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Sjogren Syndrome: Neurologic Complications Veronica P Cipriani MD MS ( Dr

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Sjogren syndrome: neurologic complications Veronica P Cipriani MD MS ( Dr. Cipriani of the University of Chicago Medical Center received consulting fees from Genetech as an advisory board participant ) Francesc Graus MD PhD, editor. ( Dr. Graus of the University of Barcelona has no relevant financial relationships to disclose.) Originally released June 28, 2006; last updated June 30, 2018; expires June 30, 2021 Introduction This article includes discussion of the neurologic complications of Sjögren syndrome, Gougerot-Sjögren syndrome, and Sicca complex. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Neurologic manifestations occur in 20% to 27% of patients with Sjögren syndrome, often preceding the diagnosis of this systemic autoimmune disease. The peripheral nervous system, skeletal muscles, and central nervous system may be involved. Sjögren syndrome has been associated with neuromyelitis optica with positive serum aquaporin autoantibody. The symptoms of neurologic Sjögren syndrome may also mimic multiple sclerosis. HTLV-1 infection and vitamin B12 deficiency can complicate Sjögren myeloneuropathies. In this article, the author reviews the clinical presentations and postulated pathogenesis of these complications and offers current treatment recommendations. Key points • Sjögren syndrome is a common autoimmune disease, particularly among postmenopausal women, and it is manifested by dry mouth, dry eyes, fatigue, and arthralgias. • Neurologic symptoms occur in 20% to 27% of patients with Sjögren syndrome due to involvement of cranial nerves (Bell palsy, trigeminal neuralgia, diplopia), peripheral nerves (sensorimotor neuropathies), skeletal muscles (fibromyalgia, polymyositis), and the central nervous system. • Sjögren syndrome can mimic the symptoms and radiographic features of multiple sclerosis. • Sjögren syndrome is closely associated with neuromyelitis optica, a demyelinating disease of the central nervous system caused by antibodies to aquaporin-4 (NMO IgG). • A high index of suspicion is required given the pleomorphic manifestations and the fact that neurologic symptoms often precede the clinical diagnosis of Sjögren syndrome. Historical note and terminology In 1933, Henrik Sjögren described the association of keratoconjunctivitis sicca (filamentary keratitis) with arthritis (Sjögren 1933). Morgan and Castleman noted the histopathological commonality between the keratitis described by Sjögren and the glandular enlargement described by Mikulicz (Morgan and Castleman 1953; Mikulicz 1892). By 1973, the term “Sjögren syndrome” became widely accepted as these disorders were considered variants of the same process (Mason et al 1973). The name Gougerot-Sjögren syndrome is commonly used in the French literature (de Seze et al 2005) given that Henry Gougerot first reported, in Paris, the typical symptoms of xerostomia and xerophthalmia due to atrophy of salivary and lachrymal glands (Gougerot 1925). Clinical manifestations Presentation and course Sjögren syndrome is a chronic, multisystem autoimmune disorder. Primary Sjögren syndrome presents as dry eye and dry mouth secondary to autoimmune dysfunction of the exocrine glands. In secondary Sjögren syndrome, these manifestations occur in the presence of another autoimmune disease. Overall, there is no increased mortality in patients with primary Sjögren syndrome (Martens et al 1999). Systemic involvement in Sjögren syndrome includes: chronic fatigue affecting as many as 50% of patients; arthralgias present in 53%; esophageal dysmotility in 36%; hematological abnormalities including anemia and leukopenia (33%), increased erythrocyte sedimentation rate (22%), hypergammaglobulinemia (22%); inflammatory myalgias (22%); and skin lesions such as “burning skin” (18%), cutaneous vasculitis (10%), alopecia, vitiligo, papular lesions, and annular erythema (Kassan and Moutsopoulos 2004; Ramos-Casals et al 2005b). Lymphoma may develop in 5% to 7% of patients with primary Sjögren syndrome, often associated with cutaneous purpura (Voulgarelis et al 1999). Less common manifestations include lung involvement with lymphocytic alveolitis, lymphocytic interstitial pneumonitis, fibrosis, pulmonary pseudolymphoma, and pulmonary hypertension. Other less common manifestations include pericarditis, vascular lesions manifested by Raynaud phenomenon, renal tubular lesions, interstitial nephritis and glomerulonephritis, malabsorption due to lymphocytic infiltrates of the intestine, mild pancreatitis, and hepatitis. Exclusion criteria for the diagnosis of Sjögren syndrome include infections with HIV, HTLV-1, or hepatitis C virus (Ramos-Casals et al 2005a). Table 1 summarizes the current consensus criteria for the diagnosis of Sjögren syndrome. Table 1a. Revised International Classification Criteria for Sjögren Syndrome I. Ocular symptoms: A positive response to at least 1 of 3 validated questions: 1. Have you had daily, persistent, troublesome dry eyes for more than 3 months? 