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Neurologic manifestations of rheumatoid arthritis

Neurologic manifestations of rheumatoid arthritis
Literature review current through: Jan 2024.
This topic last updated: Oct 19, 2023.

INTRODUCTION — Rheumatoid arthritis (RA) is associated with various nonarticular manifestations, including a range of neurologic abnormalities, such as cervical spine instability, compressive neuropathy (eg, of the median nerve at the wrist, which results in carpal tunnel syndrome [CTS]), and an often subclinical sensory or sensorimotor axonal neuropathy; as well as rare manifestations including central nervous system (CNS) vasculopathy, rheumatoid meningitis, and ischemic neuropathy due to rheumatoid vasculitis (RV) [1]. Muscle disorders may also occur, and some medications used in RA infrequently have adverse neurologic effects.

Neurologic and muscular disorders associated with RA will be reviewed here. Other nonarticular and non-neurologic problems associated with RA are presented separately, as are detailed discussions of the clinical manifestations, diagnosis, and treatment of RV. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Treatment of rheumatoid vasculitis".)

CLASSIFICATION AND EPIDEMIOLOGY — Neurologic and muscular complications of rheumatoid arthritis (RA) may occur by several mechanisms, including direct effects of compression or invasion of neural tissues and as a consequence of vasculitic neuropathy. Rheumatoid synovitis and pannus may compress or invade adjacent structures (including the spinal cord and peripheral nerves), resulting in myelopathy, radiculopathy, and entrapment neuropathies.

Vasculitic neuropathy is a frequent component of rheumatoid vasculitis (RV), although RV itself is infrequent; the neuropathy in these patients results from infarction of individual peripheral nerves by vasculitis affecting the vasa nervorum [2-4]. Cerebral vasculitis is rarely associated with RA [5]. It has been hypothesized that damage to endothelium may trigger thrombus formation, which might result in ischemia or hemorrhage in that area served by the blood vessel [5].

More than half of patients with RA can exhibit a peripheral neuropathy on electrophysiologic studies, but less than half of these are symptomatic or have signs on examination [6]. A sensory neuropathy is most common; sensorimotor changes can also occur [7,8]. Approximately 40 percent of patients with RV have a sensory neuropathy, and up to 20 percent develop manifestations of a mixed motor and sensory neuropathy. Both mononeuritis multiplex and a distal symmetric sensory or sensorimotor neuropathy can occur [2,9,10]. (See 'Noncompressive neuropathies' below and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)

Central nervous system (CNS) involvement can rarely cause rheumatoid meningitis or a CNS vasculitis. Although rare, CNS involvement may cause ischemia, infarction, or bleeding that may result in transient ischemic attacks, stroke, quadriplegia, or paraparesis. (See 'Central nervous system' below and "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Neurologic disease'.)

The introduction of biologic medications, along with more aggressive and effective strategies for the treatment of RA, has coincided with a reduction in the frequency of some of the neurologic and other extraarticular manifestations of RA [11-13].

CENTRAL NERVOUS SYSTEM — Disorders of the central nervous system (CNS) due to rheumatoid arthritis (RA) itself are rare. These conditions include cervical myelopathy, vasculitis, rheumatoid nodules located within the CNS, meningitis, and, very rarely, progressive multifocal leukoencephalopathy (PML). PML, when it does occur, is usually in association with use of immunosuppressive medications.

Stroke also occurs with increased frequency, but the basis for this association is not well understood. Cerebral involvement is rare and is more likely to represent diseases not unique to RA, such as arteriosclerotic cerebrovascular disease, embolic stroke, or infection (especially in the context of immunosuppression) [14]. Posterior reversible encephalopathy syndrome (PRES) has been reported [15].

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 consisting of case reports of intracranial arteritis [16-23]. CNS lesions, as described below, are also infrequent on imaging (by a range of techniques) in patients with systemic rheumatoid vasculitis (RV), which can affect both small and medium-sized arteries in which the histopathologic changes of involved medium-sized vessels are similar to those of polyarteritis nodosa [9,22,24,25].

Clinical manifestations – Headache and mental status changes were the most common reported symptoms in these cases [8,16-23,26]. Seizures, cranial nerve palsies, blindness, paralysis, dementia, aphasia, gait disorders, and intracranial hemorrhage have also been reported. Fever is not typically present, and blood pressure is usually normal.

