestation of RA and can occur at any time during the disease [2,38,40,41]. In different series, CTS occurred in 23 to 69 percent of patients [39,42-44]. The probable cause of CTS is finger-flexor tenosynovitis, since these tendons also pass through the carpal tunnel.
Symptoms, findings, neurodiagnostic testing, and differential diagnosis of CTS in patients with RA is similar to that for other patients. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis" and "Carpal tunnel syndrome: Etiology and epidemiology".)
Conservative and surgical therapies are also similar and are discussed separately. (See "Carpal tunnel syndrome: Treatment and prognosis" and "Surgery for carpal tunnel syndrome".)
Tarsal tunnel syndrome — Tarsal tunnel syndrome, which is less common than CTS, is due to compression of the posterior tibial nerve as it passes near the medial malleolus [38,45,46]. Tarsal tunnel syndrome may result from tenosynovitis, inflammation of the flexor retinaculum, valgus deformities, adjacent bone fracture or dislocation, or posttraumatic edema and fibrosis. Symptoms include paresthesia and pain in the sole of the foot and the first through third toes. Findings of atrophy and weakness of the intrinsic foot muscles occur with more advanced disease. From 5 to 25 percent of RA patients have electrophysiologic abnormalities characteristic of tarsal tunnel syndrome, although not all of these patients are symptomatic [47-49].
Treatment of the tarsal tunnel syndrome in patients with RA is similar to the approach for other patients.
Other compression neuropathies — Although unusual, compression of other peripheral nerves has been reported in patients with RA. Affected nerves include the anterior and posterior interosseous, ulnar, common peroneal, and tibial [38,40,41,45,46,50,51].
●An entrapment neuropathy and symptomatic cervical spine disease with nerve root compression may present concurrently and is termed the "double crush" syndrome [38].
●The common peroneal and tibial nerves may be compressed by a popliteal cyst. (See "General evaluation of the adult with knee pain", section on 'Popliteal cyst' and "Popliteal (Baker's) cyst".)
Treatment of compression neuropathies — Nonsurgical management involves treatment of the underlying disease process. Additional modalities include splints, antiinflammatory medications, and local corticosteroid injections. Surgical decompression is indicated if motor deficits or denervation are present, or if sensory symptoms worsen despite adequate nonsurgical therapy [48,51].
Noncompression neuropathies — Neuropathic abnormalities detected by nerve conduction studies (NCS) and electromyographic (EMG) studies are reportedly more common in patients with RA than in controls [52]. Distal sensory neuropathy and sensorimotor neuropathy have been reported in 1 to 18 percent of patients [44]. Vasculopathy and vasculitis have been implicated in the pathogenesis of these neuropathies [9,41,50,53-55].
Distal sensory neuropathy — Peripheral sensory polyneuropathy, which typically presents in a slowly progressive fashion, has the following additional clinical features:
●Symptoms may be difficult to distinguish from those due to arthritis [41,53].
●Symmetric paresthesias and burning sensations tend to be worse in the feet than in the hands [41,53,56].
●Vibratory, pinprick, and light touch sensation are decreased, while proprioception is spared.
●Reflexes may be lost, and both sensory and motor nerve conduction studies may be abnormal [53,55].
In one study of 25 patients, neuropathy usually developed after the arthritis, and there was no relation between duration of RA and neuropathy [53]. Studies employing sural nerve biopsy reveal mild proliferative endarteritis or normal vasculature with segmental demyelination and remyelination with areas of axonal degeneration [54,55]. There is mild loss of predominantly large myelinated fibers [40,53]. The yield of biopsy may be low, given the mild pathological changes and patchy distribution of lesions.
Overall, distal sensory neuropathy has a good prognosis. It is uncommon for patients to progress to a more severe neuropathy [50,53]. In most patients, the severity of neuropathy is not altered with steroid therapy; 75 percent of patients recover partially or completely.
Combined sensorimotor neuropathy — Combined sensorimotor neuropathy is associated with long duration seropositive, nodular RA, male gender, other extraarticular involvement, systemic constitutional symptoms, and other signs of vasculitis including palpable purpura, livedo reticularis, skin ulcerations, nailfold and digital infarcts, and Raynaud phenomenon [9,26,41,50,53,55-57]. High rheumatoid factor titers, a polyclonal increase in immunoglobulins, and low complement levels are also common.
