NEUROLOGY
Atypical Neurologic Complications in Patients with Primary Sjögren’s Syndrome: Report of 4 Cases Laure Michel, MD,* Frédérique Toulgoat, MD,† Hubert Desal, MD, PhD,† David Axel Laplaud, MD, PhD,* Armelle Magot, MD,‡ Mohamed Hamidou, MD,§ and Sandrine Wiertlewski, MD*
Background: Neurologic involvement occurs in approximately 25% of patients with primary Sjögren’s syndrome. Manifestations are diverse and can affect the entire neuroaxis. Central nervous system dysfunction involves the brain as well as the spinal cord and may recur over time. Due to a variety of presentations, Sjögren’s syndrome with neurologic involvement may be difficult to diagnose. Methods: We report 4 cases of patients with primary Sjögren’s syndrome who presented with atypical neurologic manifestations. Results: The first case describes a patient with a pseudotumoral lesion. The second patient was a 54-year-old woman suffering from a multiple mononeuropathy. The third case describes a 66-year-old man whose primary Sjögren’s syndrome presented as progressive multiple sclerosis, and the fourth case reports a 57-year-old woman patient suffering from myelitis along with progressive cognitive disorders. Conclusions: Neurologic impairment in Sjögren’s syndrome is probably underestimated and the diagnosis is often delayed. Primary Sjögren’s syndrome should be suspected in patients presenting with atypical clinical and radiologic neurologic manifestations. © 2011 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 40:338-342 Keywords: Sjögren’s syndrome, central nervous system, atypical manifestations, autoimmunity, neurologic
S
jögren’s syndrome (SS), first described in 1892, is a chronic autoimmune disease of the exocrine glands characterized by focal lymphocytic infiltration and destruction of these glands. SS is a relatively common disease (the second most frequent systemic disease after rheumatoid arthritis). The population prevalence is about 0.5% to 3%, with a female preponderance. Neurologic complications have been reported in 8% to 70% of SS patients, de-
*Service de Neurologie, Centre Hospitalier Universitaire de Nantes, Hôpital Laennec, Nantes Cedex, France. †Service de Neurophysiologie, Centre Hospitalier Universitaire de Nantes, Hôtel Dieu, Nantes Cedex, France. ‡Service de Neuroradiologie, Centre Hospitalier Universitaire de Nantes, Hopital Laennec, Nantes Cedex, France. §Service de Médecine Interne, Centre Hospitalier Universitaire de Nantes, Hôtel Dieu, Nantes Cedex, France. Address reprint requests to Laure Michel, MD, Department of Neurology, Hôpital Laënnec, CHU de Nantes, 1 Place Alexis Ricordeau, 44093 Nantes, Cedex 1, France. E-mail:
[email protected].
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pending on the study (1-3). Data on involvement of the peripheral nervous system indicate a mean incidence of 15% in patients (2-4). There is no consensus regarding the prevalence of central nervous system (CNS) involvement in SS. In 2002, Garcia-Carrasco and coworkers reported a prevalence of 1% (5), while in 1986 Alexander reported CNS involvement in 20% of patients with primary SS (PSS) (6). CNS manifestations in SS are diverse and span the entire neuroaxis. The variability of the neurologic presentation may considerably delay the diagnosis after the onset of symptoms. However, myelopathy remains the most frequent manifestation (7). Diagnosis of SS requires a set of rigorous clinical and immunologic criteria. Several classifications have been proposed, the most widely used being the European criteria of Vitali (8,9). This classification presents good sensitivity (96.1%) and specificity (94.2%), the most sensitive item being the salivary gland biopsy. Using these criteria, the diagnosis of PSS is certain if the patient presents 4 of the 6 of the items.