In most reports, patients with CNS vasculitis had a long duration of erosive, seropositive RA with rheumatoid nodules [16,18-20,22,25,27]. However, not all patients had synovitis at the time of vasculitis diagnosis. Isolated spinal vasculitis has also been reported in a patient with longstanding seropositive RA [28].

The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically elevated [27]. Cerebral spinal fluid (CSF) with high protein, pleocytosis, and low glucose suggests RA with CNS involvement, but not all patients exhibit these findings [29].

Diagnosis – CNS vasculitis should be suspected when some of the reported clinical features are present and cannot be otherwise explained by an infection, malignancy, medication side effect, metabolic abnormalities, or other conditions. A brain biopsy is the most specific diagnostic test and is needed to make a definitive diagnosis. If there are signs of vasculitis in other organs or tissues, a biopsy of that lesion may be helpful. The diagnostic approaches to CNS and other forms of vasculitis are discussed in detail separately. (See "Primary angiitis of the central nervous system in adults", section on 'Diagnostic approach' and "Overview of and approach to the vasculitides in adults".)

Findings on magnetic resonance imaging (MRI) and computed tomographic (CT) angiography are nonspecific. In patients with neurologic features suggesting a CNS process, we obtain a brain MRI scan and CT angiography to identify abnormalities supporting the diagnosis and to help exclude other disorders that may have a similar clinical presentation. In rheumatoid CNS vasculitis, a brain MRI typically shows T2 hyperintensities in the subcortical and periventricular white matter, and CT angiography of the brain may be normal or show nonspecific vascular abnormalities. A normal brain MRI helps exclude the possibility of CNS vasculitis, while an abnormal MRI with subcortical T2 hyperintensities is nonspecific for this diagnosis.

Conventional angiography often does not show signs of vasculitis. Moreover, evidence suggests that MRI abnormalities among symptomatic patients with RA cannot be ascribed to vasculitis alone but may be due to unrelated factors. One study, for example, compared the incidence of hyperintense white matter lesions detected by brain MRI scan in 33 asymptomatic patients with RA and 48 control individuals [30]; the results showed no significant difference in the number of such lesions between the two groups.

CSF findings alone cannot be used to exclude CNS vasculitis in RA [8]; they are neither sufficiently sensitive nor specific but may be useful in supporting the diagnosis.

Treatment – The treatment of CNS vasculitis in patients with RA 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", section on 'Treatment'.)

Rheumatoid nodules — Rheumatoid nodules have been reported rarely in the CNS [29,31]. Most patients with CNS nodules have severe seropositive erosive joint disease, peripheral subcutaneous rheumatoid nodules, high titer rheumatoid factors, and, less commonly, additional extraarticular features, including pulmonary or ocular involvement [32-34]. (See "Rheumatoid nodules".)

Rheumatoid nodules have been reported in cerebral leptomeninges and within the choroid plexus [21,33-37]. Extradural nodules in the spinal canal may cause nerve root compression, spinal cord compression, and spinal stenosis [32,38].

These nodules are typically detected by MRI and, if suspected, proven to be rheumatoid in nature by biopsy. Biopsy is performed only if clinically warranted due to diagnostic uncertainty and if the results will affect management. A nodule causing neurologic symptoms can be unexpected. In one case, for example, a patient with transient ischemic attack-like episodes was found to have leptomeningeal enhancement on brain MRI, which was later found on meningeal biopsy to be rheumatoid nodules [37]. In another example, a patient underwent laminectomy for persistent severe symptoms of left lower extremity radiculopathy and was found to have a rheumatoid nodule causing S1 and S2 nerve root compression [32].

No medication has been reported effective in inducing regression of CNS rheumatoid nodules. Rheumatoid nodules attributed to methotrexate (MTX) in other locations have regressed in up to 70 percent of patients an average of six months after MTX was stopped [39,40]. Rituximab was effective treatment for one patient with severe subcutaneous nodules [41]. Surgical decompression should be performed if a rheumatoid nodule is compressing a vital structure.

Rheumatoid meningitis — Rheumatoid meningitis, or aseptic meningitis in a patient with RA, is a rare condition characterized by an inflammatory infiltrate of the meninges without distinct rheumatoid nodules [29,42-50]. Most patients have longstanding seropositive disease [49]. Symptoms are variable between patients and may include altered mental status, fever, headaches, seizures, cranial nerve dysfunction, and hemiparesis or paraparesis. Fever is more commonly reported than in RA patients with CNS rheumatoid nodules or CNS vasculitis.

