Connective Tissue Diseases, Vasculitis, and the Nervous System

Systemic Disease

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with up to 150 cases per 100,000 population worldwide. SLE can manifest with a wide spectrum of systemic and neurologic findings and symptoms, each with varying severity. The 10-year mortality rate of SLE is about 30 percent. Proposed diagnostic criteria have undergone multiple revisions to improve sensitivity and specificity. In 2019, the European League Against Rheumatism and the American College of Rheumatology (EULAR/ACJR) jointly released updated, validated classification criteria for SLE, incorporating weighted criteria ( Table 50-1 ). In the validation cohort, these criteria had a sensitivity of 96 percent and specificity of 93 percent for SLE, an improvement over previous classification schemes. Care should be exercised in applying such criteria clinically, particularly for those seronegative for antinuclear antibodies (ANAs).

Patients with SLE present with systemic symptoms including fever, fatigue, and malaise. The most strongly suggestive findings are acute cutaneous (e.g., malar rash or generalized maculopapular rash), musculoskeletal (e.g., synovitis, joint tenderness, and morning stiffness), cardiac (e.g., acute pericarditis), and renal (e.g., nephritis; Table 50-1 ). Other systemic manifestations include hematologic (e.g., autoimmune hemolytic anemia, leukopenia, thrombocytopenia), neuropsychiatric (e.g., delirium, psychosis, seizure), and serosal. Inflammation can be evident in many tissues and organs, involving not only the heart and kidneys, but also the eyes, lungs, and gastrointestinal tract, among others.

As a systemic autoimmune disease, SLE is characterized by the detection of a variety of autoantibodies. The detection of ANAs at a ratio of at least 1:80 are a mandatory criterion; the threshold is in place since approximately 10 percent of the general population are seropositive at low titers. A minority of SLE patients are seronegative for ANA. Low-level ANA seropositivity has been observed in other inflammatory diseases including connective tissue disorders described later in this chapter such as rheumatoid arthritis, Sjögren syndrome, and systemic sclerosis as well as neurologic diseases such as multiple sclerosis. Other, more specific autoantibodies can be detected in patients with SLE, including anti-Smith (anti-Sm) and antidouble-stranded DNA (anti-dsDNA), which are included in the 2019 EULR/ACR criteria. More than 200 different autoantibodies have been described in SLE, although only a handful are routinely used in clinical practice. Some of these antibodies can occur in subclinical SLE or be predictive very early in the disease course [e.g., anti-Ro60/SSA, anti-Sm, anti-dsDNA, antinuclear ribonucleoprotein (anti-RNP), antihistone, antiscleroderma 70 kDa antigen (anti-Scl70)], whereas others are pathogenic (e.g., ds-DNA). Of note, some of these antibodies are also detected in other connective tissue disorders (e.g., anti-Ro60/SSA and anti-La/SSB in Sjögren syndrome).

Antiphospholipid antibodies, most commonly those directed to anticardiolipin, are frequently detected in patients with SLE. These antibodies prolong the partial thromboplastin time for patients with SLE and are paradoxically associated with thrombosis more than hemorrhage. Care should be exercised in using anticardiolipin antibodies for diagnostic purposes as they can be detected in those without SLE or other autoimmune diseases, may be detectable only transiently, may be detected in the setting of other systemic illnesses, and may be found in the healthy general population. While 10 percent of healthy blood donors are seropositive for antiphospholipid antibodies, only 1 percent remain seropositive on follow-up testing at 1 year.

Patients with SLE who are seropositive for antiphospholipid antibodies are more likely to develop stroke as well as other neurologic syndromes such as headache, chorea, and myelitis. These patients also are more likely to develop mild cognitive impairment compared to SLE patients who are seronegative for the antibodies. The development of ischemic stroke may be the consequence of the antiphospholipid antibody syndrome, which is characterized by clinical episodes of thrombosis (e.g., deep venous thrombosis, pulmonary embolism, nonbacterial endocarditis, ischemic stroke) or morbid events of pregnancy (e.g., miscarriages typically after 10 weeks gestation, fetal death, pre-eclampsia, eclampsia), especially in the setting of persistence of moderate or high levels of anticardiolipin antibodies. When evaluating patients for concern for antiphospholipid antibody syndrome, additional clinical events or findings should be considered, including a history of arthralgias, livedo reticularis, cardiac valve disease, hemolytic anemia, thrombocytopenia, pulmonary hypertension, acute or chronic renal vascular lesions, and Reynaud phenomenon.