Combined sensorimotor neuropathy is more severe and presents more acutely than distal sensory neuropathy [41,53]. Symptoms include significant asymmetric pain and paresthesias. Weakness may develop within hours to days of the initial onset of symptoms. Wrist and foot drops are most common, and deep tendon reflexes are decreased or absent. Asymptomatic sensorimotor neuropathy may be more common, being reported in one series in 26/40 patients studied [58]. Mononeuritis multiplex or a polyneuropathy have been reported. Electrophysiologic studies demonstrate axonal degeneration or severe demyelination [53,55]. These findings are suggestive of nerve damage due to vasculitis. (See "Diagnosis and treatment of vasculitic neuropathy".)
The following observations relate to vasculitic neuropathy seen specifically in patients with RA:
●Arterial pathology of affected peripheral nerves includes fibrinoid necrosis of the media with infiltration by polymorphonuclear leukocytes, eosinophils, and mononuclear cells. Perivascular infiltration with mononuclear cells, intimal proliferation with minimal cellular infiltrates, and/or fibrosis also can be observed [55]. Vasculitis of the epineural arteries results in vessel ischemia with resulting axonal degeneration and neuronal demyelination [45,55].
●The arteritis may be immune complex-mediated. Sural nerve examination has demonstrated IgG, IgM, complement, and fibrin depositions in areas of acute necrotizing arteritis, while these deposits are usually absent in vessels without acute inflammation [56].
There is no standard treatment regimen for this neuropathy. Patients have been treated as for immune complex-mediated necrotizing vasculitis [45]. Both corticosteroids and cyclophosphamide, in oral doses and intravenous pulses, have been used. Small case series and case reports document successful treatment of rheumatoid vasculitis with tumor necrosis factor inhibitors (see "Treatment of rheumatoid vasculitis"). There is no convincing evidence that steroids are helpful or that antimalarials and gold alter the course of disease [41,53]. Plasmapheresis has been used in refractory cases, but without great success [57].
Combined sensorimotor neuropathy has a poor prognosis, with most patients progressively worsening [26,41,50,53]. Death may result from visceral disease or immunosuppressive therapy-related infections. Most individuals who improve have residual sensory and motor deficits.
Autonomic neuropathy — An increased incidence of autonomic neuropathy, as determined by abnormal cardiovascular reflexes, has been reported [59].
NEUROMUSCULAR DISORDERS — Neuromuscular disorders are frequently found in rheumatoid arthritis (RA). Muscle weakness and/or atrophy have been observed in approximately one-third of patients [60]. Neuromuscular disorders include myopathy and myositis.
Myopathy — Myopathic processes, which are subdivided into disuse or denervation atrophy, must be distinguished from a muscular dystrophy, such as myopathy and weakness due to corticosteroid use.
Disuse atrophy — Muscle weakness and wasting with disuse atrophy results from pain due to synovitis. Muscle biopsy reveals type II fiber atrophy; there is no muscle inflammation, necrosis, regeneration, or vasculitis [54,60-62]. Effective treatment requires control of joint inflammation and reduction in pain, which is followed by a strengthening exercise program.
Denervation atrophy — Motor nerve demyelination and degeneration due to angiopathic neuropathy, such as mononeuritis multiplex, can lead to muscle fiber atrophy, necrosis, and regeneration, with minimal muscle inflammation on biopsy [54,60]. Treatment for weakness due to ischemia or infarction of peripheral nerve is directed at control of vasculitis (see "Treatment of rheumatoid vasculitis"). If vasculitis is arrested, strength may recover slowly as remyelination and axonal regeneration occur.
Muscular dystrophy-like myopathy — Muscular dystrophy-like myopathy in those with RA is similar to muscular dystrophy both clinically and pathologically. There is loss of muscle tissue, replacement by adipose tissue, fiber caliber variation, and fibrosis without inflammatory infiltrates [54]. Motor innervation is not disturbed. This may represent late chronic myositis.
Glucocorticoid-induced myopathy — Glucocorticoid-induced or steroid myopathy is characterized by proximal muscle weakness without significant serum muscle enzyme elevations. Muscle biopsy reveals type II fiber atrophy [62,63]. Gradual reduction in the glucocorticoid dose and a muscle strengthening rehabilitation program are the mainstays of treatment. (See "Glucocorticoid-induced myopathy" and "Glucocorticoid withdrawal".)
Myositis — With myofiber necrosis and regeneration, there is focal or diffuse infiltration of lymphocytes, plasma cells, and mononuclear cells into the endomysium, perimysium, and perivascular areas [54,60,61,64]. Since it may be impossible to distinguish myositis in RA from idiopathic polymyositis, this process may represent an overlap syndrome [2,54,60].
One author has suggested that the pathologic abnormalities in rheumatoid myositis are less severe and patchier than those of polymyositis, and that RA patients tend to respond to lower prednisone doses than polymyositis patients [61]. In this study, rheumatoid myositis was also associated with elevated serum creatine kinase levels, reflecting muscle fiber damage, and with disproportionately elevated erythrocyte sedimentation rates for the mild degree of synovitis.
