Systemic Disease

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by the presence of a broad spectrum of autoantibodies, including antinuclear antibodies (ANAs). It is protean in its neurologic and systemic manifestations. Its severity varies from relatively mild skin problems and arthralgias to life-threatening multiorgan failure. The American College of Rheumatology (ACR) classification criteria are helpful for assessing the possibility of SLE and for understanding its diversity ( Table 50-1 ). These criteria were designed for classification purposes for research studies and must be used cautiously for diagnosis as many are nonspecific. The criteria are also insensitive, and some patients have SLE even though they meet fewer than four criteria. The prevalence of SLE is 100 per million; 90 percent of patients are women, and the disease is more prevalent in blacks than whites. Peak age at onset is 15 to 25 years old.

SLE usually causes systemic symptoms such as fatigue, malaise, and fever. Perhaps 80 percent of patients have skin manifestations, such as sun sensitivity or the classic malar rash, and arthralgias or nondeforming arthritis. Other systemic manifestations include pericarditis, pleuritis, renal disease (ranging from asymptomatic proteinuria or hematuria to severe glomerulonephritis), anemia (classically autoimmune hemolytic anemia), thrombocytopenia, leukopenia, or lymphopenia. Inflammation can affect nearly any part of the body, including the lungs, gastrointestinal tract, and eyes.

Autoantibodies are present universally in patients with SLE. ANAs are present in nearly all lupus patients but also occur in about 10 percent of the general population, usually at a low titer, and in many other inflammatory diseases including rheumatoid arthritis (RA), Sjögren syndrome, systemic sclerosis, polymyositis, and multiple sclerosis. Patients with SLE often have other antibodies against more specific nuclear antigens, such as extractable nuclear antigen (anti-ENA), anti-Ro (SSA), anti-La (SSB), anti-Sm (anti-Smith, not to be confused with anti-SM, which is anti–smooth muscle), and antiribonucleoprotein (anti-RNP). Anti-Ro is often positive in the rare lupus patient who lacks ANA. Anti-dsDNA (double-stranded DNA) is also strongly suggestive of SLE. Depressed levels of complement components C3 and C4 are common in patients with lupus, especially during flares of inflammation, and suggest immune- complex deposition, classically glomerulonephritis.

Many patients with SLE have serum antiphospholipid antibodies; the most commonly assayed antibody is directed against cardiolipin. Some of these antibodies may prolong the partial thromboplastin time and are referred to as lupus anticoagulants. However, antiphospholipid antibodies rarely cause bleeding and paradoxically are frequently associated with thrombosis. Antiphospholipid antibodies may also be responsible for false-positive non-treponemal serologic tests for syphilis Most people with antiphospholipid antibodies do not have lupus or other autoimmune disease. Antiphospholipid antibodies may be present transiently, especially after acute viral infections, and may occur in many other systemic illnesses ( Table 50-2 ).

The antiphospholipid antibody syndrome is defined as the persistence of moderate to high titers of antiphospholipid antibodies combined with a clinical episode of thrombosis or of pregnancy morbidity. This syndrome is associated with thrombosis, especially deep venous thrombosis, pulmonary embolism, nonbacterial thrombotic endocarditis, and stroke and may accompany failures of pregnancy, including miscarriage, fetal death, premature birth due to placental insufficiency, pre-eclampsia, or eclampsia. Other phenomena that occur in antiphospholipid antibody syndrome include livedo reticularis, arthralgias, cardiac valve abnormalities, hemolytic anemia, thrombocytopenia, pulmonary hypertension, and Raynaud phenomenon. The antiphospholipid antibody syndrome may occur in patients with SLE or in isolation, in which case it is called primary antiphospholipid antibody syndrome. Patients with SLE who have antiphospholipid antibodies are more likely to develop neurologic manifestations including stroke and nonischemic syndromes such as headache and less common syndromes, such as chorea or myelitis. Further discussion of the antiphospholipid antibody syndrome is provided in Chapter 11 , Chapter 25 .

A variety of autoantibodies, including antibodies against endothelium, neurofilament, glial fibrillary acidic protein, neurons, microtubule-associated protein 2, lymphocytes, ribosomal P protein, NMDA receptor subtype 2, and gangliosides, occur in some patients with neurologic manifestations of lupus. None of these has proven pathogenic action or diagnostic value.

Central Nervous System Disease

The central nervous system (CNS) manifestations of SLE vary tremendously in their symptoms, severity, mechanisms, and treatment. Although at times they are referred to collectively as neuropsychiatric lupus, they are best analyzed as a number of separate syndromes ( Table 50-3 ). Depending on diagnostic criteria used, between 12 and 95 percent of patients with SLE have one of these symptoms during the course of their illness, and many patients will have more than one. Neurologic events may be due to factors other than the direct effects of inflammatory disease (e.g., hypertension, uremia, other metabolic derangements, drug toxicity, opportunistic infections, coincident illnesses); in one series, more than 40 percent of neurologic syndromes in patients with lupus were not directly due to lupus affecting the nervous system.