Along with these autoantibodies, complement protein levels are incorporated in the recent clinical criteria, and they play a role in monitoring disease activity. Patients with SLE commonly have levels of complement components C3 and C4 below normal limits, and complement protein levels are particularly low during inflammatory flares. The lowering of circulating levels of these complement proteins is suggestive of immune-complex deposition.

Neuropsychiatric Systemic Lupus Erythematosus

Neuropsychiatric systemic lupus erythematosus (NPSLE) refers to the syndromes of the central, peripheral, and autonomic nervous system as well as the psychiatric syndromes that have been observed in patients with SLE, excluding those syndromes attributable to other causes ( Table 50-2 ). These syndromes can present at any point in the course of SLE, including prior to other systemic manifestations and in those in clinical remission. The reported prevalence of NPSLE and respective syndromes varies widely by study, with estimated prevalence of over 50 percent.

The central neurologic manifestations of NPSLE are widely varied in terms of presentation, severity, mechanisms, and treatment. Seizure, psychosis, and delirium feature in the 2019 EULR/ACR criteria; however, these capture only some of the neurologic syndromes SLE patients may develop as a consequence of SLE and its treatment. Headache, seizure, cognitive dysfunction, and cerebrovascular disease are common central nervous system (CNS) syndromes ( Table 50-2 ).

Headache, in the form of migraine and tension headaches, can occur in patients with SLE; however, it is not clear that these occur more commonly than in the general population. Patients with SLE can develop a new headache syndrome secondary to another etiology, such as posterior reversible encephalopathy syndrome (PRES) in the setting of severe hypertension and some immunosuppressive agents, infection in the setting of chronic immunosuppression, and stroke in the setting of SLE itself.

A minority of patients with SLE have a seizure at some point during the course of their illness, either accompanying one-time events such as metabolic derangements, drug toxicity, or PRES, or in the form of recurrent seizures in the setting of focal brain injury such as stroke.

Cognitive dysfunction is common among patients with SLE, affecting up to one-third of patients. Patients with SLE are nearly three times as likely as healthy individuals to develop cognitive impairment. Such dysfunction is typically mild and rarely severe. Concomitant neuropsychiatric conditions such as mood disorders and stroke can contribute to cognitive dysfunction in SLE.

Psychosis and delirium can develop in patients with SLE from a variety of etiologies, including direct parenchymal inflammation as well as secondary to other systemic processes such as hypertensive encephalopathy and PRES, metabolic derangements, and drug toxicity. Medications commonly used in the acute and chronic treatment of SLE are associated with encephalopathy (e.g., corticosteroid encephalopathy and psychosis), PRES (e.g., cyclosporine, tacrolimus), and opportunistic infections.

An estimated 8 percent of patients with SLE have cerebrovascular disease. Patients with SLE are at increased risk for both ischemic and hemorrhagic stroke, with mechanisms including emboli and thrombosis (usually as a manifestation of antiphospholipid syndrome), atherosclerotic disease, and rarely secondary CNS vasculitis. Given this increased risk, patients with SLE should be treated to address common stroke risk factors for primary stroke prevention. In the event of a stroke, patients should not only undergo brain imaging as part of a secondary stroke prevention assessment, but also a thorough evaluation for vascular stenoses of the head and neck, cardiac evaluation for a cardioembolic source, and evaluation for the presence of antiphospholipid antibodies to characterize risk and individualize treatment.

Other CNS syndromes such as chorea, myelopathy, and aseptic meningitis rarely occur among patients with SLE. Chorea may be unilateral or bilateral, develop slowly at any point through the course of SLE, and resolve spontaneously. Patients often have increased levels of antiphospholipid antibodies. Patients with acute myelopathy as a manifestation of SLE typically present with a syndrome characterized by flaccid, hyporeflexic paraplegia and urinary retention, accompanied by nausea, vomiting, and evidence of active systemic lupus ( Fig. 50-1 ). Their prognosis is poor for neurologic recovery. Patients may also develop a subacute spastic hyperreflexic paraparesis over the course of days, typically in the absence of fever or other signs of systemic lupus, which may have a relapsing, remitting course. Patients who present with episodes of myelopathy and optic neuropathy may have a neuromyelitis optica (NMO) spectrum disorder, a minority of whom are aquaporin-4 antibody seropositive.