Rheumatoid meningitis should be suspected in patients whose brain MRI scan shows meningeal thickening and/or enhancement (enhancement may be restricted to only the pachymeninges [49]); examination of the CSF helps to exclude infectious and carcinomatous meningitis. Elevated CSF protein is the most common abnormality, but pleocytosis and depressed glucose have also been described. Diagnosis relies on examination of a meningeal biopsy, with presence of plasma cells, and rheumatoid nodules [51]. Rheumatoid factor and anti-citrullinated peptide antibodies have been detected in the CSF in a small number of cases [50,51]. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

In several case reports, treatment with pulse glucocorticoids (methylprednisolone 250 to 1000 mg intravenously [IV] daily for three days) followed by an oral prednisone taper improved neurologic symptoms [44,45,49,52,53]. In another case, a patient with rheumatoid meningitis had resolution of severe seizures and MRI abnormalities after treatment with two doses of rituximab (two infusions of 1 g each, with a two-week interval between infusions) plus methylprednisolone 250 mg IV daily for three consecutive days followed by an oral prednisone taper [47].

Rheumatoid meningitis has occurred in patients treated with tumor necrosis factor (TNF) inhibitors [54-56]. In all of these patients, the TNF inhibitor was stopped; most were also treated with glucocorticoids with resolution of their presenting neurologic symptoms.

Progressive multifocal leukoencephalopathy — PML, which is associated with the polyoma John Cunningham (JC) virus, has been reported, although rarely, in patients with RA taking immunosuppressive agents, most frequently rituximab. However, the absolute risk of developing PML in RA is very small. In an observational study from the United States using a nationwide inpatient sample database, 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 [57]. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis", section on 'Hypogammaglobulinemia and infection'.)

The clinical manifestations and diagnosis of PML and its management are the same in patients with and without RA. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Overview and virology of JC polyomavirus, BK polyomavirus, and other polyomavirus infections" and "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis".)

The estimated absolute risk of PML is one case per 25,000 patients with RA treated with rituximab [58]. PML was reported in only two patients with RA prior to the use of biologic disease-modifying antirheumatic drugs (DMARDs) [59]. There has been at least one case reported in association with use of adalimumab in RA [60] and another in a patient treated with tocilizumab [61]. There have been at least two cases of leukoencephalopathy in an RA patient treated with MTX [62,63].

Hyperviscosity syndrome — Hyperviscosity syndrome has been reported in a very small number of patients with seropositive RA. Its clinical manifestations are typically similar to those of Waldenström macroglobulinemia, including headache, visual changes, vertigo, tinnitus, hearing loss, and cognitive dysfunction [64]. This syndrome is discussed in more detail elsewhere. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome'.)

Stroke — Both traditional cardiovascular risk factors and markers of RA severity contribute to an increased cardiovascular risk in patients with RA, including for stroke and transient ischemic attack, as well as for myocardial infarction [65]. By contrast, reduced RA disease activity and use of MTX and/or TNF-alpha inhibitors are associated with fewer cardiovascular events, including fewer strokes [66-68].

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) [69]. Significant heterogeneity, however, was found between the studies analyzed, and some studies, including those in one population-based cohort, have not shown stroke to be increased [70]. Nevertheless, most studies have shown an increased risk of stroke in RA. For example:

In a nested case-control analysis within a longitudinal databank of 16,990 patients with RA, 226 first strokes, of which 59 were ischemic and occurred more often in patients with RA compared with patients that had noninflammatory rheumatic disease (odds ratio [OR] 1.64 for all first strokes, 95% CI 1.16-2.30 and 2.66 for ischemic strokes, 95% CI 1.24-5.70) [71]. 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.

An increase in stroke was noted in a population-based study of 25,385 Canadian adults with RA, compared with age- and sex-matched controls [72]. 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 overall 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 an absolute increase in stroke incidence 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) [73]. The risk of atrial fibrillation was also increased in patients with RA, but the degree to which this contributed to stroke risk was not determined. (See "Overview of heart disease in rheumatoid arthritis", section on 'Atrial fibrillation'.)

As in the general population, the risk of stroke in patients with RA increases with herpes zoster infection, with a 2.3-fold increased risk in the 90 days after infection shown in a large cohort of RA patients from Taiwan [74]. (See "Varicella zoster virus vasculopathy".)

Cardiovascular risk management in patients with RA includes emphasizing the benefits of lifestyle modification (eg, healthy diet, exercise, and smoking cessation), addressing the traditional risk factors for atherosclerotic disease (eg, hypertension, dyslipidemia, and diabetes) and treating with disease-modifying agents to reduce RA disease activity. (See "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management".)

