Rheumatologic Disorders and the Nervous System

Pantelis P. Pavlakis, MD, PhD Neurology of Systemic Disease p. 591-610 June 2020, Vol.26, No.3 doi: 10.1212/CON.0000000000000856
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PURPOSE This article describes the neurologic manifestations of systemic autoimmune diseases.

RECENT FINDINGS Systemic autoimmune diseases can be associated with a wide spectrum of neurologic comorbidities involving the central and peripheral nervous systems. Systemic lupus erythematosus (SLE) can be associated with a number of manifestations predominantly affecting the central nervous system (CNS), whereas peripheral neuropathy is less common. Sjögren syndrome can be associated with peripheral neuropathy in 10% of cases and CNS disease in 2% to 5% of cases. The risk of stroke is increased in SLE, rheumatoid arthritis, temporal arteritis, psoriatic arthritis, and ankylosing spondylitis. Systemic vasculitides present most commonly with mononeuritis multiplex but can also affect the CNS. Cognitive dysfunction is a common symptom among patients with systemic autoimmune diseases, most commonly seen in patients with SLE or Sjögren syndrome.

SUMMARY Neurologic manifestations of systemic autoimmune disease are important to recognize, as they may often be the presenting manifestation leading to diagnosis of the systemic disease or may be associated with increased morbidity, other complications, or mortality. Timely diagnosis and institution of appropriate treatment, often requiring multidisciplinary care, is essential to minimize morbidity and decrease the risk of permanent neurologic deficits.

Address correspondence to Dr Pantelis Pavlakis, Hospital for Special Surgery, 535 E 70th St, New York, NY, 10021, pavlakisp@hss.edu.

RELATIONSHIP DISCLOSURE: Dr Pavlakis has received personal compensation for completing an online survey from Alexion Pharmaceuticals, Inc.

UNLABELED USE OF PRODUCTS/INVESTIGATIONAL USE DISCLOSURE: Dr Pavlakis discusses the unlabeled/investigational use of biologic therapies for the neurologic manifestations of rheumatologic disorders.

INTRODUCTION

Neurologic manifestations of systemic autoimmune diseases encompass a wide spectrum of syndromes involving the central nervous system (CNS) and peripheral nervous system (PNS). Increased awareness is required as they may be the presenting manifestation leading to the diagnosis of a systemic autoimmune disease, or they may present in otherwise quiescent systemic disease. However, in other cases, they may be associated with severe systemic disease and increased risk of morbidity and mortality. Their presentation can overlap with other distinct neurologic syndromes, which further complicates their diagnosis and classification (table 3-1). Prompt recognition and initiation of treatment is required in many cases to prevent permanent neurologic dysfunction or disease progression.

SYSTEMIC LUPUS ERYTHEMATOSUS

A wide spectrum of neurologic manifestations has been observed in patients with systemic lupus erythematosus (SLE) (table 3-2). Some of these, such as headache and mood disorders, may be nonspecific; others, such as stroke, may be due to an overlapping syndrome (eg, antiphospholipid antibody syndrome) and may not necessarily be attributable to SLE. As a result, the reported frequency of neuropsychiatric manifestations has ranged widely. More recent cohorts using stricter criteria and causal attribution algorithms have estimated the frequency of neuropsychiatric events to be 13% to 21% in patients with SLE. The vast majority involve the CNS, while PNS involvement can be seen in 8% of patients. Early identification and treatment of neurologic manifestations in patients with SLE is very important, as patients with SLE and renal or neurologic involvement are considered to have severe disease, resulting in higher rates of morbidity and mortality.

The exact mechanisms leading to neurologic manifestations in SLE are unclear. Microvasculopathy, local inflammatory mediators, and autoantibodies, acting both directly and indirectly by causing blood-brain barrier dysfunction, have been implicated. Although prior studies have reported an association with specific autoantibodies, including NR2 glutamate receptor antibodies and ribosomal P protein antibodies, these results have not been validated in larger cohorts, and their diagnostic value in clinical practice remains limited. Antiphospholipid antibodies, which have been associated with strokes and seizures, are a notable exception.

Headache and mood disorders, including depression, have been the most frequently reported manifestations; however, more recent studies suggest that the overall frequency of headache is not significantly higher in patients with SLE, and neither headache nor mood disorders are associated with disease activity, making it difficult to establish a causal relationship with the underlying systemic disease.

Psychosis can present in 1.5% of patients with SLE, although its frequency has varied among published studies. The majority of cases are attributable to the underlying disease, occur early in its course, and consist of a single psychotic event. Male sex, earlier age at time of SLE diagnosis, and history of other neuropsychiatric events have been found to be associated with psychosis. This should be differentiated from steroid-induced psychiatric disorders, which may present as psychosis or mania. Onset after initiation of steroids and lack of other neuropsychiatric events can be more suggestive of the adverse effects of steroids rather than primary SLE-related psychosis.

Stroke has been reported to occur in 5% to 18% of patients with SLE, whereas more recent studies using attribution algorithms estimate stroke frequency at 5.6%. SLE has been found to be an independent risk factor for stroke (as have several of the other conditions in this article), particularly in individuals younger than age 40 or early in the course of the systemic disease. Ischemic strokes and transient ischemic attacks comprise 80% of these events. Apart from the traditional vascular risk factors, the presence of antiphospholipid antibodies, high disease activity scores, a history of prior neuropsychiatric events, and being of African descent have also been associated with increased risk of stroke.