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Table 1 Summary of Clinical, Biological, and Radiologic Findings in the 4 Patients Atypical Signs Patient 1 Acute presentation
MRI
CSF
Pseudotumoral lesion
Oligoclonal bands Patient 2 Multiple mononeuropathy Normal Normal Patient 3 Recurrent signs mimicking Multiple T2 hyperintensities — MS in white matter Patient 4 Cognitive impairment Myelitis and a small Oligoclonal cerebral hyperintensity bands
We report 4 patients who fulfilled Vitali’s criteria for PSS and presented atypical neurologic manifestations. (Table 1). CASE REPORTS Patient 1 A 63-year-old right-handed woman was first admitted in September 2002 with a history of subacute right hemiparesis and speech disturbance. She complained of 3 similar episodes of neurologic deficit (characterized by transitory motor aphasia), with a full recovery within a few days, during the previous 2 years. She suffered from Graves-Basedow’s disease, diabetes, and psoariasis. On admission, she had a right hemiparesis associated with Broca’s aphasia; the rest of the examination was normal. Magnetic resonance imaging (MRI) confirmed a large white matter lesion in the left corona radiata. It was associated with other supra- and infratentorial white matter T2-weighted hyperintensities (Fig. 1). A CNS demyelinating disease was suspected. Cerebrospinal fluid (CSF) analysis revealed a pathologic IgG index (0.71) with only 1 band. Laboratory studies revealed the presence of antinuclear antibodies (1:80). The anti-DNA test and tests for anti-SSA/Ro and antiSSB/La were negative; rheumatoid factor, total complement, and serum angiotensin convertase were normal. Human immunodeficiency virus (HIV), herpes simplex virus, and Lyme serologies and the venereal disease research laboratory (VDRL)/treponema pallidum hemagglutination assay (TPHA) test were all negative. Cryoglobulinemia was not detected. Oral and ocular sicca syndrome were suspected from history-taking and confirmed by Schirmer test and labial salivary gland biopsies (Chisholm score greater than 4 –Focus score ⬎1). No clinical evidence of scleroderma, rheumatoid arthritis, or systemic lupus erythematosus was found and PSS was diagnosed based on Vitali’s criteria. Intravenous and oral corticotherapy (1 mg/kg) for 9 months, followed by an immunosuppressive treatment (Plaquenil), improved the patient’s neurologic signs, whereas the MRI lesions remained stable.
Sicca Anti Chisolm’s Vitali Syndrome SSa/SSb Score Criteria Present
Absent
4
4/6
Present Present
Present Absent
4 3
4/6 4/6
Present
Absent
4
3/6
Patient 2 A 54-year-old woman was examined in August 2003 for swallowing and phonation difficulties, which had evolved over the previous 10 years and had recently been accompanied by distal sensory loss and dysesthesia in the right upper limb. Neurologic examination revealed areflexia and sensory loss in the right arm and clinical sensory abnormalities involving all 4 limbs. Nerve conduction studies showed a sensory multiple mononeuropathy with axonal loss predominantly in the right median and ulnar nerves. There was also a lengthdependent axonal sensory neuropathy. Needle electromyography was normal in the right extensor digitorum, abductor pollicis brevis, and extensor digitorum brevis. CSF analysis was normal, without oligoclonal bands. A polyclonal gammapathy (33.5 g/L) was discovered. Spinal cord and cerebral MRI (performed at 2 different times) findings were normal. Laboratory data showed antinuclear antibodies at a titer of 1:1560 and the presence of anti-SSA antibodies. Rheumatoid factor was positive (latex: 160 IU/mL; Waaler-Rose: 64). HIV and hepatitis C virus serologies, and VDRL/TPHA were all negative, and coagulation testings were normal. Complement components (C3, C4, and CH50) were normal and cryoglobulinemia was negative. Questioning the patient revealed sicca syndrome with xerophthalmia and xerostomia during the previous 2 years. Salivary gland biopsies showed a lymphocytic infiltration, scored 4 using Chisholm’s criteria (Focus score ⬎1). Her swallowing difficulties were likely due to the progressive development of the sicca syndrome. Right arm pain was effectively treated with gabapentin. Because of the absence of a motor deficit and the stability of the neuropathy, corticosteroid therapy has not yet been initiated. Patient 3 In 2004, a 66-year-old man consulted for buzzing in his left ear. In 2002, he had presented with vertical diplopia. Cerebral MRI at that time showed supratentorial white matter T2-weighted hyperintensities and a periventricular lesion on the floor of the fourth ventricle. In 2003, he
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Figure 1 Patient 1. (A) Axial cerebral T2-weighted image showing a large hyperintensity in the white matter of the left corona radiata with mass effect. Smaller subcortical hyperintensities are visible on the opposite side. (B) Same level: contrasted T1-weighted image showing an incomplete ring-shaped enhancement of the periphery of the lesion with a hypointense center. (C) Sagittal FLAIR image showing frontal mass with concentric ring-like hyperintense areas.