Cognitive dysfunction affects up to 80 percent of patients with SLE at some time during the illness. The cognitive difficulties can be relatively mild and transient; irreversible deficits and dementia are much less common.

Migraine or tension headaches occur in patients with lupus, but whether they are more common in these patients is unclear. When patients with lupus develop a new headache pattern, the differential diagnosis includes meningitis, stroke, posterior reversible encephalopathy syndrome, or pseudotumor cerebri.

More than one-tenth of patients with SLE seize at some time during the course of their illness. Seizures can be one-time events, particularly if related to reversible conditions, such as metabolic derangements, drug toxicity, posterior reversible encephalopathy syndrome, or infections. However, SLE may also cause recurrent focal or generalized seizures, particularly in patients who have antiphospholipid or anti-Sm antibodies, stroke, or other focal brain lesions.

Patients with SLE are at increased risk of ischemic and hemorrhagic stroke via a variety of mechanisms, including cardiogenic emboli (in patients with myocardial infarction, atrial fibrillation, or nonbacterial endocarditis), atherosclerosis of large or small vessels, thrombosis associated with antiphospholipid antibodies, and rarely, vasculitis. Patients with lupus are more than twice as likely as matched controls to develop carotid plaque. All lupus patients need aggressive primary stroke prevention with attention to well-known risk factors such as smoking, hypertension, hyperlipidemia, and diabetes. When a patient does have a stroke, brain imaging is usually supplemented with a thorough evaluation of cardiac sources of emboli, vascular imaging of the head and neck, and measurement of antiphospholipid antibodies to clarify the etiology of the stroke and plan secondary stroke prevention.

Chorea occurs in perhaps 1 percent of patients with lupus. The movement disorder can be unilateral or bilateral, evolve slowly, and remit spontaneously; it may be the first clinical sign of lupus or appear later in the disease. The chorea is often sensitive to variations in female steroid hormones. Patients with chorea often have increased levels of antiphospholipid antibodies but rarely have evidence of focal cerebral ischemia. Other movement disorders, such as cerebellar ataxia or reversible parkinsonism, are rare.

Acute or subacute transverse myelopathy occurs in 1 to 2 percent of patients with SLE, sometimes as the initial presentation. Some patients evolve within 24 hours a flaccid, hyporeflexic paraplegia with urinary retention; these patients often have nausea, vomiting, fever, and active systemic disease. Their prognosis for neurologic recovery is poor. Other patients evolve over days a spastic hyperreflexic paraparesis. They are usually afebrile and do not have active systemic disease; they may recover, or have recurrent episodes. Patients with optic neuritis or recurrent episodes of myelopathy may have neuromyeltitis optica with aquaporin-4 spectrum autoimmunity.

Magnetic resonance imaging (MRI) of the spinal cord often shows T2 intramedullary signal extending over many spinal segments. Spinal fluid commonly shows a mild pleocytosis and elevated protein concentration and occasionally contains oligoclonal bands that are not present in the serum.

Acute episodes of aseptic meningitis occur in less than 1 percent of patients with SLE. Spinal fluid studies are necessary to exclude an infectious cause, particularly in immunosuppressed patients. In patients with aseptic meningitis, spinal fluid usually shows a mononuclear pleocytosis, normal glucose, variable protein levels, and no evidence of a causative organism by culture, polymerase chain reaction, or serology. Drug-induced meningitis is an important consideration in the differential diagnosis. The aseptic meningitis of lupus can be self-limited or corticosteroid-responsive but is sometimes recurrent.

Patients with lupus commonly experience depression, anxiety, and other affective disorders. Perhaps one-fifth of patients will experience major depression during their lives, and many more will have difficulty with mood or anxiety. These disorders do not correlate with brain inflammation and are treated with routine psychiatric drugs, such as selective serotonin reuptake inhibitors and benzodiazepines, rather than with immunosuppressive therapy.

Patients with lupus are at risk of psychosis, delirium, or acute confusional states. When these occur, the differential diagnosis includes a wide variety of causes of encephalopathy, such as CNS inflammation directly from lupus, hypertensive encephalopathy, uremia, other metabolic derangements, drug toxicity, or seizures. Patients with hypertension, renal failure, or taking drugs such as corticosteroids or cyclosporine may develop the posterior reversible encephalopathy syndrome. In psychotic patients on corticosteroids, differentiating lupus psychosis from steroid psychosis is important to plan therapy.

The focal neurologic syndromes of SLE may mimic many clinical features of multiple sclerosis. The ACR classification ( Table 50-3 ) refers to these as demyelinating syndromes, but a more general description is that of multifocal white matter lesions. Like the lesions of multiple sclerosis, these lesions are often associated with relapsing-remitting focal syndromes involving areas such as the optic nerve, brainstem, and spinal cord. In patients with lupus, MRI of the brain often shows areas of T2 signal in the cerebral white matter, including periventricular lesions. Occasionally patients with lupus have oligoclonal bands in the cerebrospinal fluid (CSF) that are not present in serum or increased intrathecal immunoglobulin G synthesis. Conversely, some patients with MS have systemic autoantibodies such as ANAs or antiphospholipid antibodies.

