Neurologic Complications of Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis

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1 425 Neurologic Complications of Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Shamik Bhattacharyya, MD, MS 1,2,3 Simon M. Helfgott, MD 4,5 1 Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 2 Department of Neurology, Brigham and Women s Hospital, Boston, Massachusetts 3 Department of Neurology, Harvard Medical School, Boston, Massachusetts 4 Department of Rheumatology, Brigham and Women s Hospital, Boston, Massachusetts 5 Department of Rheumatology, Harvard Medical School, Boston, Massachusetts Address for correspondence Shamik Bhattacharyya, MD, MS, Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA ( sbhattacharyya3@partners.org). Semin Neurol 2014;34: Abstract Keywords systemic lupus erythematosus Sjögren syndrome rheumatoid arthritis cervical spine subluxation antiphospholipid syndrome neuromyelitis optica myelitis peripheral neuropathy Neurologic complications are frequent and often morbid in systemic lupus erythematosus, Sjögren syndrome, and rheumatoid arthritis. Although all are systemic inflammatory syndromes, each disease affects the nervous system distinctly, such as peripheral neuropathy in Sjögren syndrome, cerebrovascular disease in lupus, and cervical spine subluxation in rheumatoid arthritis. Some neurologic complications share convergent pathophysiology across diseases, such as neuromyelitis optica spectrum disorders in both Sjögren syndrome and lupus. Ill-defined cognitive complaints are especially common in lupus and Sjögren syndrome. For the majority of the complications, evidence for treatment efficacy is limited and requires further investigation. Systemic lupus erythematosus, rheumatoid arthritis, and Sjögren syndrome are three of the more common rheumatological diseases. Patients with these diseases can develop neurologic complications with significant morbidity, such as ischemic stroke, sensory ataxia, cognitive decline, or myelopathy. The following review aims to describe the pathology, clinical manifestations, and treatments of the wide range of neurologic complications associated with these three diseases. Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder of unclear etiology. Women are affected disproportionately compared with men in an estimated ratio of 9:1, with increased prevalence of disease in those of African ancestry. 1 Systemic lupus erythematosus typically becomes clinically manifest between the late teens and early forties. 1 The current diagnostic criteria for SLE were formulated by the American College of Rheumatology (ACR) initially in 1982 and then revised in 1997 ( Table 1). 2,3 As reflected by the clinical breadth of the diagnostic criteria, SLE is a heterogeneous disease with varying presentations. The criteria were notably not developed to diagnose individual patients, but rather to create an operational definition. 3 Thus, individual patients may clinically have SLE and respond to its treatment without satisfying the official criteria. Issue Theme Neurorheumatology; Guest Editor, Tracey A. Cho, MD, MA Copyright 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) DOI /s ISSN

2 426 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott Table 1 Diagnostic criteria for systemic lupus erythematosus 4 of the following 11 features: Facial erythema over the malar eminences and/or bridge of the nose (butterfly rash) Erythematous raised patches with keratotic scaling and follicular plugging (discoid lupus) Photosensitivity defined as any skin reaction from exposure to sunlight Oral or nasopharyngeal ulcers (often painless) Nonerosive arthritis characterized by tenderness, swelling, or effusion of 2 or more peripheral joints Serositis typically pleuritis or pericarditis Renal disorder manifesting as proteinuria or cellular casts Neurologic disorder broadly characterized by seizures or psychosis Hematologic disorder consisting of hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia Presence of antidouble-strand DNA (dsdna), anti-smith (Sm), or antiphospholipid antibodies Presence of antinuclear antibody The pathogenesis of SLE is likely multifactorial and includes genetic susceptibility (locus in chromosome 1), environmental factors (occupational exposure to silica or infection with Epstein-Barr virus), and hormonal factors (women of childbearing age). 1 One of the hallmarks of SLE is autoantibodies against intracellular components. These autoantibodies are thought to arise from a defect in apoptosis or clearance of apoptotic cells resulting in sensitization of the immune system. 1 In total, there have been at least 116 autoantibodies described in patients with SLE, though the vast majority are not tested clinically. 4 The antinuclear antibody (ANA) is present in approximately 95% of patients. It is not specific and can be present in a variety of conditions including asymptomatic healthy individuals, hepatic disease, malignancies, chronic infections, and other autoimmune conditions such as Sjögren syndrome or rheumatoid arthritis. The anti-dsdna antibody is less sensitive, but tends to correlate with disease activity. The anti-sm antibody has low sensitivity (20 40%), but is highly specific. 4 Since Hebra and Kaposi first reported stupor associated with SLE in 1875, the fact that SLE can affect the nervous system has been well appreciated. 5 However, the pathogenesis of neurologic involvement still remains debated today. In a seminal study by Johnson and Richardson in 1968 examining the neuropathology of patients with SLE, microinfarcts were the most commonly described abnormalities. 6 These microscopic infarcts were often asymptomatic clinically and did not correlate with the presence of Libman-Sacks endocarditis (found in 33% of patients) or signs of systemic embolism. There was no evidence of generalized arteritis in the brain. 6 A separate autopsy series by Devinsky also did not find signs of central nervous system (CNS) arteritis, but discovered mitral valvulitis in 46% and embolic infarcts as the primary abnormality. 7 Although the conclusions of the two series appear contradictory, patients included in the two series differ in time and clinical course, and CNS injury likely occurs from both small vessel disease and embolic events. Central nervous system injury may additionally be antibody and cytokine mediated. Antiphospholipid antibodies, for instance, create a procoagulant state that contributes directly both to small vessel vasculopathy and large vessel thrombosis. 8 Antineuronal antibodies in the cerebrospinal fluid, in particular antibodies to the N-methyl-D-aspartate (NMDA) receptor NR2 subunit, are associated with neuropsychiatric symptoms (in contrast to conventional NMDA receptor encephalitis, which is associated with antibodies against the NR1 subunit). 