Focal and generalized seizures have been reported in patients with SLE, and prospective studies using attribution algorithms have estimated their frequency at 4.6%. They usually occur early in the course of the disease and are associated with higher disease activity, a history of psychosis, and antiphospholipid or Sm antibodies.

Posterior reversible encephalopathy syndrome (PRES) has also been associated with SLE. Whether this represents a manifestation of the systemic disease or the presence of SLE is simply a risk factor for developing PRES is unclear. PRES is uncommon, seen in 0.69% to 1.8% of patients with SLE. Recurrent episodes can be seen in 20% of patients with PRES. Other risk factors for PRES present in patients with SLE may include endothelial dysfunction, which is thought to occur in these patients, or the immunosuppressive medications that are often used to treat the systemic disease. A high index of suspicion is required, as PRES can mimic other SLE-related neuropsychiatric syndromes and is associated with greater morbidity and complications, including intracerebral hemorrhage, more permanent neurologic deficits, and higher mortality rates. Younger females seem to be more frequently affected; hypertension, renal dysfunction, dyslipidemia, and active SLE have been associated with PRES in patients with SLE. Treatment is mostly supportive, consisting of blood pressure control and antiepileptic medications when seizures are present; high-dose corticosteroids have been used, but no randomized clinical trials have assessed their efficacy.

The frequency of myelitis in SLE has been estimated at 1.2% in larger case series (case 3-1). Although uncommon, it is important to diagnose and treat myelitis promptly as it can cause significant neurologic deficits, with subsequent effects in morbidity and quality of life. It may be the presenting manifestation or present later in the course of the disease, and it may accompany active SLE or disease in remission. Cases presenting with predominant signs of gray matter dysfunction (eg, flaccid paresis) have been associated with higher disease activity, double-stranded DNA, and antiphospholipid antibodies, whereas cases with predominant white matter dysfunction have been associated with anti–aquaporin-4 (AQP4) seropositivity. Antibodies against AQP4 have been identified in patients with SLE and myelitis; however, these are highly specific for neuromyelitis optica spectrum disorders (NMOSDs) and are not present in patients with systemic autoimmunity in the absence of neurologic involvement. Therefore, their presence is more suggestive of overlapping NMOSD rather than a manifestation of the underlying systemic autoimmune disease.

CASE 3-1

A previously healthy 45-year-old woman presented to the emergency department with 2 days of progressive bilateral leg weakness and numbness. She reported low-grade fever, malaise, and arthralgia 1 week earlier and urinary retention 1 day before the onset of her leg symptoms. Her general examination was notable for malar rash and swollen joints, which were tender to palpation.

On neurologic examination, her mental status and cranial nerves were intact. Muscle tone was increased in both legs. Strength was normal in the arms. In her legs, strength was 3/5 in bilateral hip flexion, knee flexion, and ankle dorsiflexion. Sensation to touch and pinprick was decreased below the level of the umbilicus, and vibration sense was absent in both legs up to the anterior superior iliac spines. Deep tendon reflexes were normal in the arms and hyperactive (3+) in both knees and ankles. Babinski sign was present bilaterally. She had a spastic gait and required two canes to walk.

Blood work was notable for anemia, lymphopenia, and thrombocytopenia. C3 and C4 complement levels were decreased. Antinuclear and anti–double-stranded DNA antibodies were positive. MRI of the thoracic spine showed a T2-hyperintense lesion at T10, which enhanced after gadolinium administration. Aquaporin-4 antibodies were negative.

She was immediately treated with IV methylprednisolone 1000 mg, and after three daily doses, her leg strength and sensation improved partially, but she was still not able to walk unassisted. Rheumatology was consulted, and she was diagnosed with systemic lupus erythematosus (SLE). Treatment with cyclophosphamide was initiated, and 6 months later she was able to walk unassisted.

COMMENT

The history and examination findings in this case localized to the spinal cord, and MRI confirmed the presence of a myelopathy; her systemic manifestations (malar rash, arthritis) and laboratory studies (anemia, lymphopenia, thrombocytopenia, hypocomplementemia, positive antinuclear and anti–double-stranded DNA antibodies) were suggestive of SLE.

It is common for neurologic syndromes to be the presenting manifestation of systemic autoimmune diseases. The differential diagnosis includes vasculitis (which can also affect the spinal cord but would also be expected to involve other areas of the central nervous system, such as the brain, or the peripheral nervous system), multiple sclerosis, or neuromyelitis optica spectrum disorder (NMOSD). NMOSD can coexist with SLE or Sjögren syndrome, and aquaporin-4 antibody testing is important in cases such as this as a positive result would confirm NMOSD as the cause rather than a neurologic manifestation of the systemic autoimmune disease. Another important point illustrated in this case is that prompt initiation of treatment is required to mitigate or prevent permanent neurologic dysfunction.

Optic neuropathy is another uncommon manifestation of SLE, either in the form of demyelinating optic neuritis or anterior ischemic optic neuropathy. Testing for antibodies against AQP4 in patients with optic neuritis is important, as this can present in the absence of myelitis and earlier institution of treatment could mitigate further neurologic burden in patients with NMOSD.