Peripheral Nervous System Disease

The peripheral nervous system is frequently affected in a variety of connective tissue disorders, including SLE. A minority of SLE patients have evidence of peripheral neuropathies; however, many of these are due to other systemic or noninflammatory causes, such as diabetes or carpal tunnel syndrome, and are therefore not directly attributable to SLE. Sensory predominant or sensorimotor axonal polyneuropathies are the most common manifestations of a symptomatic inflammatory neuropathy due to SLE, affecting 2 to 8 percent of patients ( Table 50-2 ). Mononeuropathy and cranial neuropathy (most commonly of the facial nerve) are rare, while mononeuritis multiplex, acute inflammatory demyelinating polyradiculopathy, and chronic inflammatory polyneuropathy are even rarer ( Table 50-2 ). SLE patients may occasionally develop autonomic neuropathy, sometimes independent of sensory neuropathy, with impairment of sweating, cardiovascular reflexes, and gastrointestinal mobility. Polyneuropathy due to SLE is usually mild, rarely necessitates nerve biopsy, and does not require directed aggressive immunosuppression in addition to the treatment a patient with SLE is already receiving.

Treatment

There are a variety of treatments for SLE, with selection guided by the severity of the disease and its impact on affected organs. Aspirin was the first drug approved by the U.S. Food and Drug Administration (FDA) for treatment of SLE, followed by corticosteroids, and later the antimalarial drug hydroxychloroquine. In 2011, belimumab, a monoclonal antibody that blocks the B-lymphocyte stimulator protein, was the first medication specifically approved by the FDA for treatment of SLE. Immunosuppressive medications including cyclophosphamide, methotrexate, azathioprine, and mycophenolate mofetil are also commonly used in the treatment of SLE, particularly in the setting of severe renal or visceral disease.

Symptom-directed therapies play an important role in the treatment of SLE. Just as arthralgias may be treated with nonsteroidal anti-inflammatory drugs, many of the neurologic manifestations of SLE can be managed directly, including headache and mood disorders. Behavioral and cognitive therapy approaches also play an important role in addressing associated cognitive dysfunction.

In addition to symptomatic treatment, syndrome specific treatment is also appropriate in those with neurologic manifestations of SLE. Those with NPSLE presenting with psychosis may be managed with antipsychotic medications as well as steroids (assuming corticosteroid-induced psychosis has been excluded). Catatonia has also been observed in NPSLE and is typically treated with benzodiazepines and rarely with electroconvulsive therapy, in addition to immunosuppressive therapies. Intravenous immunoglobulin (IVIg) and plasmapheresis are mainstays of treating SLE-associated acute inflammatory demyelinating polyradiculopathy. Corticosteroids, plasmapheresis, and immunosuppressive medications such as cyclophosphamide are important considerations for the acute treatment of SLE patients presenting with optic neuritis, focal white matter lesions, and myelitis.

Primary stroke prevention strategies should be employed for patients given the prevalence of stroke among those with SLE. Warfarin is a consideration for those with cardioembolic strokes and the antiphospholipid antibody syndrome, but otherwise antiplatelet medications are the focus of secondary prevention in SLE.

Systemic Disease

Sjögren syndrome is another common systemic autoimmune disease, affecting over 1 million American adults. It affects females more than males, with a peak incidence in midlife. It is characterized by an exocrinopathy, commonly manifesting with xerostomia and xerophthalmia, fatigue, and arthralgias, symptoms which are present in over 80 percent of patients. It may be primary, occurring in isolation or along with organ-specific autoimmune diseases such as thyroiditis or primary biliary cirrhosis or secondarily in association with other systemic autoimmune diseases (e.g., SLE, rheumatoid arthritis).

In 2016, the ACR/EULAR jointly released validated classification criteria for Sjögren syndrome. The classification criteria are based on the weighted sums of five items, applied to those patients who have ocular or oral symptoms of dryness or have suspicion for Sjögren syndrome based on one of the domains of the EULAR Sjögren Syndrome Disease Activity Index ( Table 50-3 ). Those patients who have a total score of at least four meet the criteria for Sjögren syndrome. Although designed for purposes of classification, these ACR/EULAR criteria may be useful clinically in the context of common symptoms.

Sjögren syndrome most commonly presents with symptoms of oral and ocular dryness as well as fatigue, symptoms which in and of themselves are common within the general population and may be related to other syndromes including fibromyalgia, medication side effects, aging, and the use of contact lenses. Other constitutional symptoms such as myalgias, weight loss, and fever are reported commonly. Importantly, approximately 30 to 40 percent of patients may present with other systemic manifestations due to involvement of the exocrine glands of not only the eyes and mouth, but also of the skin, lungs, and vagina. Lymphocytic infiltration of epithelia of the kidneys, gall bladder, and lungs may lead to interstitial nephritis, primary biliary cholangitis, and obstructive bronchiolitis, respectively. B-lymphocyte hyperactivity may cause immune complex deposition, resulting in manifestations such as palpable purpura, glomerulonephritis, and interstitial pneumonitis. Thyroid syndromes (thyroiditis, hypothyroidism), gastrointestinal syndromes (atrophic gastritis), and liver disease (biliary cirrhosis) along with organomegaly (spleen and liver) and lymphadenopathy may be observed.