9,10 Antiribosomal P antibody was initially thought to be a marker of neuropsychiatric involvement in SLE, but its sensitivity and specificity overall are now estimated at 26% and 80%, respectively, for neuropsychiatric involvement, limiting its clinical utility. 11 Cytokines elevated in SLE, such as IL6 and IFNα, are associated with an increased risk of seizures and psychosis, respectively, and may represent another pathway for neuronal dysfunction. 12 Clinically, SLE is associated with a variety of symptoms ranging from headache to psychosis to polyneuropathy, grouped collectively as neuropsychiatric symptoms. The study of neurologic involvement in lupus has historically been hindered by varying definitions and terms (such as lupus cerebritis). In 1999, the ACR set forth a standard nomenclature identifying 19 separate central and peripheral nervous system syndromes ( Table 2). 5 Using these definitions, the prevalence of neuropsychiatric involvement in SLE is approximately 56%, though estimates ranging from 12 to 95% have been published. 13 The most frequent syndrome is headache (28 57%), followed by mood disorder (21%), cognitive dysfunction (20%), seizures (10%), and cerebrovascular disease (8%). 13 Autonomic dysfunction and acute inflammatory demyelinating polyradiculoneuropathy are very infrequent. No convincing case of plexopathy associated with SLE has been published. At the time of diagnosis of SLE, approximately 28% of patients have one of these syndromes. 14 The ACR definitions provide standardized reporting nomenclature, but do not imply causation. In an individual patient, other etiologies should be investigated and excluded before attributing a syndrome to SLE. Although headache is the most commonly associated neurologic symptom in SLE, it is likely no more prevalent in SLE than in the general population. Complaint of headache is also culturally biased. Cohorts of SLE with large Asian representation report a much lower frequency of headaches. 15 If Asian populations are excluded, the pooled estimate of headache from controlled studies is 57%, which is not significantly different than the prevalence of headache in the general population. 16 Neither tension type nor migraine headache is more prevalent in SLE. 16 Headache also does not appear to be a consistent marker of generalized systemic lupus activity. 16 In the absence of other signs of disease activity, headache in SLE should generally be treated symptomatically rather than by escalation of immune suppression. Similar to headache, depression is commonly reported with SLE, but is also prevalent in the general population. Estimates of prevalence of depression in adults with SLE has ranged from 2 to 60%. 17 The heterogeneity is secondary to varying assessment techniques, such as the use of a

3 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott 427 Table 2 Nomenclature of neuropsychiatric syndromes in systemic lupus erythematosus Aseptic meningitis Cerebrovascular disease Demyelinating syndrome (central nervous system) Headache Movement disorder Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis Acute inflammatory demyelinating polyradiculoneuropathy Autonomic disorder Mononeuropathy, single/multiplex Myasthenia gravis Cranial neuropathy Plexopathy Polyneuropathy structured interview versus specific depression scales. One of the larger cross-sectional studies examined 326 white women with SLE in the San Francisco region using a structured phone interview. 18 Major depressive disorder was present in 47%, which is a higher prevalence than in a similar group of healthy U.S. white women. 18 About 46% of these women had the onset of depression prior to the diagnosis of SLE. Elevated disease activity (measured by Systemic Lupus Activity questionnaire) mildly increased the odds of having major depression by approximately 10%. 18 Other studies examining the relationship of disease activity with depression have yielded contradictory results. 17 In summary, depression appears to be more prevalent in SLE, but causality between SLE disease activity and depression is uncertain. The psychosocial burden of having a chronic disease may affect the prevalence of depression within this group as well. Psychosis in SLE is less frequent estimated prevalence of 2 to 11% but more closely associated with disease activity. 19,20 Delusions with paranoid ideations and hallucinations are the most common features of psychosis. The psychosis can be the initial presentation of SLE in as many as 20 to 60%, and often occurs concurrently with generalized systemic disease activity. 19,20 Brain magnetic resonance imaging (MRI) is typically normal. 20 In patients with SLE and psychosis, prior to attributing causality to SLE, it is important to exclude the contribution of steroids and decrease the dose of steroids if possible. Although data are limited, psychosis associated with SLE generally responds to treatment of the SLE flare and symptomatic antipsychotic therapy. 19 Compared with psychiatric effects, cognitive dysfunction is a more underrecognized comorbidity of SLE. When tested by standard neuropsychological batteries and compared with age and gender norms, mild to severe cognitive impairment is detected in approximately 60 to 80% of patients with SLE data which have been reproduced in several relatively large studies Although there is no stereotypic pattern of cognitive impairment, most common deficits are in visuospatial processing, and verbal and visual memory. 21,22 Only approximately 38% of those with impairment by testing have cognitive complaints, but the presence of cognitive dysfunction is associated with less-skilled occupation and depressive symptoms, which may also worsen cognitive performance. 21,24 The pathophysiology of how cognitive dysfunction develops is unclear. Many of the larger studies did not include brain MRI to look for structural defects. In smaller studies, imaging evaluations including single photon emission computerized tomography (SPECT) have not been particularly revealing. 23 The presence of anti-nmda receptor antibodies, anticardiolipin IgM levels, and positive ANA titers have been associated with cognitive impairment. 23,25,26 At this point, who should be tested for cognitive impairment, whether cognitive deficits are static or progressive, and how the clinician should treat progressive changes are unclear and are areas of future enquiry. Estimates of seizure prevalence in SLE range from 7 to 40%. 