Peripheral neuropathies have been described in cohorts of patients with SLE in variable frequencies; based on the results of larger-scale studies, the frequency of peripheral neuropathy attributable to SLE has been estimated at 3.9%. Sensory and sensorimotor axonal polyneuropathy are most frequently encountered, followed by small fiber neuropathy. These may present with a length-dependent or non–length-dependent distribution of symptoms (figure 3-1). Mononeuropathy, mononeuritis multiplex, and, less commonly, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), or plexopathy have also been reported.

The evidence regarding treatment of the neurologic manifestations of SLE is limited, and its pathogenetic and phenotypic heterogeneity prevent the development of uniform treatment guidelines. A general approach is that thrombotic processes are treated with antiplatelet agents or anticoagulation, while inflammatory processes are treated with corticosteroids and immunosuppression.

Severe inflammatory neurologic syndromes, including myelitis, are treated with high-dose IV methylprednisolone and additional immunosuppression. Among various immunosuppressants tried, IV cyclophosphamide has the most evidence supporting its use; however, its efficacy should be weighed against its significant toxicity, including nephrotoxicity, sterility, and malignancies. Various other immunosuppressants have been tried with mixed results. Rituximab has been used with success in cases refractory to cyclophosphamide. It is noteworthy that the majority of literature available on treatment of myelitis associated with SLE was published before NMOSD was recognized as a distinct disorder; therefore, in cases of myelitis, it is very important to identify cases of overlapping NMOSD, as these should be treated as a coexisting primary neurologic disorder.

SJÖGREN SYNDROME

The PNS is more frequently affected than the CNS in Sjögren syndrome. Estimated frequencies of both vary significantly among published studies because of different diagnostic criteria of Sjögren syndrome applied and differences in the definition of neurologic involvement. Among studies with larger numbers of patients, PNS involvement was seen in 10% of patients, while CNS involvement was seen in 2% to 5%. Neurologic manifestations may be the initial feature or may present later in the course of the disease; they may be associated with mild glandular manifestations or part of active disease with other extraglandular manifestations. Making a diagnosis of Sjögren syndrome in patients presenting with neurologic syndromes and sicca symptoms (dry eyes and dry mouth due to lymphocyte infiltration of exocrine glands, which are the hallmark histopathologic findings of Sjögren syndrome) is important, as Sjögren syndrome can be associated with increased risk of developing lymphoma.

Sensory neuropathies seem to be the predominant type, and isolated small fiber neuropathy seems to be the most common neuropathy in Sjögren syndrome (table 3-3). However, different types of neuropathy may coexist in the same patient. Sensory symptoms may present in a length-dependent or non–length-dependent distribution; a variable degree of autonomic symptoms may be present if autonomic fibers are involved. By definition, patients with small fiber neuropathies have no symptoms or signs of large fiber dysfunction and normal nerve conduction studies. Sensory and sensorimotor large fiber axonal polyneuropathies typically present with length-dependent sensory or motor symptoms and deficits, and nerve conduction studies show a pattern of axonal dysfunction.

Although individual presentations may vary, small fiber neuropathy tends to present earlier in the course of the disease and is less frequently associated with other extraglandular manifestations (eg, arthritis, Raynaud phenomenon, pulmonary involvement, interstitial nephritis, glomerulonephritis, purpura) than large fiber sensory axonal neuropathy, and patients are less frequently seropositive for anti-Ro and anti-La antibodies. Therefore, negative serology does not preclude the diagnosis of Sjögren syndrome in a patient with sicca symptoms and neurologic involvement.

Sensory ataxic neuropathy is a rare but relentlessly progressive and disabling form of sensory neuronopathy. Patients may present with variable sensory symptoms, gait instability, loss of proprioception, and sensory ataxia. Pseudoathetoid hand movements may be seen due to loss of proprioception, which can lead to an initial diagnosis of a movement disorder. The onset may be subacute or more insidious, and symptoms and signs follow a non–length-dependent distribution. Strength is normal, and reflexes are absent. Nerve conduction studies show a non–length-dependent loss of sensory amplitudes or absent sensory responses with normal motor responses. Pathologic studies have shown lymphocyte infiltration of the dorsal root ganglia in patients who are affected, while imaging studies have shown T2 hyperintensities on MRI of the dorsal root ganglia. However, the use of these diagnostic modalities in clinical practice is limited.

Mononeuropathy and mononeuritis multiplex are uncommon but can be present in Sjögren syndrome, usually in the setting of active systemic disease, and have been associated with vasculitic involvement of other organs, such as glomerulonephritis or purpura. The clinical presentation is similar to other vasculitic neuropathies (refer to the section on systemic vasculitides). Serologic markers of active systemic disease, such as low C4 complement levels, hypergammaglobulinemia, or even cryoglobulinemia, are usually present. Although the diagnosis can often be made on clinical grounds, nerve biopsy can confirm the diagnosis, showing findings of vasculitis. In these cases, combined nerve and muscle biopsy is recommended to achieve maximal diagnostic yield. Due its rapid onset, prompt diagnosis and treatment of this neuropathy is required to prevent further neurologic deterioration or irreversible neurologic deficits.