The pathogenesis of Sjögren syndrome is uncertain. Current models of disease implicate the activation of mucosal epithelial cells, potentially by viruses, leading to an innate and an adaptive immune response, complete with secretion of autoantibodies. These autoantibodies contribute to the formation of immune complexes, leading to immune system activation against, and resultant damage to, affected tissues. In support of this hypothesis, patients with Sjögren syndrome commonly have evidence of systemic autoimmunity, including ANA and anti-SSA/Ro and anti-SSB/La antibodies. The anti-SSA/Ro antibodies are the most specific for Sjögren syndrome. Anti-SSB/La seropositivity in the absence of anti-SSA/Ro seropositivity is not specific and thus does not feature in the recent ACR/EULAR criteria. Both anti-SSA/Ro and anti-SSB/La may be detected in patients with other autoimmune diseases, such as SLE. Antibodies not typically seen in Sjögren syndrome can be helpful in distinguishing it from other syndromes, such as anti-dsDNA antibodies, which are included in the classification criteria for SLE. Tissue biopsy and measures of exocrine function are recommended for establishing the diagnosis of Sjögren syndrome.

Providers should be mindful that patients with Sjögren syndrome have an approximate 10 percent lifetime risk for B-cell lymphoma attributed to chronic B-cell activation. These malignancies are primarily B-cell non-Hodgkin lymphomas, often developing in the organs where Sjögren syndrome is primarily active, such as the salivary glands. Thus, it is recommended that every 1 to 2 years, lymphocyte counts and protein electrophoresis along with biomarkers associated with development of lymphoma, namely rheumatoid factor, complement proteins C3 and C4, and cryoglobulins, are assessed.

Central Nervous System Disease

Approximately 2 percent of patients with Sjögren syndrome develop CNS syndromes. However, this figure is likely an underestimate as many symptoms, such as headache and cognitive dysfunction, may be mild or nonspecific. The most common focal CNS findings in Sjögren syndrome are lesions of the spinal cord. Patients may develop a myelopathy, with various presentations in terms of tempo (rapid vs. slowly evolving), extent of involvement (local vs. more generalized), and presentation (complete transverse myelopathy or Brown-Séquard syndrome). Importantly, as in the case of SLE, Sjögren syndrome patients may also present with longitudinally extensive myelopathies as part of NMO spectrum disorder, often in the setting of aquaporin-4 antibody seropositivity.

In addition to myelopathy, patients with Sjögren syndrome may have demyelinating lesions of the brain parenchyma and optic nerves, with associated clinical syndromes. These may have a relapsing-remitting course, placing Sjögren syndrome as a differential consideration in evaluating patients for possible multiple sclerosis. These radiographic findings are often consistent with those described in NMO, with patients frequently being seropositive for aquaporin 4 antibodies, arguing for their testing in patients presenting with lesions of the CNS.

Syndromes associated with the gray matter, such as seizures, and meningitis are less common. Patients may develop focal brain lesions with associated mononuclear infiltrates of the cerebrovascular system (venous and less commonly arterial) and typically microscopic infarcts of the surrounding brain tissue. Meningeal vessels are also often involved. Patients may present with an aseptic meningitis, with CSF analyses demonstrating a mild mononuclear pleocytosis and elevated protein level. There is rarely detection of unique intrathecal oligoclonal bands or increased immunoglobulin G synthesis relative to the serum in patients with Sjögren syndrome.

Peripheral Nervous System Disease

Peripheral nervous system disease is more common than CNS disease in Sjögren syndrome. Many patients develop neuropathy prior to the diagnosis of Sjögren syndrome, with sicca symptoms preceding or following neuropathic symptoms with equal frequency. The most common of these peripheral nervous system syndromes are sensory neuronopathy and small-fiber neuropathy. Patients less commonly develop trigeminal neuropathy, multiple mononeuropathies, multiple cranial neuropathies, polyradiculoneuropathies, and autonomic neuropathies.