27 The wide range of estimates partly reflects the varying pathophysiology resulting in seizures. For instance, in a series of 519 consecutive patients with SLE followed prospectively, seizures occurred in 88 patients (17%), of whom 5 had preexisting epilepsy diagnoses, 23 (4.4%) had acute provoking factors such as electrolyte abnormalities and uremia, and 60 (11.6%) had seizures thought to be primarily related to SLE. 28 Seizures primarily associated with SLE can be generalized or focal in origin and occur either at the onset of SLE or during the course of disease. 28,29 Factors predicting seizures with SLE include a history of stroke and presence of lupus anticoagulant, elevated serum antiphospholipid antibodies, and positive serum anti-sm antibody. 30 The majority of seizures are single episodes (88%) and do not result in epilepsy. 28 Higher baseline disease activity is associated with recurrent seizures. 27,30 Although antineuronal antibodies have been associated with seizures, whether to test for them and which ones to test for in a patient with only seizures are unclear. Magnetic resonance imaging often shows cortical atrophy and small periventricular and cortical/subcortical lesions consistent with small vessel disease. 28,30 Therapeutically, seizures in the context of SLE should be treated similar to seizures in the general population, keeping in mind that the majority of seizures are single events and do not necessarily require starting antiepileptic therapy if MRI and electroencephalogram (EEG) studies are within normal limits. 31 Systemic lupus erythematosus is associated with an increased risk of ischemic stroke compared with the general population. The estimated prevalence of ischemic stroke is between 2 to 15%, though strokes disproportionately account for 20% to 30% of deaths in SLE. 32 Hemorrhagic strokes are rare. The pathophysiology of ischemia in SLE is varied. Conventional risk factors such as hypertension, dyslipidemia, and diabetes mellitus are present at a higher frequency in patients with SLE and lead to accelerated atherosclerosis. 8,32 Part of this worsening risk profile is secondary to corticosteroids, which cause insulin resistance and increase weight, blood pressure, and cholesterol levels. Patients with SLE should be screened routinely for modifiable risk factors, including smoking, and treated aggressively.

4 428 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott Besides conventional risk factors, antiphospholipid antibodies are predictive of ischemic stroke. About 65% of patients with SLE and ischemic stroke have antiphospholipid antibodies. 32 To diagnose antiphospholipid syndrome, current revised classification criteria from 2006 require a clinical event consisting either of thrombosis (arterial or venous) or a pregnancy complication (fetal loss beyond the 10th week of gestation, eclampsia, or severe pre-eclampsia resulting in premature birth before the 34th week of gestation, or three or more unexplained consecutive abortions before the 10th week of gestation). 33 In addition to one of these clinical events, persistent elevated titers of one of the following autoantibodies needs to be present for greater than 12 weeks: (1) lupus anticoagulant, (2) IgG or IgM isotype antibody to cardiolipin, or (3) IgG or IgM isotype antibody to β2-glycoprotein Among these three serological markers, the presence of lupus anticoagulant confers the highest risk of thrombosis. 33 Although a clinical event is required for diagnosis of antiphospholipid syndrome, patients persistently positive for all three markers have an estimated risk of 5.3% per year for the first thrombotic event. 33 Primary prophylaxis with aspirin may be beneficial in this subgroup. 34 Clinically, antiphospholipid syndrome should always be suspected in a patient with SLE presenting with stroke. On MRI, there is no characteristic lesion pattern. Ischemic infarcts associated with antiphospholipid syndrome can appear as large territorial infarcts, localized cortical infarcts, bilateral border zone infarcts, anterior basal ganglia lesions, or even stenotic arterial lesions ( Fig. 1). 35 In general, there is greater white matter T2 hyperintensity in patients with SLE and antiphospholipid syndrome than in those without. 35 Treatment at this time is largely geared toward secondary prevention after a thrombotic event. Long-term anticoagulation with warfarin is the current recommended treatment, with a goal international normalized ratio (INR) of 2 to Randomized controlled trials have not demonstrated superiority of higher INR goals (such as between 3 4), though some experts may recommend higher goals with persistent embolism. 36 Data for novel oral anticoagulants such as Factor Xa inhibitors are lacking. If not on anticoagulation, patients with SLE presenting with acute ischemic stroke should be considered for thrombolytic therapy and treated similarly to the general population. 31 Demyelinating disorders and myelopathy are infrequent in SLE with an estimated prevalence less than 1%. 13 Given the similar at-risk population of women of childbearing age, relapsing and remitting demyelinating lesions in the brain may represent concurrent multiple sclerosis or SLE-related demyelinating disease. 37 Lupus-related myelopathy, on the other hand, has been recently proposed to be distinct, with two clinical subsets. 38 The largest cohort described consists of 22 patients presenting with acute myelitis. 39 Half of these patients presented with lower motor neuron findings including flaccidity and hyporeflexia, and rapidly deteriorated to clinical nadir within 6 hours. These lower motor neuron signs persisted over time and did not appear to be transient spinal shock. This pattern of myelitis was associated with a clinical prodrome of fever, active systemic inflammatory disease from SLE, and a cerebrospinal fluid (CSF) profile consisting of a neutrophilic predominant pleocytosis, elevated protein, and low glucose. 39 The other half of the cohort presented with classic signs of white matter disruption myelitis, including spasticity and hyperreflexia. Magnetic resonance imaging of the spinal cord in both patterns of myelitis frequently showed longitudinally extensive lesions spanning more than three vertebral segments. Patients with white matter patterns of myelitis, however, more often had an associated history of optic neuritis, and approximately 80% satisfied criteria for a neuromyelitis optica (NMO) spectrum disorder. 39 On followup, patients presenting with lower motor neuron pattern Fig. 1 Ischemic strokes in systemic lupus erythematosus associated antiphospholipid syndrome result in a variable pattern of injury. Some examples are subcortical T2 hyperintense lesions (A:axialfluid attenuated inversion recovery [FLAIR] sequence with right hemispheric subcortical lesions) and acute infarcts in left occipital cortex and midbrain (B: axial diffusion weighted imaging).