A demyelinating neuropathy similar to CIDP has been reported to occur rarely in association with Sjögren syndrome. Patients present with subacute or insidious-onset proximal and distal weakness, sensory loss, and areflexia. Nerve conduction studies reveal a demyelinating pattern of dysfunction, and CSF studies can show elevated protein levels with normal cell count.

Cranial neuropathies have been reported in patients with Sjögren syndrome; the trigeminal nerve seems to be more frequently involved, and facial neuropathy and sensorineural hearing loss have been reported. These may occur in isolation or with other peripheral neuropathies. However, the occurrence of multiple cranial neuropathies with headache or systemic symptoms should raise suspicion for underlying aseptic meningitis or CNS vasculitis.

Autonomic symptoms of variable severity, including cardiovascular, gastrointestinal, or genitourinary symptoms, as well as autonomic dysfunction on respective testing, have been reported in Sjögren syndrome. In the majority of cases, these are of mild severity, whereas clinically overt, severe, autonomic neuropathy is less common. Autonomic neuropathy may occur in isolation or may be accompanied by other types of neuropathy, usually sensory. The presence of an Adie tonic pupil in a patient with Sjögren syndrome is suggestive of underlying autonomic dysfunction and should prompt further evaluation.

Myopathy is uncommon in Sjögren syndrome. Inclusion body myositis may be more frequently associated with Sjögren syndrome; in a case series, Sjögren syndrome was the most common rheumatologic comorbidity, present in 15% of patients with inclusion body myositis.

CNS involvement is less commonly encountered in Sjögren syndrome and is estimated at 2% to 5%. This usually comprises focal or multifocal CNS involvement with corresponding deficits, which are usually of acute or subacute onset due to vasculitis or demyelination. Optic neuritis and transverse myelitis can also be seen in patients with Sjögren syndrome, as can overlapping NMOSDs or, less frequently, multiple sclerosis (MS). Less common syndromes include aseptic meningitis, cerebellar ataxia, focal or generalized seizures, and a motor neuron disease–like syndrome with a presentation very similar to amyotrophic lateral sclerosis, although its rate of progression may be slower.

Symptomatic treatments for neuropathic pain include topical agents, such as lidocaine or capsaicin, and oral agents, including gabapentin, pregabalin, or duloxetine. Tricyclic antidepressants, although efficacious for neuropathic pain treatment, should be used with caution as they can exacerbate sicca symptoms because of their anticholinergic properties. Physical therapy is very important in cases of motor or balance deficits.

No randomized placebo-controlled trials of immunotherapies for peripheral neuropathies associated with Sjögren syndrome have been conducted. Mononeuritis multiplex and cases of neuropathy with documented vasculitis are treated with immunotherapies as in any case of vasculitis, including high-dose corticosteroids, rituximab, azathioprine, or cyclophosphamide. Demyelinating neuropathy can be treated similarly to CIDP, with steroids and IV immunoglobulin (IVIg). Sensory and sensorimotor axonal polyneuropathy are thought to be less responsive to immunotherapies; however, some cases have improved after IVIg treatment. Axonal neuropathies associated with Sjögren syndrome and lymphoma have also been reported to improve after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Sensory ataxic neuropathy is the most challenging neuropathy to treat, and patients typically progress despite receiving various immunotherapies, including corticosteroids, IVIg, plasma exchange, infliximab, or D-penicillamine. However, cases showing response to rituximab or mycophenolate mofetil have been reported. The treatment of small fiber neuropathy is mostly symptomatic; however, cases have been reported in which symptoms responded to IVIg.

CNS disease is treated with high-dose IV corticosteroids, and typically an additional immunosuppressive agent (eg, cyclophosphamide or rituximab) is also needed. Although no randomized clinical trials have been conducted, rituximab is often preferred because of less severe toxicity compared to cyclophosphamide. Other treatments, including plasma exchange, IVIg, azathioprine, and mycophenolate mofetil have been tried with mixed results.

RHEUMATOID ARTHRITIS

Cervical spinal stenosis due to synovitis and pannus formation is present more frequently in patients with rheumatoid arthritis, involving the atlantoaxial, atlantooccipital, or subaxial level. It has been associated with longer duration of disease and increased disease activity. Earlier use of biologics may reduce the risk and burden of degenerative spine disease. Presentations may range from asymptomatic to severe myelopathy. Respiratory involvement or even sudden death due to medullary compression can be seen in cases of upper cervical or occipitocervical involvement. In suspected cases, MRI should be obtained, as it is optimal compared to other modalities in evaluating for pannus formation and visualizing the spinal cord. Surgical intervention is indicated in cases with myelopathic signs or refractory pain.

Aseptic meningitis is a rare manifestation of rheumatoid arthritis and can lead to severe neurologic impairment. It is often a later manifestation and may present in the absence of active systemic disease. Presenting symptoms include altered mental status, headache, seizures, and, rarely, cerebral infarcts in cases accompanied by cerebral vasculitis. In suspected cases, other causes such as infection and other autoimmune diseases, including sarcoidosis, systemic vasculitides, and IgG4-related disease, should be excluded. Apart from meningeal enhancement, the presence of rheumatoid nodules in the meninges can be a suggestive finding. CSF testing shows lymphocytic pleocytosis and elevated protein levels. In diagnostically challenging cases, meningeal biopsy may be needed, which may show inflammatory infiltrates, findings of vasculitis, or rheumatoid nodules. Treatment usually consists of high-dose IV corticosteroids and immunomodulatory treatments, such as azathioprine or cyclophosphamide. Cases responsive to rituximab have also been reported.