Peripheral Nervous System Disease

The peripheral nervous system is also affected in SLE ( Table 50-4 ). Carpal tunnel syndrome is probably the most common manifestation, occurring in up to 30 percent of patients in different series. Patients occasionally have other compression neuropathies. A number of patients develop a distal symmetric axonal sensory or sensorimotor peripheral neuropathy, which is usually relatively mild. Patients with mild neuropathy rarely need nerve biopsy or aggressive immunosuppression, even though the nerve, if biopsied, might show some epineurial vasculitis. Findings of autonomic neuropathy, such as abnormal pupillary responses, impaired sweating, loss of cardiovascular reflexes, and impaired gastrointestinal mobility, can also occur in lupus patients, regardless of whether they have sensory neuropathy.

Acute demyelinating polyneuropathy, clinically and electrodiagnostically similar to Guillain–Barré syndrome, affects up to 1 percent of patients with lupus, depending on the series. This is higher than in the general population. The differential diagnosis of acute motor neuropathy in patients with lupus includes vasculitic neuropathy, particularly if the presentation is asymmetric; however, this is uncommon. Patients with lupus also have increased risk of chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, and possibly neuralgic amyotrophy.

Less than 2 percent of patients with lupus develop cranial mononeuropathies, most often of the facial nerve.

Treatment

Treatment of SLE, with or without neurologic involvement, must be individualized based on the organ systems involved and the severity of involvement. Thus, mild arthralgias might be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), whereas severe renal or other visceral disease often justifies aggressive immunosuppression with cyclophosphamide or mycophenolate mofetil. Many of the neurologic manifestations of SLE can be treated symptomatically. Examples include recurrent headache, mood and anxiety disorders, carpal tunnel syndrome, and length-dependent peripheral neuropathy. Cognitive dysfunction usually requires no specific therapy; behavioral approaches to cognitive therapy deserve exploration.

All patients with SLE should attend to factors for stroke prevention. Those who have had a stroke associated with atrial fibrillation or some other cardiac sources are often treated with warfarin. The appropriate treatment (anticoagulation versus antiplatelet medications) for patients with stroke and antiphospholipid antibodies is debated, as discussed in Chapter 11 .

Patients with lupus psychosis can be managed with antipsychotic drugs, and, once corticosteroid-induced psychosis has been excluded, with steroids. Patients with Guillain–Barré syndrome or myasthenia can be treated with intravenous immunoglobulin (IVIg) or plasmapheresis; however, some patients do not respond to these but appear responsive to corticosteroids combined with cyclophosphamide. Patients with focal CNS inflammatory syndromes such as myelopathy, optic neuritis, or focal cerebral white matter lesions are sometimes treated with corticosteroids alone, but prognosis is better if this is combined with immunosuppressives such as cyclophosphamide.

Systemic Disease

Sjögren syndrome is a chronic autoimmune disorder that causes inflammation in many organs but particularly in the exocrine glands, primarily the salivary and lacrimal glands, leading to dry mouth (xerostomia) and dry eyes (xerophthalmia) that can be severe enough to damage the conjunctiva or cornea (keratoconjunctivitis sicca). In many cases, Sjögren syndrome is associated with other rheumatic diseases such as rheumatoid arthritis, SLE, or systemic sclerosis. Sjögren syndrome occurring without another connective tissue disease is known as primary Sjögren syndrome, which is the focus in the following discussion. Most (90%) patients with Sjögren syndrome are women, usually middle-aged. The prevalence is difficult to determine because of varying definitions, but in the United States it may exceed 1,000 cases per million. The European classification criteria are listed in Table 50-5 .

In addition to dry eyes and dry mouth, Sjögren syndrome may cause dysfunction of other exocrine glands, resulting in dry skin, vagina, or upper respiratory tract. Patients commonly have systemic symptoms such as arthralgias, myalgias, or fatigue, and less often weight loss or fever. They may have palpable purpura due to small-vessel vasculitis, but inflammation of larger arteries is uncommon. Sjögren syndrome may also cause renal (interstitial nephritis, renal tubular acidosis), thyroid (thyroiditis, hypothyroidism), gastrointestinal (atrophic gastritis, dysphagia), pulmonary (interstitial pneumonitis), and liver disease (biliary cirrhosis, sclerosing cholangitis). Liver, spleen, or lymph nodes may be enlarged. Patients have an increased risk of developing lymphoma.

The common symptoms of dry eyes or dry mouth have numerous alternative causes including drugs, aging, or the local effects of contact lenses. In patients with sicca, parotid enlargement, systemic symptoms, and neurologic findings, sarcoidosis is often prominent in the differential diagnosis.