5 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott 429 myelitis were more likely to have persistent paraplegia, while most with white matter symptoms regained function. Whether these recently described subsets of myelitis hold true in other cohorts remains to be seen. Given the significant association with NMO, all patients with SLE and myelitis should be tested for antibody to aquaporin-4 and, if positive, treated similarly to NMO. The treatment for seronegative myelitis is unclear, though immunomodulation is commonly used, including cyclophosphamide, plasmapheresis, intravenous (IV) immunoglobulin, and rituximab. 39 Estimates of peripheral neuropathy in SLE vary widely ranging from 1% to 13%. 13,40 Among patients with neuropathy, the most common subtypes are polyneuropathy (55%), peripheral mononeuropathy (11%), and cranial neuropathy (12%). 40 Mononeuritis multiplex is less common (estimated at 9%). Affected cranial nerves included III, V, VI, and VII. 40 About 60% of cases of neuropathy in SLE are attributable to SLE; the rest have another cause. 40 Nerve conduction studies typically show axonal neuropathy in the majority of patients. Nerve biopsies often show perineural inflammatory infiltrates. 40 Small fiber neuropathies have also been described in the context of SLE, presenting with pain either in a stocking-and-glove distribution or in a nonlength dependent distribution. 41 There are no controlled trials testing therapy for peripheral neuropathy in the context of SLE. Expert recommendations include use of glucocorticoids alone or in combination with IV immunoglobulin, plasma exchange, and rituximab. 31 Response rates with these therapies are estimated at 60% to 75%, and the majority of patients have static symptoms. 31 Sjögren Syndrome First described by Henrik Sjögren in 1933, Sjögren syndrome (SS) is characterized clinically by sicca syndrome (dry mouth and dry eyes) and pathologically by focal lymphocytic infiltration of exocrine glands. 42,43 Sjögren syndrome most commonly afflicts postmenopausal women. The average age of diagnosis for primary SS is 55 years with an estimated ninefold to 20-fold predominance of women over men. 44,45 The pathogenesis of SS remains unclear. Several factors of uncertain individual significance have been implicated in the pathogenesis of SS, including specific HLA class II alleles, estrogen deficiency, epithelial cell dysfunction, and environmental factors such as Epstein-Barr virus (EBV) and coxsackie virus infections. 44,46 Among exocrine glands, the salivary and lacrimal glands are most frequently affected, and show infiltration with CD4þ T cells and foci of plasma cells and B cells, which can form ectopic germinal centers. 47,48 These germinal centers, present in 17% to 28% of salivary gland biopsies, are believed to be the site of antibody production leading to observed laboratory findings including autoantibodies, hypergammaglobulinemia, and elevated titers of rheumatoid factor (RF). 44,47,48 The autoantibodies associated with SS are anti-ro/ssa and anti-la/ssb, with estimated sensitivities of 52% and 34%, respectively, for primary SS. 49 Anti-Ro/SSA is less specific for Sjögren syndrome and can be found in patients with other autoimmune disorders, such as cutaneous lupus and neonatal lupus and congenital heart block. 50 However, the presence of anti-la/ssb is felt to be more specific for SS even if occurring within the context of other autoimmune disorders. 50 Other antibodies associated with Sjögren syndrome include antinuclear antibodies and cryoglobulins consisting of monoclonal IgMκ immunoglobulins. 50 The American European consensus diagnostic criteria for primary SS assign primacy to the clinical symptoms of dry eyes and dry mouth. 42 The diagnostic criteria require four out of the following six criteria: dry ocular symptoms, dry oral symptoms, objective signs of ocular exocrine dysfunction (positive Schirmer test or Rose Bengal stain), objective signs of salivary gland dysfunction (decreased unstimulated salivary flow, abnormal parotid sialography, or abnormal salivary scintigraphy), histopathology of the salivary gland showing lymphocytic foci, or positive serology for anti-ro/ SSA and/or anti-la/ssb. 42 The diagnosis of primary SS requires positive histopathology findings or abnormal serology. In patients with another underlying disease such as rheumatoid arthritis, secondary SS can be diagnosed by signs and symptoms of sicca syndrome without requiring positive serology or histopathology. 42 Although extraglandular disease does not enter the consensus classification criteria, patients with SS can suffer from a wide array of complications, ranging from polyarticular joint pain and swelling to gastrointestinal malabsorption to tubulointerstitial renal disease to debilitating fatigue (present in almost 50%). 50 The neurologic manifestations of SS span both the central and peripheral nervous systems. The CNS is estimated to be affected in SS anywhere from 2% to 60%, depending on the definition of CNS involvement. 49,51 The lower estimate includes only focal structural changes, while the higher estimate includes functional alterations as well. There is a substantial burden of headache (47%), cognitive dysfunction (44%), and mood disorders (38%). 51,52 Migraine without aura is the most common type of headache reported. 51 Subjective complaints of difficulty with attention and memory are common, and detailed neuropsychological testing in series of patients has shown deficits of subcortical frontal executive function and verbal memory. 51,52 When compared with agematched healthy controls, or controls with rheumatoid arthritis, patients with Sjögren syndrome are also more likely to exhibit symptoms of depression and anxiety. 53,54 However, these data must be interpreted with caution because they are frequently cross-sectional and often do not have a wellmatched control comparator group. Also, whether these neuropsychiatric changes are the result of the underlying autoimmune disease, a reaction to it or a consequence of treatment is unclear. Nonetheless, there is significant and often underrecognized cognitive and psychiatric comorbidity associated with Sjögren syndrome. Besides these functional alterations, SS can lead to focal brain abnormalities. When asymptomatic patients with primary SS undergo brain MRI, white matter lesions are present in 52% to 80% of patients, which is a higher burden than an age-matched control population. 55 Diffusion tensor imaging in apparently asymptomatic patients with SS demonstrates