2. Do you have a recurrent sensation of sand or gravel in the eyes? 3. Do you use tear substitutes more than 3 times a day? II. Oral symptoms: A positive response to at least 1 of 3 validated questions: 1. Have you had a daily feeling of dry mouth for more than 3 months? 2. Have you had recurrent or persistently swollen salivary glands as an adult? 3. Do you frequently drink liquids to aid in swallowing dry foods? III. Ocular signs: Objective evidence of ocular involvement defined as a positive result to at least 1 of the following 2 tests: 1. Schirmer's test, performed without anesthesia (≥ 5 mm in 5 min) 2. Rose Bengal score or other ocular dye score (≥ 4 according to van Bijsterveld's scoring system) IV. Histopathology: Focal lymphocytic sialoadenitis in minor salivary glands, with a focus score of 1. V. Salivary gland involvement: Objective evidence of salivary gland involvement defined by a positive result to at least 1 of the following diagnostic tests: 1. Unstimulated whole salivary flow (≤ 1.5 mL in 15 min) 2. Parotid sialography showing the presence of diffuse sialectasis 3. Salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer VI. Autoantibodies - presence in the serum of the following autoantibodies: 1. Antibodies to Ro/SS-A or La/SS-B antigens, or both Table 1b. Revised Rules for Classification Exclusion criteria • Past head and neck radiation treatment • Hepatitis C infection • AIDS • Preexisting lymphoma • Sarcoidosis • Graft-versus-host disease • Use of anticholinergic drugs For Primary Sjögren syndrome a. Any 4 of the 6 items, as long as item IV (histopathology) or VI (serology) is positive b. Any 3 of the 4 objective criteria items (items III, IV, V, VI). For Secondary Sjögren syndrome In patients with a potentially associated disease (for example, another well-defined connective tissue disease), the presence of item I or item II plus any 2 from among items III, IV, and V may be considered as indicative of secondary Sjögren syndrome (Vitali et al 2002). The American College of Rheumatology, in consensus with the Sjögren s International Collaborative Clinical Alliance (SICCA) investigators, proposed new provisional criteria to improve the criteria s specificity for enrollment in trials for biologic agents and other therapies. These criteria require at least 2 of the following 3 findings: 1. Positive serum anti-SSA and/or anti-SSB or positive rheumatoid factors and ANA ≥ 1:320 2. Ocular staining score ≥ 3 3. Presence of focal lymphocytic sialadenitis with focus score ≥ 1 focus/4mm2 in labial salivary gland biopsies. These criteria were found to have a sensitivity of 93% and a specificity of 95% (Shiboski et al 2012). A number of neurologic manifestations have been reported in about 20% of patients with Sjögren syndrome (range 6% to 70%) (Lafitte et al 2001; Delalande et al 2004; de Seze et al 2005; Mori et al 2005). In most cases, neurologic symptoms precede the diagnosis (Barendregt et al 2001; Mori et al 2005). Historically, the most common symptoms include involvement of the peripheral nervous system and skeletal muscles. More recent reports emphasize the involvement of the central nervous system that went underrecognized in the past, often mimicking the clinical symptoms of primary progressive or relapsing-remitting multiple sclerosis. An observational, single center study from Italy found that 5.8% of patients presenting to rheumatology clinic with a diagnosis of Sjögren syndrome had central nervous system involvement (Massara et al 2010). Table 2 lists some of the most common neurologic manifestations of primary Sjögren syndrome. Table 2. Neurologic Manifestations of Primary Sjögren Syndrome PNS manifestations Neuropathies Painful sensory neuropathy Sensorimotor (axonal) polyneuropathy Sensory ataxic ganglionopathy Radiculoneuropathy (demyelinating polyradiculoneuropathy) Vasculitic neuropathy Mononeuritis multiplex Entrapment neuropathies Multiple cranial neuropathies Trigeminal neuralgia Sensorineural hearing loss Autonomic neuropathy Motor neuron disease (rare) CNS manifestations Focal brain lesions Stroke with motor or sensory deficits, associated with CNS vasculitis Aphasia or dysarthria Focal epilepsy CNS T-cell lymphoma Movement disorders and cerebellar syndromes Parkinsonism Chorea Brainstem syndromes Central pontine myelinolysis (rare) Painful tonic or dystonic spasms Cerebellar atrophy Cerebellar ataxia Diffuse nonfocal symptoms Acute or subacute encephalopathy White matter abnormalities
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