PERIPHERAL NERVOUS SYSTEM — Peripheral neuropathies, including both compressive (entrapment) and noncompressive neuropathies, are the most common neurologic manifestations of rheumatoid arthritis (RA). (See 'Compression or entrapment neuropathy' below and 'Noncompressive neuropathies' below.)

In addition to entrapment neuropathies (eg, carpal tunnel syndrome [CTS]), noncompressive neuropathies may cause sensory and motor nerve dysfunction. Estimates of the frequency of the different types of peripheral nerve involvement vary depending on the methods for patient selection and the extent of neurologic testing.

A 2014 review found that the most common disorders of the peripheral nervous system in patients with RA were mononeuritis multiplex, sensorimotor neuropathy, and entrapment neuropathy [4]. Almost one-half of sural nerve biopsies are normal in patients with sural nerve involvement by electrophysiologic studies [4,6,75,76].

In a series of 33 nondiabetic patients with RA, electrodiagnostic testing found 6 percent of these patients had CTS and 17 percent had mononeuritis multiplex [75].

In another study of 108 patients with RA, pure sensory or sensory motor axonal neuropathy accounted for 85 percent of abnormal electrophysiological studies, while the remainder showed demyelinating neuropathy [6].

Compression or entrapment neuropathy — Entrapment neuropathies are diagnosed in up to 45 percent of patients with RA, according to a 2002 report [14]. A more recent literature analysis from 2016 reported a 14 percent prevalence of subclinical CTS in patients with RA [77]. Compared with controls, the odds ratio (OR; adjusted for body mass index [BMI]) of CTS in patients with RA was 2.43 [78]. Joint deformities and inflamed synovium, ligaments, or tendon sheaths may compress peripheral nerves in close proximity to joints or bursae. There is no correlation between compression neuropathies and sex, duration of RA, functional class, the presence of other extraarticular disease, seropositivity, or the level of acute phase reactants [79]. (See 'Carpal tunnel syndrome' below and 'Tarsal tunnel syndrome' below and 'Other compressive neuropathies' below.)

Electromyography (EMG) and nerve conduction studies are the most useful tests for evaluating suspected compression of peripheral nerves; ultrasonography has also been utilized [80,81]. In patients suspected of a compressive neuropathy based upon symptoms and findings, we perform an EMG and nerve conduction study and ultrasound to determine the anatomic site of compression.

Nonsurgical management involves treatment of the underlying disease process. Otherwise, treatment of these syndromes is the same as in patients without RA. Additional modalities may include splints, antiinflammatory medications, and local glucocorticoid injections. Surgical decompression is sometimes indicated if motor deficits or denervation are present or if sensory symptoms worsen despite adequate nonsurgical therapy [6,81,82]. (See "Carpal tunnel syndrome: Treatment and prognosis" and "Surgery for carpal tunnel syndrome" and "Overview of upper extremity peripheral nerve syndromes" and "Overview of lower extremity peripheral nerve syndromes".)

Carpal tunnel syndrome — CTS, which is due to compression of the median nerve as it travels through the carpal tunnel of the wrist, is commonly associated with pain and paresthesia, and less commonly weakness, in the median nerve distribution. Symptoms are often worse at night or with activities involving wrist flexion, and sometimes occur in the volar forearm. CTS is detected in 6 to 10 percent of RA patients undergoing electrophysiologic studies [6,75,76]. In one study, there was a 6.8 percent incidence of CTS in 1070 patients with RA, and the CTS did not correlate with disease activity or duration of RA [83].

Clinical manifestations, diagnosis, and treatment of CTS are similar in patients with RA to those without RA and are described in detail separately. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis" and "Carpal tunnel syndrome: Pathophysiology and risk factors" and "Carpal tunnel syndrome: Treatment and prognosis" and "Surgery for carpal tunnel syndrome".)

Tarsal tunnel syndrome — Tarsal tunnel syndrome is uncommon; it is due to compression of the tibial nerve as it passes near the medial malleolus [84]. It may result from tenosynovitis, inflammation of the flexor retinaculum, or valgus deformities. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Tarsal tunnel syndrome'.)

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. Prior to the availability of biologic medications, from 5 to 25 percent of RA patients had electrophysiologic abnormalities characteristic of tarsal tunnel syndrome, although not all of these patients were symptomatic [84-87].