The pathogenesis of Sjögren syndrome is unknown. The pathologic changes in exocrine glands are lymphocytic infiltrates. Patients with Sjögren syndrome commonly have serologic evidence of autoimmunity including ANAs (present in perhaps three-fourths of patients). The anti-Ro (SSA) and anti-La (SSB) antibodies are more specific to Sjögren syndrome but are also sometimes present in patients with SLE and other autoimmune disease and have limited sensitivity, occurring in between one-fourth and three-fourths of patients. Blood studies may also show rheumatoid factor, anemia, lymphopenia, and hypergammaglobulinemia; monoclonal gammopathy occurs less frequently.

Central Nervous System Disease

The prevalence of CNS disease in patients with Sjögren syndrome is unclear, with wide-ranging estimates. Part of this discrepancy is because the most common CNS problems are mild and nonspecific, such as subtle cognitive dysfunction, headache, or affective disorders. Probably 10 percent or less of patients with Sjögren syndrome have serious neurologic complications, such as focal brain lesions, which may present abruptly, simulating a stroke, or more gradually. The cerebral hemispheres or the brainstem can be affected; white matter syndromes are more common than gray matter syndromes. Neuropathologic examination of the focal brain lesions shows mononuclear infiltrates of veins, venules, and, less commonly, small arteries or arterioles. The surrounding brain tissue may show focal infarcts, which are usually microscopic. Meningeal vessels are often involved. Syndromes clinically associated with gray matter disease, such as seizures, may occur but are less common.

Even though the pathologic process in patients with Sjögren syndrome often includes the meninges, clinical meningitis is not common; however, instances of aseptic meningitis do occur and at times become chronic or recurrent. The CSF typically shows mild mononuclear pleocytosis, occasional elevation of protein level, and, less frequently, oligoclonal bands that are not present in the serum or evidence of increased intrathecal IgG synthesis.

Lesions localized to the spinal cord are one of the most common focal CNS findings in Sjögren syndrome. The myelopathy may evolve slowly or rapidly, be generalized or localized, with presentations as varied as transverse myelopathy or Brown-Séquard syndrome. Some patients also have episodes of optic neuritis. In most cases, spinal MRI shows T2-hyperintense intramedullary lesions spanning multiple spinal segments. Sometimes the cord appears swollen, and some lesions enhance with gadolinium. Patients with optic neuritis or longitudinally extensive myelopathy may be part of the spectrum of neuromyelitis optica and often have aquaporin 4 antibodies.

The CNS lesions of Sjögren syndrome can evolve with a relapsing-remitting course that approximates that of multiple sclerosis. When Sjögren syndrome causes optic neuritis, focal paresthesias, brainstem syndromes such as internuclear ophthalmoplegia, or myelopathy, the diagnosis may erroneously be that of multiple sclerosis.

Peripheral Nervous System Disease

In patients with Sjögren syndrome, peripheral nervous disease is more common than CNS disease, and can be the presenting manifestation. The peripheral neuropathies of Sjögren syndrome can be separated into a number of clinical syndromes, but many patients have overlapping features ( Table 50-6 ).

Distal sensory or sensorimotor neuropathy, clinically evident in up to one-fifth of patients with Sjögren syndrome, is the most common peripheral neuropathy. Other patients will have asymptomatic neuropathy detectable by nerve conduction studies. The typical presentation is a chronic distal axonal neuropathy including small and large sensory fibers. Distal motor involvement is less common. Nerve biopsy specimen usually shows nonspecific axonal loss rather than vasculitis. Some patients with otherwise idiopathic axonal neuropathy will meet diagnostic criteria for Sjögren syndrome. However, if neuropathy patients have dry eyes or a dry mouth but no other objective supportive findings, they are unlikely later to develop systemic manifestations of Sjögren syndrome.

Sensory neuronopathy presents acutely or indolently as asymmetric dysfunction of large and small sensory fibers. Patients often have impaired distal or proximal cutaneous touch, pain, temperature, and joint position senses. They may have pseudoathetosis and sensory ataxia with depressed tendon reflexes. Many patients also have trigeminal or autonomic neuropathy. On electrodiagnostic studies, most patients have some low-amplitude or unobtainable sensory nerve action potentials and somatosensory evoked potentials. Spinal cord MRI often shows T2-hyperintense signal in the posterior columns. Sensory nerve biopsy shows axonal loss of large and small myelinated fibers and of unmyelinated fibers, but few biopsy specimens show vasculitic changes or lymphocytic infiltrates. Pathologic findings in the dorsal root ganglia may include neuronal destruction and lymphocytic infiltration. In addition to dry eyes and dry mouth, these patients often fully meet diagnostic criteria for Sjögren syndrome, including objective evidence of xerophthalmia and xerostomia and abnormal lip biopsy samples; however, they usually do not have other systemic manifestations.