6 430 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott microstructural injury in multiple major white matter tracts, though the clinical significance is still uncertain. 56 Clinically, SS has been associated with demyelinating disorders, though data exist largely at the case report and series level. The largest case series of relapsing and remitting symptoms includes twelve patients (all meeting diagnostic criteria for primary SS with positive anti-ro/la) presenting with recurrent lesions in the brain, optic nerves (primarily optic neuritis), or spinal cord. 57 In the brain, 10 had lesions adjacent to the third and fourth ventricles, and eight patients had longitudinal lesions from the internal capsule to the brainstem features that are suggestive of NMO. The AQP4 antibody was tested in eight patients and was found in six. 57 It is unclear at this time how many patients with recurrent brain lesions in the context of SS have concurrent NMO and whether they should be treated as such. We would advocate testing for AQP4 antibodies in patients with a suggestive history and MRI ( Fig. 2). In addition to NMO-like lesions, there are rare case reports describing tumefactive, steroid-responsive frontal or parietal white matter lesions In one case, oral prednisone at a dose of 1 mg/kg was used, while IV steroids with subsequent oral prednisone at 1 mg/kg was given in the other. Besides demyelinating lesions, recurrent meningoencephalitis is the other described pattern of brain involvement in primary SS. Data again exist at the case report and series level. The largest case series describes five patients with meningoencephalitis, four of whom had recurrent episodes. 61 All of these patients presented with fever, myalgias, meningismus, and delirium. Recurrence occurred with time intervals ranging from 1 week to 40 months. Cerebrospinal fluid typically shows leukocytosis (ranging from cells/μl withvariable neutrophilic or lymphocytic predominance), mildly elevated protein, and an elevated CSF IgG index. A brain MRI obtained on a patient suffering from one of these episodes showed reversible cortical and subcortical T2 hyperintensities. 62 The pathophysiology of meningoencephalitis is unclear, though vasculitis has been suggested. Three of the five patients in the series mentioned above underwent biopsies of skin or muscle, showing concurrent vasculitis in the walls Fig. 2 Longitudinal dorsal midbrain and pontine lesion in a patient with Sjögren syndrome suggestive of neuromyelitis optica. of veins, arterioles, and small arteries, though diagnostic cerebral angiogram failed to show suggestive vascular changes (no brain biopsies were performed). 61 A separate series of recurrent meningoencephalitis cases described intracranial angiographic changes suggestive of vasculopathy and biopsies consistent with vasculitis. 63 On the other hand, an autopsy on a patient suffering from meningoencephalitis showed inflammatory panencephalitis without arteritis. 64 The presence of anti-ro/ssa has been associated with more severe CNS disease. 63 In terms of treatment, these episodes often resolve spontaneously surprisingly without treatment though oral prednisone at doses from 40 to 60 mg daily have also been used. 61,62,64 Sjögren syndrome is also associated with transverse myelitis, which is frequently longitudinally extensive (greater than three vertebral segments), recurrent, and located in the cervical spinal cord, unlike idiopathic transverse myelitis, which is most often located in the thoracic spinal cord. 65 Many patients with longitudinally extensive myelitis and SS meet criteria for NMO and test positive for AQP4 antibody. In a review of published cases of longitudinally extensive myelitis associated with SS, approximately 89% (17 of 19 patients) had positive AQP4 antibody. 66 Patients with SS and AQP4 antibody behave like patients with conventional NMO in terms of relapse frequency and imaging findings in the brain and spine. 67 In the acute phase for myelitis, IV corticosteroids are the first-line treatment, with consideration of plasma exchange or cyclophosphamide for patients with refractory symptoms. 67 For patients positive for AQP4 antibodies, rituximab is usually administered, though the combination of azathioprine and steroids has also been used. 67 Although CNS complications from SS are being increasingly appreciated, ever since Attwood in 1961 described a patient with SS suffering from multiple cranial neuropathies, peripheral neuropathy has been the commonly associated neurologic complication of SS. 43 The estimated prevalence of neuropathy ranges anywhere from 2% to 64% depending on the diagnostic criteria for SS, referral biases, definition of peripheral neuropathy, and use of electrodiagnostic criteria. 68 Principally, there have been three identified patterns of neuropathy in SS: pure sensory, symmetric sensorimotor axonal polyneuropathy, and less frequent subtypes such as demyelinating neuropathy or multiple mononeuropathy. Pure sensory neuropathy constitutes approximately 25% to 60% of cases of neuropathy. 69,70 The pure sensory neuropathy can either take the form of sensory ataxic neuropathy characterized by non-length dependent loss of joint position sense, or present as a painful distal neuropathy with relatively preserved joint position sense. Sensory ataxic neuropathy often starts with asymmetric paresthesias in the digits of the foot or hand and progresses over the space of months to years to include the limbs, trunk, and face. 69,70 The subjective sensory symptoms can remain asymmetric or multifocal. The initial symptoms of neuropathy often precede the diagnosis of primary Sjögren syndrome by years. 70 On examination, patients frequently have a positive Romberg sign, generalized areflexia, and sensory ataxia while walking. Electrodiagnostic studies are consistent with a