Treatment of tarsal tunnel syndrome in patients with RA is similar to the approach for patients without RA. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Tarsal tunnel syndrome'.)

Other compressive 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 [82,88-93]. Median nerve entrapment at the elbow causes pronator teres syndrome; ulnar nerve entrapment at the elbow causes cubital tunnel syndrome and at the wrist, Guyon canal syndrome [81]. Femoral nerve palsy complicates distended synovitis of the hip and may lead to sensory and motor defects [87]. The common peroneal and tibial nerves may be compressed by a popliteal cyst. (See "Popliteal (Baker's) cyst".)

The term "double crush" syndrome refers to the concurrent presentation of an entrapment neuropathy and symptomatic cervical spine disease with nerve root compression [88].

Noncompressive neuropathies — Several forms of noncompressive neuropathy are seen in patients with RA, including a distal sensory neuropathy; a less common combined sensorimotor neuropathy; and an autonomic neuropathy. Neuropathic abnormalities detected by nerve conduction studies and EMG studies, which are more common in patients with RA than in controls, are most often axonal, although demyelinating features are sometimes present [6,94]. Before biologic medications were available, distal sensory neuropathy and sensorimotor neuropathy were reported in 1 to 18 percent of patients in the first several years of disease [95]. Pathologic findings range from normal histopathology to perineural thickening to vasculopathy, and rarely, vasculitis or amyloidosis, suggesting these neuropathies have varied pathogenesis [6,9,90,93,96-98].

Distal sensory neuropathy — Peripheral sensory polyneuropathy, which typically presents in a slowly progressive fashion and is generally not associated with rheumatoid vasculitis (RV), has the following clinical features:

Symmetric paresthesias and burning sensations, which tend to be worse in the feet than in the hands [90,96,99]

Discomfort that may be difficult to distinguish from myalgia and arthralgia but is neuropathic in origin [90,96]

Decreased vibratory, pinprick, and light touch sensation

Decreased or absent deep tendon reflexes, and abnormalities of both sensory and motor nerve conduction [96,98]

In one study of 25 patients, neuropathy usually developed after the arthritis, and there was no relation between duration of RA and neuropathy [96]. Studies employing sural nerve biopsy most often reveal mild proliferative endarteritis or normal vasculature with segmental demyelination and remyelination and areas of axonal degeneration [97,98]. There is mild loss of predominantly large myelinated fibers [89,96]. The yield of biopsy may be low, given the mild pathologic changes and patchy distribution of lesions.

It is important to exclude other causes of peripheral neuropathy, including vitamin deficiency and diabetes. (See "Overview of polyneuropathy".)

Combined sensorimotor neuropathy — Combined sensorimotor neuropathy is rare; it is usually due to ischemic neuropathy caused by RV. Both symmetric sensorimotor neuropathy and asymmetric mononeuritis multiplex ("vasculitis") have been described in case reports of patients with RA. Other clinical features in these patients include long-duration seropositive, nodular RA, male sex, other extraarticular involvement, systemic constitutional symptoms, palpable purpura, livedo reticularis, skin ulcerations, nailfold and digital infarcts, and Raynaud phenomenon [9,90,93,96,98-101]. High rheumatoid factor titers, a polyclonal increase in immunoglobulins (Igs), and low complement levels are also common. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Neurologic disease'.)

Combined sensorimotor neuropathy is more severe and presents more acutely than distal sensory neuropathy [90,96]. 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. Electrophysiologic studies demonstrate axonal degeneration or severe demyelination [96,98]. These findings are suggestive of nerve damage due to vasculitis. (See "Treatment and prognosis of nonsystemic 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 can also be observed [98]. Vasculitis of the epineural arteries results in vessel ischemia with resulting axonal degeneration and neuronal demyelination [91,98].

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 [99].

The treatment of sensorimotor neuropathy due to RV is described in detail separately. (See "Treatment of rheumatoid vasculitis".)

Autonomic neuropathy — An increased incidence of autonomic neuropathy, as determined by abnormal cardiovascular reflexes, has been reported [102]. Autonomic nervous system dysfunction has been noted in 15 to 47 percent of RA patients [103-105].

MUSCLE DISORDERS — In patients with rheumatoid arthritis (RA), muscle weakness is common. In the era before 1980, muscle weakness and/or atrophy were observed in approximately one-third of patients [106]. Muscle disorders in patients with RA include myopathy (eg, due to disuse or glucocorticoid therapy) and frank myositis.