Trigeminal neuropathy impairs sensation, usually in the mandibular or maxillary divisions, unilaterally or bilaterally, with acute or subacute evolution, but causes no trigeminal motor dysfunction. Electrodiagnostic studies suggest abnormality of the trigeminal ganglion with impaired blink reflexes but normal masseteric reflexes.

Mild autonomic neuropathy, with manifestations such as Adie pupil, orthostatic hypotension, impaired sweating, constipation or diarrhea, and abnormal cardiac reflexes, often accompanies the other neuropathies of Sjögren syndrome. In an occasional patient, more severe autonomic dysfunction, sometimes accompanied by antibodies against the ganglionic acetylcholine receptor, is the predominant neurologic problem.

Mononeuritis multiplex or multiple cranial neuropathies may also occur. In contrast to trigeminal sensory neuropathy, the multiple cranial neuropathies may also affect motor function and can include nerves III, V, VI, VII, IX, X, and XII. Biopsy of an involved peripheral nerve is likely to show epineurial vasculitis.

Other neuropathic presentations occasionally found in patients with Sjögren syndrome include painful asymmetric sensory neuropathy, proximal radiculoneuropathy, Guillain–Barré syndrome, and lower motor neuronopathy. Predominantly motor neuropathy is less common in patients with Sjögren syndrome. Motor neuron disease is only linked to Sjögren syndrome by case reports. Carpal tunnel syndrome occurs in some patients with Sjögren syndrome.

Treatment

Treatment varies greatly depending on the organs involved and the severity of disease. Dry eyes may be treated with artificial tears or topical approaches; arthralgias may be controlled with nonsteroidal anti-inflammatory drugs or with antimalarials such as hydroxychloroquine. There is no specific cure for some neurologic syndromes, such as mild cognitive impairment, trigeminal neuropathy, or distal sensory neuropathy. Myelopathy or symptomatic focal brain lesions are often treated with corticosteroids, sometimes in conjunction with cyclophosphamide. Mononeuritis multiplex or multiple cranial neuropathies also appear responsive to corticosteroids, sometimes with cyclophosphamide added. A minority of patients with sensory neuronopathy improve after treatment with corticosteroids, IVIg, or other immunosuppressants.

Systemic Disease

Scleroderma with visceral involvement is called systemic sclerosis; this is further divided into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis. Patients with limited cutaneous systemic sclerosis may have “CREST syndrome”: subcutaneous calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly (tight digital skin), and telangiectasia. The esophageal disease often causes dysphagia. Some patients have only CREST and no other systemic disease; however, systemic sclerosis can also cause pulmonary fibrosis, renal or cardiac involvement, especially with hypertension, hypothyroidism, sicca syndrome, arthralgias, and tenosynovitis. Almost all patients with systemic sclerosis have some serologic evidence of autoimmunity, including ANAs and antibodies directed against antigens such as centromeres, topoisomerase, U1-RNP, RNA polymerase III, U3-RNP, and Th/To. These antibodies have some prognostic value: for example, patients with anticentromere antibodies usually have the CREST syndrome, are at risk of pulmonary hypertension, but usually do not develop more diffuse systemic disease. Perhaps those with anti-U1-RNP or anti-Scl-70 are more prone to neurologic complications.

Central Nervous System Disease

CNS disease is not particularly common in patients with systemic sclerosis, so whether reported cases represent true pathogenic associations is often problematic. For example, nearly one-third of patients with systemic sclerosis have migraine, but a pathologic association has not been proven. Case reports link systemic sclerosis to intracerebral vasculopathy, presenting with transient ischemic attacks (TIAs), ischemic strokes, or intracranial hemorrhages. Other case reports link systemic sclerosis to multiple sclerosis, optic neuropathy, memory impairment, or affective disorders.

About one-third of patients with systemic sclerosis, compared to less than one-tenth of control patients, have basal ganglia calcification visible by computed tomography (CT) scan. Patients with SLE may also have an increased prevalence of basal ganglia calcification.

Peripheral Nervous System Disease

Patients with systemic sclerosis probably are at increased risk of developing carpal tunnel syndrome. Trigeminal sensory neuropathy, similar to that described in Sjögren syndrome, affects 1 percent or more of patients with systemic sclerosis. Distal symmetric axonal neuropathy, plexopathies, and mononeuritis multiplex occur infrequently.

Many forms of autonomic dysfunction affect patients with systemic sclerosis, including abnormal sympathetic skin responses, even in nonsclerodermatous skin, abnormal cardiovascular reflexes, impaired urodynamics, erectile dysfunction, and abnormal pupillary responses to sympathetic or parasympathetic stimuli. With the exception of erectile dysfunction, these autonomic changes are usually asymptomatic.

Treatment

Data on the treatment of neurologic disease in patients with systemic sclerosis are scant. Trigeminal neuropathy or mild distal neuropathy is usually not specifically treated. Case reports suggest a possible benefit of cyclosporine in patients with cerebral vasculopathy.