Entrapment neuropathies are the most common form of peripheral neuropathy encountered in rheumatoid arthritis. Carpal tunnel syndrome is the most common focal neuropathy seen, with patients with rheumatoid arthritis having a threefold increased risk. Axonal sensorimotor polyneuropathy can be seen less frequently. Demyelinating neuropathy has been reported and is seen more frequently with the use of tumor necrosis factor-α (TNF-α) inhibitors (refer to the section on neurologic complications of TNF-α inhibitors). Mononeuritis multiplex associated with vasculitis can be seen, although this is rare with earlier use of biologic therapies.

Patients with rheumatoid arthritis have a higher frequency of cardiovascular disease, including stroke, and a higher resulting mortality rate. This is thought to derive from a combination of traditional risk factors and systemic inflammation. Management includes lifestyle and traditional vascular risk factor modification as well as treating the systemic disease, which theoretically should mitigate the atherogenic effects of chronic inflammation; however, studies addressing the effect of biologic therapies on cardiovascular disease in rheumatoid arthritis have yielded mixed results.

SYSTEMIC VASCULITIDES

Vasculitis can affect the nervous system either in the form of a primary vasculitic syndrome, such as the ones described in this section, or as a manifestation of a systemic autoimmune disease (such as SLE, Sjögren syndrome, or rheumatoid arthritis). However, the latter is not encountered as frequently as it was previously, as the immunotherapies used now are more efficacious in controlling these systemic diseases. Peripheral neuropathy is the most frequent neurologic manifestation seen in primary vasculitic syndromes; it may occur concurrently with CNS manifestations or in isolation, usually as mononeuritis multiplex (case 3-2) and less frequently as distal symmetric polyneuropathy. Clinical features suggestive of a vasculitic neuropathy include constitutional symptoms, subacute-onset neurologic deficits corresponding to the individual nerve(s) distribution accompanied by pain, and stepwise progression; however, the progression may be insidious, and confluent neurologic deficits over time can mimic a distal symmetric polyneuropathy. Elevated erythrocyte sedimentation rate and C-reactive protein may be present, as well as cryoglobulins in certain cases. Electrophysiologic studies show an axonal dysfunction pattern but may reveal transient pseudoconduction block over the area of nerve infarction, which later subsides after wallerian degeneration occurs. Although often diagnosed on clinical and electrophysiologic grounds, histopathology can confirm the diagnosis; in these cases, combined nerve and muscle biopsy is recommended to increase the diagnostic yield.

CASE 3-2

A 35-year-old man presented to the emergency department reporting excruciating left dorsal foot pain and left footdrop, which he noticed upon awakening the day before. He denied ever having problems with back pain or pain radiating down his legs. Four weeks earlier, he had developed persistent numbness in the right fourth and fifth fingers. Six months earlier, he had developed a dry cough and sinusitislike symptoms, which persisted despite being treated with over-the-counter antihistamines and later a course of azithromycin. On review of systems, he described having an episode of hematuria 1 week earlier.

On general examination, his temperature was 38.3°C (101°F), and his vital signs were otherwise normal. He had a palpable maculopapular erythematous rash on his distal legs. On neurologic examination, his mental status and cranial nerves were intact. Strength in the arms was normal except for right finger abduction and flexion of the fourth and fifth digits, which were 3/5. Strength in the legs was normal except for left ankle dorsiflexion and eversion, which were 2/5. Sensation was decreased to light touch and pinprick in the palmar and dorsal aspects of the right fifth digit, the medial half of the right fourth digit, the left dorsal foot, and left lateral calf. Reflexes were symmetric, and Babinski sign was absent bilaterally.

Blood work was notable for leukocytosis and elevated blood urea nitrogen and creatinine levels. Erythrocyte sedimentation rate and C-reactive protein were elevated, and cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) and cryoglobulins were present. Urinalysis showed proteinuria, and microscopic analysis showed red blood cell and protein casts.

He was started on IV methylprednisolone for 3 days, and then rituximab infusions were initiated. He later underwent renal biopsy, which showed pauci-immune glomerulonephritis and granulomas. Electrodiagnostic studies done after 3 weeks showed evidence of right ulnar and left common fibular (peroneal) axonal neuropathies.

COMMENT

In this case, the subacute onset and stepwise progression of symptoms localizing to individual nerve distributions raise the suspicion of a mononeuritis multiplex. The presence of constitutional symptoms and pain, which reflects the underlying nerve infarction, as well as vasculitic involvement of other organs (such as palpable purpura in the skin and glomerulonephritis) are also typical of systemic vasculitides. In this case, the presence of sinusitis and renal involvement with pauci-immune glomerulonephritis and c-ANCA are suggestive of granulomatosis with polyangiitis (previously known as Wegener granulomatosis). Electrodiagnostic studies in patients with mononeuritis multiplex reflect the multifocal distribution of symptoms and deficits, showing axonal dysfunction in the affected nerves. However, electrodiagnostic testing is not helpful in the acute phase, as abnormalities may not be present during the first 3 to 4 weeks after symptom onset. In diagnostically challenging cases, combined nerve and muscle biopsy is recommended to maximize diagnostic yield. Although the diagnosis of vasculitis is confirmed by pathology, treatment should be initiated as soon as possible to prevent permanent neurologic dysfunction and further progression of the disease.