Myopathy — Myopathy in patients with RA includes disuse atrophy, glucocorticoid-induced myopathy, and myositis.

Disuse atrophy — Sarcopenia was newly classified as a disease entity in 2016; it is characterized by low muscle mass and low skeletal muscle strength or low physical performance [107]. Sarcopenia occurs especially in older adults and is frequently associated with RA. Muscle weakness and wasting can result from disuse due to synovitis and pain. This is most commonly seen in RA patients who have knee pain and/or inflammation resulting in quadriceps weakness and when hands and wrists become inflamed and/or are painful, resulting in decreased grip strength. Muscle biopsy reveals type II fiber atrophy; there is no muscle inflammation, necrosis, regeneration, or vasculitis [97,106,108,109]. Effective treatment requires adequate medical therapy for the RA to control joint inflammation and reduce pain, which is followed by a strengthening exercise program. (See "Approach to the patient with muscle weakness".)

Chronic inflammation due to RA may also directly impair muscle function via effects on muscle metabolism and adipose tissue [110].

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 [109,111]. 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 — Very infrequently, inflammatory myositis can occur as part of an overlap syndrome with RA [112,113]. Histopathology shows myofiber necrosis and regeneration, with focal or diffuse infiltration of lymphocytes, plasma cells, and mononuclear cells into the endomysium, perimysium, and perivascular areas [97,106,108,114]. (See "Initial treatment of dermatomyositis and polymyositis in adults" and "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Overlap syndromes'.)

AMYLOID — Rheumatoid arthritis (RA) may rarely be complicated by AA (secondary) amyloidosis, which may result in abnormalities in both the central and peripheral nervous systems [17]. Amyloid deposits have been reported in brain arterioles in four patients with RA and central nervous system (CNS) vasculitis [18,19]. Peripheral neuropathy can also result from AA amyloidosis [17]. (See "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

DRUGS — Medications utilized to treat rheumatoid arthritis (RA) can lead to various neurologic complications [4]:

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 adverse effects of systemic glucocorticoids" and 'Glucocorticoid-induced myopathy' above.)

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, which is mostly of historical interest, can be complicated by peripheral neuropathy, cranial nerve palsies, and Guillain-Barré syndrome [115].

Methotrexate (MTX) can cause headaches and impair the ability to concentrate. (See "Major side effects of low-dose methotrexate".)

Sulfasalazine and leflunomide can both cause headaches. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)

Leflunomide is associated with peripheral neuropathy. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

Tumor necrosis factor (TNF)-alpha inhibitors may increase the risk of demyelinating disorders of the central nervous system (CNS). Very rarely, progressive multifocal leukoencephalopathy (PML) and peripheral neuropathy have been reported in patients treated with anti-TNF therapies (as it has with rituximab). (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Demyelinating disease' and 'Progressive multifocal leukoencephalopathy' above.)

SUMMARY AND RECOMMENDATIONS

Pathogenesis – 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 nerve damage from rheumatoid vasculitis (RV). (See 'Classification and epidemiology' above.)

Central nervous system manifestations – Disorders of the central nervous system (CNS) that are associated with RA are infrequent, but include cervical myelopathy, rheumatoid nodules located within the CNS, meningitis, vasculitis, and, very rarely, progressive multifocal leukoencephalopathy (PML). Stroke, particularly ischemic stroke, occurs with increased frequency in patients with RA. Therapy of patients with RA and CNS vasculitis is similar to that for patients with isolated CNS vasculitis. (See 'Central nervous system' above.)

Compression neuropathies – Compression neuropathies are the most common neurologic manifestation of RA. The most common entrapment neuropathy in RA is carpal tunnel syndrome (CTS). Other syndromes due to nerve compression or entrapment include tarsal tunnel syndrome, due to compression of the tibial nerve near the medial malleolus; syndromes involving 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 – 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. An increased incidence of autonomic neuropathy may also be present in patients with RA. (See 'Noncompressive neuropathies' above.)

Muscle disorders – Muscle disorders can occur in RA and may result in muscle weakness and/or atrophy. These disorders include disuse muscle atrophy and glucocorticoid myopathy. Myositis rarely occurs in patients with RA and may be due to an autoimmune overlap syndrome. (See 'Muscle disorders' above.)

Drug side effects – Many of the medications used to treat RA, including nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs), are associated with neurologic complications. (See 'Drugs' above.)

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Topic 7480 Version 29.0

References

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