Systemic Disease

Patients with rheumatoid arthritis can develop systemic manifestations such as subcutaneous rheumatoid nodules, sicca syndrome, Felty syndrome of hypersplenism, amyloidosis, scleritis or episcleritis, lung or heart involvement, anemia of chronic disease, eosinophilia, and thrombocytosis. A rare but serious complication is widespread rheumatoid vasculitis, with neurologic complications such as those of other medium-vessel vasculitides (discussed later). A community-based survey of rheumatoid arthritis found extra-articular manifestation in nearly one-half of patients over 30 years of follow-up; important neurologic manifestations were cervical myelopathy in 2 percent, neuropathy in 2 percent, and major organ vasculitis in less than 1 percent.

Central Nervous System Disease

Patients with rheumatoid arthritis are probably at increased risk of headache and neck ache but rarely develop serious or focal cerebral disease. Strokes due to rheumatoid vasculitis are quite infrequent. Pachymeningitis caused by rheumatoid nodules or pannus is a rare complication of chronic rheumatoid arthritis. The lesions are visible by contrast-enhanced MRI, which can demonstrate focal or irregular dural thickening. Clinical manifestations can be absent, focal (e.g., optic neuropathy, spinal cord compression), or nonfocal (e.g., headache, mental status changes).

Cervical myelopathy caused by atlantoaxial subluxation and by soft-tissue pannus is a feared late complication of rheumatoid arthritis due to the laxity of inflamed ligaments. Subluxation is usually anterior but can be in any direction. It is rare in the first years of rheumatoid arthritis but develops in more than one-fourth of those who have had the disease for more than 15 years. The subluxation is usually asymptomatic; however, the risk of cord compression increases as subluxation increases, particularly in those with a small spinal canal. Signs of myelopathy (quadriparesis, spasticity, sensory loss, sphincter disturbance) may evolve slowly or worsen suddenly. Patients with high cervical instability are at particular risk of spinal cord injury during intubation.

Vertical atlantoaxial subluxation can lead to brainstem compression; possible symptoms, in addition to those of cervical myelopathy, include bulbar palsy, trigeminal or high cervical sensory loss, ophthalmoparesis, nystagmus, drop attacks, hydrocephalus, and sleep apnea. A rare presentation is vertebral arterial stroke due to the subluxed neck.

Cervical collars can decrease neck ache or headache due to atlantoaxial subluxation; however, a halo and cervical traction are needed if neck stabilization is required. Surgical stabilization in patients with myelopathy or brainstem compression can prevent further neurologic loss but often does not improve existing neurologic deficits.

Peripheral Nervous System Disease

Carpal tunnel syndrome is the most common neurologic manifestation of rheumatoid arthritis. Estimates of its prevalence vary; careful questioning of patients with rheumatoid arthritis reveals median-distribution sensory symptoms in more than half. Patients are more likely than age-matched controls to develop carpal tunnel syndrome, especially when they have hand flexor tenosynovitis. The carpal tunnel syndrome can improve with successful treatment of the arthritis or after carpal tunnel surgery, occasionally supplemented by tenosynovectomy.

Ulnar nerve compression at the ulnar groove, radial or posterior interosseus nerve compression, compression of the fibular or posterior tibial nerves by a Baker cyst in the popliteal region, tarsal tunnel syndrome, and digital neuropathies may affect patients with rheumatoid arthritis.

Mild length-dependent symmetric sensory neuropathy is a potential late effect of rheumatoid arthritis, especially in those with more severe disease. If a nerve biopsy is performed, the specimen may show vasculitic changes, but this is not indicative of systemic vasculitis and is not an indication for immunosuppressive treatment. Patients may also have autonomic neuropathy with impaired sweating or abnormal postural and cardiovascular reflexes, even in the absence of sensory neuropathy. Patients who develop rheumatoid vasculitis are at risk of developing a mononeuritis multiplex.

Systemic Disease

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by the presence of a broad spectrum of autoantibodies, including antinuclear antibodies (ANAs). It is protean in its neurologic and systemic manifestations. Its severity varies from relatively mild skin problems and arthralgias to life-threatening multiorgan failure. The American College of Rheumatology (ACR) classification criteria are helpful for assessing the possibility of SLE and for understanding its diversity ( Table 50-1 ). These criteria were designed for classification purposes for research studies and must be used cautiously for diagnosis as many are nonspecific. The criteria are also insensitive, and some patients have SLE even though they meet fewer than four criteria. The prevalence of SLE is 100 per million; 90 percent of patients are women, and the disease is more prevalent in blacks than whites. Peak age at onset is 15 to 25 years old.

SLE usually causes systemic symptoms such as fatigue, malaise, and fever. Perhaps 80 percent of patients have skin manifestations, such as sun sensitivity or the classic malar rash, and arthralgias or nondeforming arthritis. Other systemic manifestations include pericarditis, pleuritis, renal disease (ranging from asymptomatic proteinuria or hematuria to severe glomerulonephritis), anemia (classically autoimmune hemolytic anemia), thrombocytopenia, leukopenia, or lymphopenia. Inflammation can affect nearly any part of the body, including the lungs, gastrointestinal tract, and eyes.