Vasculitis may affect the CNS as a manifestation of an underlying systemic autoimmune disease (such as SLE, rheumatoid arthritis, or Sjögren syndrome) or a primary systemic vasculitic syndrome (such as antineutrophil cytoplasmic antibody [ANCA]–associated vasculitides, polyarteritis nodosa, Takayasu arteritis, or giant cell arteritis). It should be differentiated from primary CNS vasculitis, other systemic autoimmune diseases such as neurosarcoidosis, CNS infections, or demyelinating disease.

The presence of constitutional symptoms and other organ involvement, including mononeuritis multiplex, is suggestive of a systemic process rather than a vasculitis confined to the CNS. Clinical presentation consists of acute- or subacute-onset focal or multifocal deficits. Mental status changes, headache, or seizures may also be present. Meningeal enhancement, which is often accompanied by multiple cranial neuropathies, cerebral infarcts, or hemorrhages, may be present on MRI. CSF studies show lymphocytosis and elevated protein in the majority of cases and can be helpful in distinguishing from other causes, such as infections. As MRI and CSF studies often yield nonspecific findings, vessel imaging can be helpful in confirming the clinical diagnosis. Magnetic resonance angiography (MRA), CT angiography, and conventional angiography can show abnormalities in large and medium vessel vasculitides, while their sensitivity is lower in small vessel vasculitides. Novel vessel imaging techniques, such as high-resolution vessel wall imaging, are becoming more readily available and eventually will provide noninvasive alternative diagnostic modalities. In diagnostically challenging cases, brain or meningeal biopsy may be needed.

Takayasu Arteritis

Headache and dizziness are common symptoms in patients with Takayasu arteritis, and the frequency of stroke or transient ischemic attacks has been estimated to be between 10% and 20%. Stenosis or occlusion of large arteries, such as the common carotid or subclavian, is often seen in these cases. Intracranial hemorrhage is less common and has been associated with descending aortic or renal artery stenosis. In a series of consecutive patients with Takayasu arteritis undergoing vessel imaging, 13% of patients had intracranial vessel abnormalities and cerebral aneurysms were present in 3.9%.

Temporal Arteritis

Headache is a common presenting symptom of patients with temporal (giant cell) arteritis. Of patients with temporal arteritis, 30% have been estimated to sustain permanent vision loss. Of cases of vision loss, 90% are due to anterior ischemic optic neuropathy, followed by central retinal artery occlusion. Rarely, extraocular muscle weakness may coexist because of cranial nerve involvement. Clinical symptoms or ultrasonographic findings of temporal artery involvement, hypertension, atrial fibrillation, carotid artery stenosis, and increased CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and previous stroke/transient ischemic attack) score have been associated with increased risk of visual impairment. Patients with temporal arteritis and involvement of large vessels, such as the aorta and its branches, have increased risk of stroke and relatively decreased inflammatory markers compared to patients without large vessel involvement. Limb claudication is also more common in patients with large vessel involvement and may present in the absence of other manifestations of temporal arteritis.

Polyarteritis Nodosa

Peripheral neuropathy affects 50% to 70% of patients with polyarteritis nodosa and in the majority is a presenting manifestation. The majority of cases consist of mononeuritis multiplex, followed less frequently by length-dependent axonal sensorimotor or sensory polyneuropathy. CNS involvement is less common in polyarteritis nodosa, presenting as headache, encephalopathy, stroke, and, rarely, intracranial hemorrhage.

ANCA-associated Vasculitides

Peripheral neuropathy is the most common neurologic manifestation of granulomatosis with polyangiitis (previously known as Wegener granulomatosis); however, cerebral and meningeal involvement, upper cranial nerve, and pituitary involvement are also seen. These are thought to reflect both vasculitic involvement and granulomatous spread from the sinuses, which are a typical site of disease involvement. Cases with pituitary involvement should be differentiated from tuberculosis, neurosarcoidosis, Crohn disease, giant cell arteritis, and IgG4-related systemic disease.

Peripheral neuropathy, usually in the form of mononeuritis multiplex and less commonly in the form of distal symmetric polyneuropathy, seems to be more frequently seen in eosinophilic granulomatosis with polyangiitis compared to the other small vessel vasculitides. CNS involvement is rare in eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis.

BEHÇET DISEASE

Behçet disease can affect the CNS in 3% to 10% of patients, whereas peripheral neuropathy is rare, seen in 0.3% of patients. The majority of patients with CNS manifestations present with parenchymal involvement due to small vessel vasculitis, whereas 20% of patients with neuro-Behçet disease develop cerebral venous sinus thrombosis. Interestingly, parenchymal disease and cerebral venous sinus thrombosis tend not to coexist in the same patient. Symptom onset in cerebral venous sinus thrombosis is typically insidious, as only 10% of patients present with acute symptoms; in two-thirds of patients, concurrent peripheral thrombotic events are present, usually deep vein thrombosis in the legs.