had presented with dizziness and left facial palsy, which regressed spontaneously within 10 days. Neurologic examination revealed a moderate lateral nystagmus, diplopia when the patient looked to the right (abducens nerve palsy), and ataxia of the left leg. He suffered from oral and ocular sicca syndrome for several months. MRI showed brainstem and 20 periventricular white matter T2-weighted hyperintensities, with a pseudotumoral lesion in the atrium of the lateral ventricle. The progressive clinical presentation and the MRI findings led us to suspect progressive multiple sclerosis (MS), but because of the presence of the sicca syndrome, we performed further tests: the Schirmer test revealed xerophthalmia (⬍5 mm on the right and left eye). It had not been possible to perform a CSF analysis in this patient. Antinuclear antibodies and anti-DNA antibodies were negative. Rheumatoid factor and serum angiotensin convertase were absent. HIV and Lyme serologies were negative. Salivary gland biopsy revealed an infiltration of lymphocytic
cells, scored 3 using Chisholm’s criteria (Focus score ⫽ 1). The patient only received symptomatic treatment for the xerophthalmia. Patient 4 A 57-year-old right-handed woman was first admitted in May 2004 with a history of sensory disorders (ataxia and hypoesthesia) in both lower limbs, which had developed over the previous 3 years. She complained of difficulties in climbing stairs, which had begun 1 year before. Neurologic examination found a proximal weakness in the lower limbs. All the symptoms had gradually increased over the previous months. Clinical examination revealed paraparesis (predominating in the right leg) and a motor weakness in the left upper limb. Sensory abnormalities (pinprick and pallesthesia) were identified involving all 4 limbs with a medullary level C8-Th1. Tendon reflexes were brisk except for the left ankle reflex, which was abolished. Plantar responses were present. The
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patient reported memory difficulties and depression, which had begun several months before. Spinal cord MRI revealed a T2-weighted hyperintensity, enhanced with gadolinium, extending from C7 to Th1. Cerebral MRI showed a white matter lesion in the left frontal region. CSF analysis revealed a pathologic IgG index. Antinuclear antibodies SSA/Ro, SSB/La were negative and rheumatoid factor, total complement, and serum angiotensin convertase were all normal. HIV, herpes simplex virus, and human type lymphotropic virus (HTLV) serologies were negative. Antinuclear antibody immunoassay performed 4 years after the beginning of the symptoms was 1/80e without specificity for anti-SSA or anti-SSB. Specific questioning indicated an oral and ocular sicca syndrome but the Schirmer test was negative. Labial salivary gland biopsies had a Chisholm score greater than 4 (Focus score ⬎1). The electromyogram revealed a motor polyneuropathy with axonal loss. Neuropsychologic tests revealed dysexecutive disturbances (with a Trail Making Test lasting 10 minutes). The patient was diagnosed as having probable PSS (Vitali’s criteria 1993) but did not fulfill the criteria of definitive PSS (European criteria 2002). However we retained the PSS diagnosis because of subjective sicca syndrome, labial salivary gland biopsies, classical myelitis, and exclusion of other diagnosis. Intravenous corticotherapy (1.5 g/d for 3 days) followed by oral corticotherapy (1 mg/kg) led to an improvement and stabilization of clinical symptoms and radiologic signs. Dysesthesia were treated successfully with gabapentin (1200 mg/d). The patient’s depression was partially improved by an antidepressant drug (Venlafaxine: 75 mg/d). DISCUSSION All 4 patients fulfilled the criteria for PSS, as proposed by Vitali and coworkers in 1993 (8,9). They presented an atypical clinical onset of the disease or unusual radiologic features, rarely described in the literature. Patient 1 presented acute and recurrent symptoms of aphasia and anarthria, associated with a right hemiparesis, mimicking a vascular