Autoantibodies are present universally in patients with SLE. ANAs are present in nearly all lupus patients but also occur in about 10 percent of the general population, usually at a low titer, and in many other inflammatory diseases including rheumatoid arthritis (RA), Sjögren syndrome, systemic sclerosis, polymyositis, and multiple sclerosis. Patients with SLE often have other antibodies against more specific nuclear antigens, such as extractable nuclear antigen (anti-ENA), anti-Ro (SSA), anti-La (SSB), anti-Sm (anti-Smith, not to be confused with anti-SM, which is anti–smooth muscle), and antiribonucleoprotein (anti-RNP). Anti-Ro is often positive in the rare lupus patient who lacks ANA. Anti-dsDNA (double-stranded DNA) is also strongly suggestive of SLE. Depressed levels of complement components C3 and C4 are common in patients with lupus, especially during flares of inflammation, and suggest immune- complex deposition, classically glomerulonephritis.

Many patients with SLE have serum antiphospholipid antibodies; the most commonly assayed antibody is directed against cardiolipin. Some of these antibodies may prolong the partial thromboplastin time and are referred to as lupus anticoagulants. However, antiphospholipid antibodies rarely cause bleeding and paradoxically are frequently associated with thrombosis. Antiphospholipid antibodies may also be responsible for false-positive non-treponemal serologic tests for syphilis Most people with antiphospholipid antibodies do not have lupus or other autoimmune disease. Antiphospholipid antibodies may be present transiently, especially after acute viral infections, and may occur in many other systemic illnesses ( Table 50-2 ).

The antiphospholipid antibody syndrome is defined as the persistence of moderate to high titers of antiphospholipid antibodies combined with a clinical episode of thrombosis or of pregnancy morbidity. This syndrome is associated with thrombosis, especially deep venous thrombosis, pulmonary embolism, nonbacterial thrombotic endocarditis, and stroke and may accompany failures of pregnancy, including miscarriage, fetal death, premature birth due to placental insufficiency, pre-eclampsia, or eclampsia. Other phenomena that occur in antiphospholipid antibody syndrome include livedo reticularis, arthralgias, cardiac valve abnormalities, hemolytic anemia, thrombocytopenia, pulmonary hypertension, and Raynaud phenomenon. The antiphospholipid antibody syndrome may occur in patients with SLE or in isolation, in which case it is called primary antiphospholipid antibody syndrome. Patients with SLE who have antiphospholipid antibodies are more likely to develop neurologic manifestations including stroke and nonischemic syndromes such as headache and less common syndromes, such as chorea or myelitis. Further discussion of the antiphospholipid antibody syndrome is provided in Chapter 11 , Chapter 25 .

A variety of autoantibodies, including antibodies against endothelium, neurofilament, glial fibrillary acidic protein, neurons, microtubule-associated protein 2, lymphocytes, ribosomal P protein, NMDA receptor subtype 2, and gangliosides, occur in some patients with neurologic manifestations of lupus. None of these has proven pathogenic action or diagnostic value.

Central Nervous System Disease

The central nervous system (CNS) manifestations of SLE vary tremendously in their symptoms, severity, mechanisms, and treatment. Although at times they are referred to collectively as neuropsychiatric lupus, they are best analyzed as a number of separate syndromes ( Table 50-3 ). Depending on diagnostic criteria used, between 12 and 95 percent of patients with SLE have one of these symptoms during the course of their illness, and many patients will have more than one. Neurologic events may be due to factors other than the direct effects of inflammatory disease (e.g., hypertension, uremia, other metabolic derangements, drug toxicity, opportunistic infections, coincident illnesses); in one series, more than 40 percent of neurologic syndromes in patients with lupus were not directly due to lupus affecting the nervous system.

Cognitive dysfunction affects up to 80 percent of patients with SLE at some time during the illness. The cognitive difficulties can be relatively mild and transient; irreversible deficits and dementia are much less common.

Migraine or tension headaches occur in patients with lupus, but whether they are more common in these patients is unclear. When patients with lupus develop a new headache pattern, the differential diagnosis includes meningitis, stroke, posterior reversible encephalopathy syndrome, or pseudotumor cerebri.

More than one-tenth of patients with SLE seize at some time during the course of their illness. Seizures can be one-time events, particularly if related to reversible conditions, such as metabolic derangements, drug toxicity, posterior reversible encephalopathy syndrome, or infections. However, SLE may also cause recurrent focal or generalized seizures, particularly in patients who have antiphospholipid or anti-Sm antibodies, stroke, or other focal brain lesions.