Parenchymal disease typically manifests as a subacute, progressive brainstem syndrome. Typical MRI findings include brainstem T2 hyperintensities, often extending to the diencephalon, followed by atrophy and necrosis.

Myelitis has been rarely described in patients with Behçet disease; this has been reported to occur either later in the course of the disease or as a presenting manifestation and tends to be accompanied with uveitis. The majority of the reported cases were treated with corticosteroids and cyclophosphamide, with mixed results.

Optic neuritis is another uncommon manifestation of Behçet disease. Compared to other neurologic syndromes, it is more likely to be the presenting manifestation of the disease, as half of cases may be present before the onset of systemic manifestations. Uveitis is often an associated comorbidity. About one-third of patients have been reported to have concurrent neurologic involvement in the form of parenchymal disease or MS-like syndromes, and one case of optic neuritis occurring along with longitudinally extensive myelitis and negative AQP4 antibodies has been reported.

SCLERODERMA

Myopathy is a common neuromuscular manifestation seen in patients with both systemic sclerosis and localized scleroderma; however, this can be difficult to distinguish from overlapping primary inflammatory myopathies in many cases. Focal and generalized seizures have been associated with limited scleroderma. Brain MRI may show increased white matter lesion burden. Focal neurologic signs and cranial neuropathies can be seen less commonly; although vasculitis can complicate scleroderma, CNS vasculitis is rare.

Peripheral neuropathy has been reported in 5% of patients with scleroderma, after excluding confounding etiologies. Autonomic dysfunction of variable degree is also seen, in the form of gastrointestinal symptoms, abnormal gastrointestinal motility testing, or abnormal cardiovascular reflex testing.

SERONEGATIVE SPONDYLARTHROPATHIES

Patients with ankylosing spondylitis are at increased risk of nerve root compression ranging from symptomatic radiculopathy to cauda equina syndrome as a result of vertebral fractures, local degenerative changes, dural ectasia, or tethering. Patients with psoriatic arthritis have increased prevalence of vascular risk factors. Patients with ankylosing spondylitis or psoriatic arthritis have a higher risk of cardiovascular disease, including a slightly higher risk of stroke compared to the general population.

COGNITIVE DYSFUNCTION AND RHEUMATIC DISEASES

Cognitive symptoms are among the most common neurologic symptoms in patients with systemic autoimmune diseases, ranging from mild, ill-defined, cognitive dysfunction often termed brain fog to more severe cognitive symptoms. The lack of objective tests can make the evaluation and classification of these symptoms difficult in day-to-day clinical practice. Overall, patient-reported symptoms tend to be more prevalent than neuropsychiatric syndromes diagnosed by various objective testing methods. Chronic somatic symptoms, including pain, and systemic inflammation are confounding factors contributing to patient-reported symptoms and further complicate their evaluation. In cases of rapidly progressing cognitive dysfunction, it is important to rule out concurrent neurologic syndromes, such as aseptic meningitis, CNS vasculitis, or other neurologic processes (eg, infections, autoimmune encephalitis, or prion diseases), which can present in a similar manner. As in every patient with cognitive symptoms, thyroid function and vitamin B12 levels should be assessed, especially given the increased frequency of coexisting Hashimoto thyroiditis and atrophic gastritis in patients with systemic autoimmune diseases.

SLE has been extensively studied, and patients with SLE seem to have increased risk of both cognitive dysfunction and dementia, according to a number of studies. Cognitive dysfunction has been reported at similar rates in Sjögren syndrome and less frequently in rheumatoid arthritis.

Cognitive symptoms have been less extensively investigated compared to other manifestations of rheumatologic diseases; however, available studies suggest that cognitive dysfunction may correlate with disease activity in SLE and rheumatoid arthritis. The underlying pathogenic mechanisms remain largely unknown, although limited evidence indicates that hypoperfusion may be associated with cognitive dysfunction, suggesting that microvasculopathy could be a potential pathogenetic mechanism. Autoantibodies, such as NR2 glutamate receptor antibodies, ribosomal P protein antibodies, and M1 muscarinic acetylcholine receptor antibodies, have been identified in subsets of patients with SLE or Sjögren syndrome and CNS involvement and have been found to cause neuronal dysfunction in animal models. However, they have poor specificity in distinguishing between neuropsychiatric manifestations, and their clinical utility remains limited.

Overall, these observations suggest that intrinsic pathogenic mechanisms likely exist in autoimmune diseases leading to cognitive dysfunction, which are further augmented by comorbid chronic pain, depression, or the effects of chronic disease on cognition. However, the presence of confounding factors and lack of reliable biomarkers hinder our ability to further classify and systematically study the cognitive symptoms of these patients.