7 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott 431 sensory ganglionopathy nerve conduction studies show preserved compound muscle action potentials (CMAPs) with absent or markedly low amplitude sensory nerve action potentials (SNAPs). 69 Both sensory and muscle nerve conduction velocities are typically preserved. Somatosensory evoked potentials can be absent. 69 Cerebrospinal fluid typically shows normal to mildly elevated protein without pleocytosis. 71 Serology is usually not helpful with estimated sensitivities of 53% and 11% for anti-ro/ssa and anti-la/ssb, respectively, when tested in patients with concurrent sensory ataxia and Sjögren syndrome. 67 In contrast, the Schirmer test is estimated to have high sensitivity (perhaps as high as 90%) for detecting Sjögren syndrome in patients with sensory ataxia. 67 Although more invasive, salivary gland biopsy is often positive as well. 67 On MRI of the spine, T2-weighted images may reveal hyperintensities in the dorsal columns, thought to be secondary to sensory ganglia neuron injury and axonal degeneration. 68 Peripheral nerve biopsies typically show marked decrease in the number of large myelinated fibers and a milder decrease in other types of fibers. 69 Biopsies can also show epineural and perivascular inflammation, with the less frequent finding of chronic vasculitis of arterioles in the epineural space. 69 Consistent with the electrodiagnostic localization, biopsy of the sensory ganglion often reveals a marked mononuclear cell infiltrate with neuronal cell death. 71 The other form of pure sensory presentation is painful sensory neuropathy. The typical clinical presentation is asymmetric pain with decreased temperature sensation in the distal extremities, progressing over the space of months and years to more proximal regions, including the trunk and the face. 69 There is relatively preserved deep position sense and reflexes and consequent lack of sensory ataxia. The presentation, however, can vary with more rapid progression or nonlength dependent painful dyesthesias. 69,72 The unmyelinated and lightly myelinated fibers are primarily affected in painful neuropathy. Hence, conventional tests for detecting neuropathy, such as a nerve conduction study, can be normal. Patients often require a skin biopsy from an affected region to evaluate intraepidermal nerve fiber density, which is decreased in patients with small fiber neuropathy. 72 Sural nerve biopsies typically show a marked reduction in the number of small fibers. 69 Magnetic resonance imaging of the spinal cord is usually normal. As in patients with sensory ataxia, serological testing is often unhelpful because of estimated sensitivities of 39% and 17% for anti-ro/ssa and anti- La/SSB, respectively. 67 The Schirmer test and lip salivary gland biopsy are positive in the majority of patients. 67 The pathophysiology driving the degeneration of the small fibers remains unclear. The other major form of neuropathy is mixed sensorimotor polyneuropathy. Although the prevalence estimates vary widely, sensorimotor neuropathy is likely as common as pure sensory neuropathy. 68,70 Typically, there is a slowly progressive distal symmetric sensory loss accompanied often by distal weakness. The distal reflexes are reduced, and nerve conduction studies show axonal neuropathy affecting both sensory and motor fibers. 68 Compared with patients with pure sensory neuropathy, sensorimotor neuropathy is associated with more severe extraglandular disease, low C4 complement levels, and cryoglobulinemia. 68 The few reports of nerve biopsies describe epineural and perivascular lymphocytic infiltrates. 70,71 The distal symmetric nature of the disease is thought to be indicative of an axonal pathology rather than ganglionic disease, which would be expected to be nonlength dependent. Other types of neuropathies associated with Sjögren syndrome include multiple cranial neuropathies, multiple mononeuropathies, demyelinating neuropathy, polyradiculoneuropathy, or a mixture of these different types in a specific patient. 68 Among cranial nerves, trigeminal neuropathy is the most common. 73 There can be autonomic involvement in addition to any of the neuropathies, presenting as sweating abnormalities, voiding dysfunction, diarrhea/constipation, or abnormal pupils (such as Adie pupils). 69 There are no randomized blinded trials establishing preferred treatment for patients with Sjögren-related neuropathy. Treatment generally focuses on ameliorating symptoms and modifying underlying SS disease activity. For symptomatic control, neuropathic pain relief is achieved with drugs such as gabapentin, pregabalin, tricyclic antidepressants, duloxetine, and topical lidocaine. A wide range of diseasemodifying drugs have been tried in SS-related neuropathy, including IV immunoglobulin (IVIg), corticosteroids, plasmapheresis, rituximab, and infliximab. 69,74 76 In retrospective small case series, corticosteroids and IVIg achieve about a 30% to 40% response rate. 69 Multiple mononeuropathies appears to have the best response to corticosteroids, while painful neuropathy responds well to IVIg. 69 These data though are derived from case series that are too small to permit definitive recommendations. Infliximab, rituximab, and plasmapheresis have all also been used successfully to treat SS neuropathy The choice of agent depends upon the patient s comorbidities and preferences as well as drug cost and availability. Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder characterized clinically by synovitis and erosive arthritis. The disease is more prevalent in Europe and North America and occurs three times more frequently in women compared with men. 77 About 0.5 to 1.0% of adults are estimated to suffer from rheumatoid arthritis. 77 The etiology of rheumatoid arthritis remains unclear. The primary clinical finding of synovitis has pathologic correlates of increased synovial vascularity, cellular hyperplasia (including pannus formation), and inflammatory infiltrates predominantly of CD4þ Tcells. 78 The intense synovial inflammation produces cytokines sustaining the disease (in particular IL-1, IL-6, and TNF-α) and stimulates B cells to produce immunoglobulins. 78 Although RA can be associated with multiple autoantibodies, particular antibodies of diagnostic utility are rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA). Rheumatoid factor is an antibody directed against the Fc region of immunoglobulin G (IgG). Rheumatoid factor can

8 432 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott itself be of IgG, IgM, or IgA isotype, though IgM RF has been studied most and is part of the official diagnostic criteria. 79 The estimated sensitivity and specificity for IgM RF for RA are 67% and 79%, respectively, with sensitivity decreasing to approximately 56% in early disease (less than 2 years in duration). 80,81 Rheumatoid factor is not specific and can be found in healthy elderly people, other autoimmune conditions such as cryoglobulinemia, and infections such as hepatitis C or subacute bacterial endocarditis. Anticitrullinated peptide antibodies target a variety of proteins that have undergone posttranslational modification by citrullination. The sensitivity and specificity for ACPA antibodies are estimated to be 67% and 96%, respectively, with a sensitivity of 57% in early disease. 81 Thus, RA cannot be ruled out on the basis of serology findings, though the presence of ACPA significantly increases the likelihood of disease. Rheumatoid arthritis classically presents with symmetric polyarthritis, particularly of the hands, with prolonged morning stiffness and joint erosion in X-ray imaging. This conception was codified by the widely adopted long-standing 1987 ACR criteria for RA, which required at least four of the signs/ symptoms of morning stiffness, arthritis of three or more joints, arthritis of hand joints, symmetric arthritis, rheumatoid nodules, positive rheumatoid factor, or suggestive radiographic changes. 82 These criteria proved useful to identify patients with established disease, but not those with early disease who might benefit from disease-modifying therapy. Consequently, in 2010, the criteria were revised to be more sensitive for early changes ( Table 3). 79 Although the clinical parts of the diagnostic criteria focus exclusively on joint disease, patients with RA can have several extra-articular disease manifestations, including pulmonary, ocular, cardiac, and neurologic involvement. Inflammatory CNS involvement in RA is infrequent, and data exist primarily at the case series and report level. The brain can be affected by rheumatoid meningitis or vasculitis. Rheumatoid meningitis is a rare entity marked pathologically by lymphocytic infiltration of the meninges, particularly of the dura. 83,84 Examination of the meninges can show rheumatoid nodules. 84 Although the pathology is in the meninges, clinical presentation often includes parenchymal dysfunction. Abrupt stroke-like episodes with fluctuating hemiparesis have been described without scalp EEG evidence of seizures. 83 Other presentations include cranial neuropathies and seizures. 85 Associated headaches range from mild to very severe. Cerebrospinal fluid analysis typically shows a mononuclear cell predominant pleocytosis (usually mild, < 100 cells/μl), normal to mildly elevated protein, and low to normal glucose. 83,84,86 Rheumatoid factor may be present in the CSF and is felt to be specific for rheumatoid meningitis, though data primarily come from case reports. 86 Typical MRI findings include impressive pachymeningeal enhancement and thickening along with leptomeningeal fluid attenuated inversion recovery (FLAIR) hyperintensities and contrast enhancement. 83,84 The EEG can range from normal to mild nonspecific slowing.incase reports, rheumatoid meningitis has responded to treatment with high-dose methylprednisolone. 83 Table 3 Classification criteria for rheumatoid arthritis (score of 6 points) Joint symptoms One large joint large joints small joints small joints 3 > 10 joints (including small joint) 5 Serology Negative RF and ACPA 0 Low-positive RF or ACPA a 2 High-positive RF or ACPA a 3 Inflammatory markers Normal CRP and ESR 0 Elevated CRP or ESR 1 Symptom duration < 6wk 0 > 6wk 1 Abbreviations: ACPA, anticitrullinated peptide antibodies; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor. a Low-positive refers to less than 3 times the upper limit of normal while high-positive is greater than this threshold. Vasculitis of the CNS with RA is rare and typically affects small caliber arteries. Pathological findings include intimal proliferation, fibrinoid necrosis, and thickening of arteries and veins with mononuclear cell cuffing. 87 The vasculitis can affect the meninges, gray matter, or white matter, and can occur either isolated to the CNS or as part of systemic involvement. 87,88 The clinical presentation is remarkably varied, ranging from acute to subacute onset of confusion, paresis, seizure, ataxia, cranial neuropathies, or visual dysfunction Laboratory abnormalities include elevated inflammatory markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). 