Patients with SLE are at increased risk of ischemic and hemorrhagic stroke via a variety of mechanisms, including cardiogenic emboli (in patients with myocardial infarction, atrial fibrillation, or nonbacterial endocarditis), atherosclerosis of large or small vessels, thrombosis associated with antiphospholipid antibodies, and rarely, vasculitis. Patients with lupus are more than twice as likely as matched controls to develop carotid plaque. All lupus patients need aggressive primary stroke prevention with attention to well-known risk factors such as smoking, hypertension, hyperlipidemia, and diabetes. When a patient does have a stroke, brain imaging is usually supplemented with a thorough evaluation of cardiac sources of emboli, vascular imaging of the head and neck, and measurement of antiphospholipid antibodies to clarify the etiology of the stroke and plan secondary stroke prevention.

Chorea occurs in perhaps 1 percent of patients with lupus. The movement disorder can be unilateral or bilateral, evolve slowly, and remit spontaneously; it may be the first clinical sign of lupus or appear later in the disease. The chorea is often sensitive to variations in female steroid hormones. Patients with chorea often have increased levels of antiphospholipid antibodies but rarely have evidence of focal cerebral ischemia. Other movement disorders, such as cerebellar ataxia or reversible parkinsonism, are rare.

Acute or subacute transverse myelopathy occurs in 1 to 2 percent of patients with SLE, sometimes as the initial presentation. Some patients evolve within 24 hours a flaccid, hyporeflexic paraplegia with urinary retention; these patients often have nausea, vomiting, fever, and active systemic disease. Their prognosis for neurologic recovery is poor. Other patients evolve over days a spastic hyperreflexic paraparesis. They are usually afebrile and do not have active systemic disease; they may recover, or have recurrent episodes. Patients with optic neuritis or recurrent episodes of myelopathy may have neuromyeltitis optica with aquaporin-4 spectrum autoimmunity.

Magnetic resonance imaging (MRI) of the spinal cord often shows T2 intramedullary signal extending over many spinal segments. Spinal fluid commonly shows a mild pleocytosis and elevated protein concentration and occasionally contains oligoclonal bands that are not present in the serum.

Acute episodes of aseptic meningitis occur in less than 1 percent of patients with SLE. Spinal fluid studies are necessary to exclude an infectious cause, particularly in immunosuppressed patients. In patients with aseptic meningitis, spinal fluid usually shows a mononuclear pleocytosis, normal glucose, variable protein levels, and no evidence of a causative organism by culture, polymerase chain reaction, or serology. Drug-induced meningitis is an important consideration in the differential diagnosis. The aseptic meningitis of lupus can be self-limited or corticosteroid-responsive but is sometimes recurrent.

Patients with lupus commonly experience depression, anxiety, and other affective disorders. Perhaps one-fifth of patients will experience major depression during their lives, and many more will have difficulty with mood or anxiety. These disorders do not correlate with brain inflammation and are treated with routine psychiatric drugs, such as selective serotonin reuptake inhibitors and benzodiazepines, rather than with immunosuppressive therapy.

Patients with lupus are at risk of psychosis, delirium, or acute confusional states. When these occur, the differential diagnosis includes a wide variety of causes of encephalopathy, such as CNS inflammation directly from lupus, hypertensive encephalopathy, uremia, other metabolic derangements, drug toxicity, or seizures. Patients with hypertension, renal failure, or taking drugs such as corticosteroids or cyclosporine may develop the posterior reversible encephalopathy syndrome. In psychotic patients on corticosteroids, differentiating lupus psychosis from steroid psychosis is important to plan therapy.

The focal neurologic syndromes of SLE may mimic many clinical features of multiple sclerosis. The ACR classification ( Table 50-3 ) refers to these as demyelinating syndromes, but a more general description is that of multifocal white matter lesions. Like the lesions of multiple sclerosis, these lesions are often associated with relapsing-remitting focal syndromes involving areas such as the optic nerve, brainstem, and spinal cord. In patients with lupus, MRI of the brain often shows areas of T2 signal in the cerebral white matter, including periventricular lesions. Occasionally patients with lupus have oligoclonal bands in the cerebrospinal fluid (CSF) that are not present in serum or increased intrathecal immunoglobulin G synthesis. Conversely, some patients with MS have systemic autoantibodies such as ANAs or antiphospholipid antibodies.

Peripheral Nervous System Disease

The peripheral nervous system is also affected in SLE ( Table 50-4 ). Carpal tunnel syndrome is probably the most common manifestation, occurring in up to 30 percent of patients in different series. Patients occasionally have other compression neuropathies. A number of patients develop a distal symmetric axonal sensory or sensorimotor peripheral neuropathy, which is usually relatively mild. Patients with mild neuropathy rarely need nerve biopsy or aggressive immunosuppression, even though the nerve, if biopsied, might show some epineurial vasculitis. Findings of autonomic neuropathy, such as abnormal pupillary responses, impaired sweating, loss of cardiovascular reflexes, and impaired gastrointestinal mobility, can also occur in lupus patients, regardless of whether they have sensory neuropathy.

Table 50-4

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