stroke. She presented a pseudotumoral lesion on MRI. Typically, brain MRI is abnormal in more than about 70% of PSS patients with neurologic disease (4,6,7,10). The great majority of patients with focal CNS disease exhibit multiple T2-weighted hyperintensities, predominantly in subcortical and periventricular white matter (1,4,6,7,11). These lesions are consistent with micro-infarcts but often cannot be distinguished from demyelinating lesions (such as plaques in MS). According to Alexander and coworkers, MRI is abnormal in about 9% of PSS patients without signs of neurologic lesions or psychiatric disorders (10). It should however be noted that, in a series of 82 patients, Delalande and coworkers described gray matter lesions in the basal ganglia in 17% of cases and in the corpus callosum in 14% (7). Descriptions of pseudotumoral lesions in the literature are
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rare, and hyperintensities are usually less than 1 cm and are often not enhanced with gadolinium. Patient 2 presented with multiple mononeuropathy predominating in the right upper arm. In the case of peripheral nervous system lesions in SS, studies report a predominance of sensory neuropathies with a distal symmetrical pattern (4,7,12,13). In 1999, Govoni and coworkers reported only 1 case of mononeuropathy in a cohort of 87 patients with PSS (4); more recently, Delalande and coworkers described 7 patients with multiple mononeuropathy in a study of 82 SS patients with neurologic manifestations (7). Multiple mononeuropathy is frequently associated with severe systemic complications (cutaneous vasculitis and cryoglobulinaemia) and the onset is generally subacute (7,13). Patient 3 presented with recurrent neurologic episodes regressing spontaneously in a few days or weeks. Clinical presentation, MRI, and CSF analysis strongly mimicked MS. However, the patient’s age and the presence of sicca syndrome made MS unlikely. Among the neurologic forms of SS, between one tenth and one third of cases present as MS (7,14). The neuroradiologic features and serologic and CSF analysis can help to distinguish between these 2 inflammatory diseases. The CSF profile in SS strongly resembles that described in MS patients, but in MS there are multiple bands, and often more than 3, whereas in SS patients 1 or 2 bands can be detected (14). Furthermore, Alexander reported that the bands disappeared in response to corticosteroid therapy in most patients with PSS, contrary to MS (14). Patient 4 presented with progressively worsening cognitive disorders. Two patterns have been described in SS: disorders mimicking Alzheimer’s disease and subcortical disorders (2,6,15). The cognitive impairment is often associated with psychiatric disorders (anxiety and depression). In 20 to 25% of cases, the neuropsychologic test shows attention impairment, anterograde memory impairment, and frontal signs (2). Our patient presented with a subcortical pattern with frontal signs. These symptoms were associated with depression. One of our patients had anti-SSA (Ro) antibodies. The frequency of anti-SSA/Ro or anti-SSB/La antibodies in PSS varies quite considerably from study to study: for example, in 1981, Alexander and coworkers reported positivity for anti-SSA antibodies in 7 of 8 patients with PSS and CNS manifestations, whereas anti-SSB antibodies were detected in only 1 patient (16); in 2004, Delalande and coworkers, in a series of 82 patients, found anti-SSA antibodies in 48% of SS patients with CNS complications (7). The prevalence of these antibodies in PSS patients with CNS dysfunction is lower than in patients without CNS lesions (cerebral angiopathy) (7,11). CNS impairment in SS is probably underestimated and the diagnosis is often delayed. PSS should be suspected in patients presenting with atypical clinical and radiologic CNS manifestations.
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ACKNOWLEDGMENTS We thank Yann Pereon and Pascal Derkinderen for advice and corrections.
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