89,90 Cerebrospinal fluid analysis does not reliably show pleocytosis and cannot be used to exclude vasculitis. 87,90 Because small caliber arteries are affected, conventional angiography often fails to show stenosis or beading suggestive of vasculopathy. 90 Brain MRI typically shows T2 hyperintensities in the subcortical and periventricular white matter. 88,89,91 Neither clinical history nor routine laboratory and radiological investigations are sensitive or specific enough to either diagnose or exclude small vessel RA-associated vasculitis. Definitive diagnosis still relies on pathological examination of tissue. The optimal approach to treatment remains unclear, but usually includes high-dose corticosteroids sometimes given in combination with additional immunosuppressive agents such as cyclophosphamide Overall, the incidence of vasculitis associated with RA has decreased by as much as four- to fivefold compared with the 1980s, suggesting that effective treatment of RA with disease-modifying agents may be protective. 92

9 Systemic Lupus Erythematosus, Sjögren Syndrome, and Rheumatoid Arthritis Bhattacharyya, Helfgott 433 Compared with inflammatory diseases of the brain, cervical spine instability with RA is a much more common complication. Pathologically, RA causes inflammation in the synovial joints, particularly of the upper cervical spine. The etiology of the tropism within the spinal column remains unclear, though a possible explanation is that the occiput C1 and C1 C2 joints are exclusively synovial without intervertebral disks like other vertebral segments. 93 The synovial inflammation leads to bony erosion, ligamentous destruction, and pannus formation, which all contribute to structural instability of the spinal column and consequent compression of the spinal cord or vertebral arteries. 94 There are three commonly observed patterns of upper cervical spine instability in RA. The most common pattern, accounting for approximately 65% of RA cervical spine changes, is atlantoaxial subluxation, characterized by instability of the joint between the atlas (C1) and axis (C2) in the axial plane. 93 Using the axis as reference, the atlas can dislocate anteriorly (most common direction of horizontal dislocation), laterally, or posteriorly (least common direction, but carrying the most direct risk of spinal cord compression). Besides atlantoaxial dislocation, the dens can also migrate upward into the foramen magnum (also known as cranial settling), accounting for approximately 20% of cervical spine complications. 93 The superior migration of the dens can result in compression of the upper cervical spinal cord or lower brainstem ( Fig. 3). The third commonly seen pattern is subaxial subluxation, accounting for 15% to 25% of cervical spine involvement. 93 This pattern is defined by variable subluxation of cervical vertebral segments below the C2 level, often resulting in a stepladder deformity when multiple levels are involved ( Fig. 4). Patients often have a combination of these patterns. Common clinical symptoms include neck pain (present in 65% of patients with RA) and C2 radiculopathy, which can result in occipital headache or ear pain when involving the auricular branch. 95 More concerning symptoms are those of upper cervical myelopathy, such as difficulty walking, numbness, hyperreflexia, or spasticity. When there is compression of vertebral arteries, signs or symptoms of vertebrobasilar insufficiency can also be present. Many more patients have radiographic evidence of cervical spine disease than have clinical symptoms of myelopathy. The technique used to evaluate the spine affects the estimated prevalence of disease as well. In a series of 40 consecutive patients with RA who underwent both X-ray and MRI, cervical spine disease was noted in 40% of X-rays, but in 70% of cervical spine MRIs. 95 Despite the high prevalence of disease on MRI, myelopathic symptoms were present in only 22% of patients. 95 Among patients with RA and radiographic spine disease, it is uncertain who will require eventual surgical intervention for myelopathy or need regular surveillance. In one long-term case series (at least 10 years of follow-up) of 41 patients with atlantoaxial subluxation, 60% had nonprogressive spine disease while approximately 27% showed progression radiographically. 96 During this period, only two patients developed myelopathic symptoms. 96 In another case series that followed patients with RA and neck complaints for Fig. 3 C1 C2 vertical subluxation with the odontoid process indenting the medulla. Fig. 4 Subaxial subluxation at multiple levels most prominently at C5 andc6witha2mmretrolisthesisofc5onc6andheightlossatc5. 5 years, the prevalence of radiographic disease increased from 43% at baseline to 70%. 97 Only 6%, however, required surgical stabilization. 97 Case series on the natural history of cervical spine disease suggest that progressive peripheral disability is a risk factor for the development of progressive spine disease. 98 In an era of more effective disease-modifying therapy, the natural history of radiographic cervical spine disease is even less clear. Patients who show myelopathic signs or symptoms, however, should undergo intervention because the majority will progress to loss of ambulation. 99 In appropriate surgical candidates, the treatment is usually cervical spine decompression and stabilization. 99 Neuropathy in RA is prevalent, but often subclinical. In a recently reported cross-sectional study of 108 patients with RA, 57% had electrodiagnostic evidence of neuropathy, while only approximately 25% had signs or symptoms of neuropathy on clinical examination. 100 Electrophysiologically, the neuropathy is primarily axonal (85%), though demyelinating features can be present. 100 The neuropathy can encompass pure sensory (most common) or sensorimotor modalities. 101 When sural nerve biopsies are performed, the pathology is