Sensory neuronopathy accounts for nearly 40 percent of all Sjögren syndrome associated neuropathies. It is typically subacute in onset and tempo (occurring over the course of weeks to months) and characterized by multifocal, asymmetric dysfunction of both large and small sensory fibers, manifesting as impaired sensation to proprioception, vibration, temperature, and painful stimuli. Patients may present with pseudoathetosis, as well as symptoms of burning pain, hyperesthesia, and allodynia. Strength usually is preserved but reflexes are diffusely absent. On nerve conduction studies, most patients have absent or low-amplitude sensory nerve action potentials and somatosensory evoked potentials. MRI of the spinal cord may demonstrate hyperintense signal within the dorsal columns. Important differential considerations for a patient presenting with sensory neuronopathy include other autoimmune syndromes such as SLE, medication or other toxicities (e.g., pyridoxine, cisplatin), infections [e.g., with human immunodeficiency virus (HIV) or varicella zoster virus], hereditary syndromes, and paraneoplastic neuronopathy (e.g., anti-Hu paraneoplastic subacute sensory neuronopathy in the setting of small cell lung cancer). Despite an exhaustive evaluation, half of cases of sensory neuronopathy are idiopathic.

The clinical presentation of a Sjögren syndrome patient with a distal sensory polyneuropathy is typically with a chronic, painful, distal axonal neuropathy involving both small and large sensory fibers. Less commonly, patients present with evidence of distal motor fiber involvement. Autonomic symptoms also are often reported. Nerve biopsy typically demonstrates nonspecific axonal loss, though of variable degree. An idiopathic axonal neuropathy can occur in patients who meet diagnostic criteria for Sjögren syndrome. Conversely, an idiopathic axonal neuropathy, even in the setting of history of dry eyes or mouth, without other objective findings supportive of Sjögren syndrome, does not predict later manifestations of Sjögren syndrome. The key to diagnosis is subsequent serologic testing, ocular and salivary function evaluation, and pathologic tissue review to establish the diagnosis.

Patients presenting with trigeminal neuralgia may present with either unilateral or bilateral numbness or paresthesia restricted to the trigeminal distribution without associated motor symptoms. The syndrome is typically indolent in progression and occasionally accompanied by sensory disturbances in the extremities. Patients may also present with autonomic symptoms including pupillary abnormalities, orthostatic hypotension, and hypohidrosis. Trigeminal involvement can be confirmed by blink reflex testing.

In addition to trigeminal neuralgia, patients may present with other or multiple cranial neuropathies. Patients may present with bilateral nerve involvement including facial diplegia, involvement initially localizable to cranial structures (e.g., oculomotor and trochlear nerve involvement suggesting localization to the cavernous sinus rather than the cranial nerves themselves), and multiple cranial neuropathies which may be misinterpreted as evidence of a meningitis. Involvement of the limbs and trunk is not commonly observed in these syndromes.

Patients may also present with a predominant and severe autonomic neuropathy, with associated symptoms and findings including Adie pupils, orthostatic hypotension, syncope, hypohidrosis or anhidrosis, constipation, and diarrhea.

Treatment

Treatment of Sjögren syndrome is directed by the organs involved and the severity of involvement. For oral and ocular dryness, muscarinic agonists such as pilocarpine have shown benefit in randomized clinical trials. Topical cyclosporine eye-drops result in better tear production in comparison to placebo. Otherwise, dry eyes are treated with artificial tears. Regular dental examinations and good oral hygiene are crucial in reducing the risks for dental caries and periodontal disease. For pain management, randomized data are lacking and clinical experience suggests the use of first-line analgesics such as acetaminophen for generalized pain and nonsteroidal anti-inflammatory medications for joint pain. Neuropathic pain is typically treated with serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine), and antiepileptics (e.g., gabapentin or pregabalin) with use of tricyclic antidepressants typically limited by the associated side effect of mouth dryness.

No systemic immunomodulatory therapies have been proven efficacious in Sjögren syndrome. In general, extraglandular involvement is treated with systemic immunosuppressive therapies. Commonly used medications are similar to those used for SLE, including azathioprine, cyclosporine, hydroxychloroquine, methotrexate, mycophenolate mofetil, and prednisone. Randomized, controlled trials of the biologic infliximab and etanercept have not demonstrated significant improvement in terms of joint pain, fatigue, and dryness. Small studies of rituximab have yielded mixed results, suggesting its potential utility in the treatment of some systemic manifestations of Sjögren syndrome.