NEUROLOGIC COMPLICATIONS OF TUMOR NECROSIS FACTOR-α INHIBITORS

Central and peripheral demyelinating syndromes have been associated with TNF-α inhibitors. Although initial animal studies showed encouraging results in treatment of experimental autoimmune encephalomyelitis, subsequent clinical trials in patients with MS showed that TNF-α inhibition increased disease activity and worsened patient outcomes. Various demyelinating syndromes of the CNS have been reported in patients with rheumatologic diseases, mostly after treatment with etanercept and infliximab, which constitute more than 80% of reported cases. Adalimumab has less commonly been associated with central demyelinating syndromes (16% of reported cases), while only 1% of reported cases were treated with golimumab. Time of neurologic symptom onset from initiation of treatment can vary widely, from days to years, but the median time of onset has been reported to range between 5 and 17 months. The majority of the demyelinating syndromes reported were MS-like syndromes, optic neuritis, and, less commonly, transverse myelitis or tumefactive demyelinating lesions. Rarely, progressive multifocal leukoencephalopathy has been reported after TNF-α inhibitor treatment. In 36% of demyelinating events, full recovery was reported after discontinuing treatment, while 21% achieved partial recovery; in 28% neurologic symptoms persisted, and three fatalities were reported, two cases with progressive multifocal leukoencephalopathy and one with an MS-like syndrome.

Apart from central demyelination, TNF-α inhibitors have also been associated with peripheral demyelination; clinical and electrophysiologic findings and CSF studies are identical to CIDP. Demyelinating neuropathy may appear early or late in the course of treatment and persists despite discontinuation of TNF-α inhibitors. Response to corticosteroids is poor, and treatment with IVIg is required. Other types of neuropathy, including multifocal motor neuropathy (MMN) with conduction block, sensory polyradiculopathy, and small fiber neuropathy, have also been reported to occur after treatment with TNF-α inhibitors. Motor neuropathy and sensory polyradiculopathy cases were reported to improve with IVIg treatment, whereas in small fiber neuropathies, symptoms improved after discontinuing TNF-α inhibitors.

CONCLUSION

Neurologic manifestations of systemic autoimmune diseases pose a number of challenges to clinicians; many of these manifestations are rare and present before the development of or in the absence of active systemic disease. In addition, significant overlap exists with other primary neurologic disorders or adverse effects of biologic therapies used to treat the systemic disease. Neurologic manifestations of rheumatologic diseases are important to recognize as they can be associated with increased morbidity or even mortality; patients may require closer monitoring for certain complications. In addition, a subset of these manifestations can be rapidly progressive and, if not treated early, can lead to significant irreversible neurologic dysfunction and resulting morbidity. Therefore, increased awareness and multidisciplinary care are required to diagnose and institute treatment in a timely manner.

KEY POINTS

  • Patients with systemic lupus erythematosus, rheumatoid arthritis, temporal arteritis, psoriatic arthritis, and ankylosing spondylitis have increased risk of stroke.
  • Patients with systemic lupus erythematosus have increased risk of developing posterior reversible encephalopathy syndrome.
  • Neuromyelitis optica spectrum disorders can overlap with systemic lupus erythematosus or Sjögren syndrome.
  • Small fiber neuropathy is the most common peripheral neuropathy in Sjögren syndrome. It may present with length-dependent or non–length-dependent distribution of symptoms and tends to be associated with fewer extraglandular manifestations than large fiber neuropathy.
  • Patients with Sjögren syndrome and small fiber neuropathy are less frequently seropositive for anti-Ro and anti-La antibodies. Therefore, their absence should not preclude the diagnosis of Sjögren syndrome in an otherwise appropriate clinical setting.
  • Sensory ataxic neuropathy (neuronopathy) can be seen in patients with Sjögren syndrome due to lymphocyte infiltration of dorsal root ganglia. The differential diagnosis includes paraneoplastic syndromes (usually in cases of small cell lung carcinoma) human immunodeficiency virus infection, platinum-based chemotherapy, or vitamin B6 toxicity.
  • Patients with rheumatoid arthritis have increased risk of cervical spinal stenosis, particularly at the atlantooccipital, atlantoaxial, or subaxial level.
  • Pannus formation is a mechanism by which patients with rheumatoid arthritis can develop cervical spinal stenosis. The imaging modality of choice to detect it is MRI.
  • Mononeuritis multiplex is the most common peripheral neuropathy associated with vasculitis. Over time, confluent neurologic deficits can mimic a distal symmetric polyneuropathy.
  • Combined nerve and muscle biopsy increases the sensitivity for vasculitis diagnosis.
  • In a patient with known or suspected systemic autoimmune disease or constitutional symptoms, coexisting deficits of subacute onset that localize to the central and peripheral nervous systems should raise the suspicion of vasculitis.
  • Peripheral neuropathy is present in more than 50% of patients with polyarteritis nodosa and is often a presenting manifestation.
  • Pituitary involvement can be seen in granulomatosis with polyangiitis.
  • Cerebral venous sinus thrombosis is associated with Behçet disease and is often of insidious onset.
  • Cognitive symptoms are common among patients with systemic autoimmune diseases, ranging from mild subjective cognitive symptoms to more severe cognitive dysfunction.
  • Patients with rapidly progressing cognitive decline should be evaluated for other central nervous system processes, such as vasculitis, infections, aseptic meningitis, autoimmune encephalitis, or prion diseases.
  • Cognitive dysfunction is seen more frequently in systemic lupus erythematosus and Sjögren syndrome, followed by rheumatoid arthritis.
  • Tumor necrosis factor-α inhibitors can cause central demyelination or demyelinating neuropathies.
  • Demyelinating neuropathy associated with tumor necrosis factor-α inhibitors persists after their cessation and requires treatment with IV immunoglobulin.

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