Treatment of myositis complicating RA is similar to the therapy of idiopathic polymyositis. (See "Initial treatment of dermatomyositis and polymyositis in adults".)
Amyloid — RA may rarely be complicated by secondary amyloidosis, which may result in abnormalities in both the central and peripheral nervous systems [2]. Amyloid deposits have been reported in brain arterioles in four patients with RA and central nervous system (CNS) vasculitis [3,4]. Peripheral neuropathy can also result from secondary amyloidosis [2]. (See "Causes and diagnosis of secondary (AA) amyloidosis and relation to rheumatic diseases".)
DRUGS — Medications utilized to treat rheumatoid arthritis (RA) are another major cause of neurologic complications [65]:
●Nonsteroidal antiinflammatory drugs (NSAIDs) may result in headaches, drowsiness, and aseptic meningitis. (See "Nonselective NSAIDs: Overview of adverse effects".)
●Glucocorticoids can cause myopathy, depression, psychosis, and benign intracranial hypertension. (See "Major side effects of systemic glucocorticoids" and "Glucocorticoid-induced myopathy".)
●Antimalarials, such as hydroxychloroquine, can cause dizziness, headache, tinnitus, seizures, and neuromyopathy. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Drug-induced myopathies".)
●Gold therapy can be complicated by peripheral neuropathy, cranial nerve palsies, and Guillain-Barré syndrome. (See "Major side effects of gold therapy".)
●Methotrexate can cause headaches and impair the ability to concentrate. (See "Major side effects of low-dose methotrexate".)
●Sulfasalazine and leflunomide reportedly cause headaches. (See "Sulfasalazine in the treatment of rheumatoid arthritis".)
●Leflunomide is associated with peripheral neuropathy. (See "Leflunomide in the treatment of rheumatoid arthritis".)
●Agents that interfere with the action of tumor necrosis factor alpha (anti-TNF therapies) may increase the risk of demyelinating disorders of the central nervous system (CNS) [66]. Progressive multifocal leukoencephalopathy and peripheral neuropathy also have occurred in patients treated with anti-TNF therapies. (See "Overview of biologic agents in the rheumatic diseases" and 'Progressive multifocal leukoencephalopathy' above.)
SUMMARY AND RECOMMENDATIONS
●Neurologic abnormalities associated with rheumatoid arthritis (RA) can result from compression or infiltration of the spinal cord or nerves by rheumatoid synovitis and pannus and from rheumatoid vasculitis. (See 'Introduction' above.)
●Disorders of the central nervous system (CNS) due to RA include cervical myelopathy, vasculitis, rheumatoid nodules located within the CNS, meningitis, organic brain syndrome (OBS), and, rarely, progressive multifocal leukoencephalopathy. Therapy of patients with RA and CNS vasculitis is similar to that for patients with isolated CNS vasculitis. (See 'Central nervous system' above.)
●Stroke, particularly ischemic stroke, occurs with increased frequency, but the basis for this association is not well understood. (See 'Stroke' above.)
●Compression neuropathies are the most common neurologic manifestation of RA. The most common entrapment neuropathy in RA is carpal tunnel syndrome, which is most likely due to finger-flexor tenosynovitis. Other syndromes due to nerve compression or entrapment include tarsal tunnel syndrome, due to compression of the posterior tibial nerve near the medial malleolus; syndromes affecting the anterior and posterior interosseous, ulnar, common peroneal, and tibial nerves; cervical nerve root compression; and common peroneal and tibial nerve compression from popliteal cysts. (See 'Compression or entrapment neuropathy' above.)
●Noncompressive neuropathies include both distal sensory neuropathy, which is usually slowly progressive, and sensorimotor neuropathy, which may have a more acute presentation and which occurs in more severely affected patients with seropositive nodular disease and other extraarticular manifestations. These conditions may result from vasculopathy and vasculitis. An increased incidence of autonomic neuropathy may also be present in patients with RA. (See 'Noncompression neuropathies' above.)
●Neuromuscular disorders are frequent in RA and may result in muscle weakness and/or atrophy. These disorders include myopathy due to disuse or to denervation, which may be confused with myopathy due to glucocorticoids, and myositis, which is similar to polymyositis and which may represent part of an overlap syndrome. (See 'Neuromuscular disorders' above.)
●Many of the medications used to treat RA, including nonsteroidal antiinflammatory drugs, glucocorticoids, and both traditional and biologic disease-modifying antirheumatic drugs (DMARDs), are associated with neurologic complications. (See 'Drugs' above.)