There are no specific treatments for some neurologic accompanying syndromes such as mild cognitive impairment, trigeminal neuropathy, and distal sensory neuropathy. Patients with CNS syndromes including transverse myelitis are typically treated with intravenous corticosteroids as first-line treatment, with plasmapheresis and cyclophosphamide used in refractory cases. Rituximab is indicated for the prevention of subsequent relapses in NMO spectrum disorders. Patients with sensorimotor neuropathy, sensory neuropathy, and small-fiber neuropathy may respond better to IVIg that those with sensory neuronopathy. Patients with mononeuropathies and cranial neuropathies are typically treated with systemic corticosteroids. Accompanying vasculitis or evidence of cryoglobulinemia may predict a response to rituximab. It is advised that treatment plans for neurologic manifestations of Sjögren syndrome be formulated in concert with the patient’s rheumatologist.

Systemic Disease

Systemic sclerosis (scleroderma) is a multisystem disease characterized by extensive fibrosis, small-vessel vasculopathy, and autoantibody production. Its affects up to 30 persons per 100,000 population, with women more commonly affected than men. Systemic sclerosis varies in presentation and prognosis, with recognized subsets including patients with limited cutaneous systemic sclerosis, diffuse cutaneous systemic sclerosis, and systemic sclerosis without skin involvement. The majority of patients have skin thickening accompanied by involvement of internal organs, most commonly within the limited and diffuse cutaneous subsets. Limited cutaneous systemic sclerosis is mainly restricted to the hands, arms, and face, with Reynaud phenomenon present years before fibrosis is evident; it is typically accompanied by pulmonary hypertension. In contrast, diffuse systemic sclerosis is rapidly progressive, affecting large areas of skin and at least one internal organ. Patients may present with subcutaneous calcinosis, Raynaud phenomenon, esophageal dysfunction (often manifesting as dysphagia), sclerodactyly, and telangiectasia (i.e., CREST syndrome). While some patients may only have CREST, others may have systemic sclerosis manifesting with additional symptoms of pulmonary fibrosis, hypothyroidism, sicca syndrome, renal or cardiac involvement (particularly hypertension), arthralgias, and tenosynovitis. Of note, patients with systemic sclerosis may present with evidence of other concomitant autoimmune syndromes such as SLE, Sjögren syndrome, and rheumatoid arthritis.

The majority of patients have serologic evidence of autoimmunity, including an elevated ANA and antibodies directed against other antigens including centromeres, topoisomerase (Scl-70), RNA-polymerases (to anti-RNA polymerase II), and ribonuclear proteins (U1-RNP and U3-RNP) among other antigens.

In 2013, the ACR/EULAR classification criteria for systemic sclerosis were proposed. Patients may be classified as having systemic scleroderma if there is evidence of skin thickening proximal to the metacarpophalangeal joints. If not present, seven additional items can be used for classification, each of varied weights ( Table 50-4 ). A score of at least 9 on these criteria is associated with good sensitivity and specificity for the diagnosis of systemic sclerosis. It is important to note that these criteria were developed for patient inclusion in studies of systemic sclerosis. These criteria are not applicable to those with finger-sparing skin thickening or a scleroderma-like disorder which may better explain their clinical findings.

Central Nervous System Disease

CNS involvement in systemic sclerosis is relatively uncommon and it is debatable whether associated neurologic syndromes are the direct result of neurologic injury due to the disease or sequelae of renal, cardiovascular, or pulmonary involvement. Descriptions are largely limited to case reports and series. The most commonly reported CNS syndromes are headache, seizures, and cognitive impairment. Stroke, transverse myelitis, and visual disturbances are described less commonly. Incidental radiographic findings have been reported, most commonly white matter lesions and irregular intracranial vessels, although it is unclear whether these finding represent true pathogenic associations.

Peripheral Nervous System Disease

Peripheral nervous system disease is more common than CNS disease among patients with systemic sclerosis; however, it is difficult to attribute pathogenesis of these syndromes directly to systemic sclerosis. Of the reported peripheral syndromes, myopathy, trigeminal neuropathy, peripheral sensorimotor polyneuropathy, and carpal tunnel syndrome are the most common. Other mononeuropathies and cranial neuropathies have also been described.

Autonomic dysfunction has similarly been reported, typically parasympathetic underactivity and sympathetic overdrive, with prevalence varying across reported case series. At times, autonomic dysfunction can develop prior to evidence of organ fibrosis. The most commonly reported findings include abnormalities of heart rate and blood pressure variability. Gastrointestinal symptoms, esophageal dysfunction, and motility disorders are correlated with autonomic involvement.