Primary Sjögren’s Syndrome Presenting as Recurrent Ischemic Strokes

Abstract

Primary Sjogren’s Syndrome (PSS) is an autoimmune exocrinopathy, with protean manifestations affecting multiple organ systems. Neurological manifestations are documented in about 20% of PSS cohorts in literature, with peripheral manifestations being commoner. Central nervous system manifestations of PSS (CNS-SS) encompass ischemic strokes, demyelinating lesions, aseptic meningitis, encephalitis, cerebellar ataxia, cognitive impairment and movement disorders. Ischemic stroke as presenting manifestation of PSS is extremely rare. We hereby describe a 50-year-old male, who presented for evaluation of 2 episodes of discrete focal neurological deficits over a duration of 6 weeks, with neuro-imaging findings revealing evidence of acute-subacute bihemispheric infarcts. Further evaluation revealed evidence of strongly positive anti phospholipid antibodies (aPL), indirect immunofluorescence antinuclear antibody (IIF-ANA), anti Sjögren’s syndrome-A (SS-A/Ro) and anti-Ribonuclear protein (RNP) antibodies, with histopathological evidence of periductal and periacinar lymphocytic infiltration as well as acinar atrophy and interstitial fibrosis of minor salivary glands on lip biopsy, consistent with a diagnosis of Sjögren’s syndrome, constituting a diagnosis of Antiphospholipid syndrome (APS) associated with PSS.

Introduction

Primary Sjögren’s syndrome (PSS) is an autoimmune exocrinopathy characterized by inflammatory lymphocytic infiltration of the exocrine glands (predominantly salivary and lacrimal glands). ¹ However, PSS is well documented to affect other major organ systems of the body, thereby contributing to neurological, nephrological, hematological as well as pulmonary manifestations.^1,2 Neurological manifestations of PSS vary in prevalence between 8%-49%, with peripheral nervous system involvement being commoner. ² We hereby describe a case of recurrent ischemic strokes with strongly positive anti phospholipid antibodies (aPL), indirect immunofluorescence antinuclear antibody (IIF-ANA), anti Sjögren’s syndrome-A (SS-A/Ro), and anti-Ribonuclear protein (RNP) antibodies. Lip biopsy showed histopathological evidence of dense perivascular as well as periacinar lymphocytic infiltrates, acinar atrophy and interstitial fibrosis of minor salivary glands, consistent with a diagnosis of Sjögren’s syndrome.

Case Description

A 50-year-old Indian man with background history of systemic hypertension, was transferred to our hospital for evaluation of 2 discrete episodes of focal neurological deficits over the past 6 weeks. First episode was characterized by acute onset of weakness of left lower extremity (distal > proximal) which improved over a course of 1 week. This was followed a month later by acute onset of weakness involving the right upper and lower limbs. He denied any other neurological symptoms. Review of systems was notable for ocular dryness, easy fatigability and unintentional weight loss of about 5 kg over the past 6 months. He did not complain of any recurrent joint pain, swelling or early morning stiffness. No history suggestive of malar rashes, recurrent oral/genital ulcers, pleuritic chest pain or Raynaud’s phenomenon was noted. Physical exam revealed subtle upper motor neuron signs in the form of loss of dexterity involving the right hand and upgoing plantar response on the right side. Hematology evaluation showed glycosylated hemoglobin (HbA1c) of 5.0 (reference range 4.8 to 5.6%), normal total cholesterol with elevated low-density lipoprotein (2.71 mmol/L with normal less than 2.59 mmol/L). He had elevated erythrocyte sedimentation rate (ESR) of 51 mm/first hour [reference range less than 20], positive IIF-ANA (homogenous pattern of 1:1280 dilution), positive anti SS-A/Ro (>8.0 AI) [reference range 0-0.9], positive anti-RNP antibody (2.8; range of 0-0.9 AI), a low titer positive Rheumatoid Factor (RF) (24 IU/ml; reference range <13) and positive anti-CCP (340 IU/ml; reference range< 16 IU/ml). His complement C4 levels were low (12; reference range of 14-44 mg/dl) with polyclonal hypergammaglobulinemia on electrophoresis (Ig G: 3306; reference range of 700-1600 mg/dl). He had strongly positive IgG anti-cardiolipin (aCL) antibodies (>160; reference range of 0-19.9 GPL U/ml) and IgG anti-beta2glycoprotein 1 (ab2GPI) antibodies (>160; range of 0-19.9 U/ml), with otherwise unremarkable antiphospholipid profile including IgM aCL, ab2GPI and lupus anticoagulant (LA). Cerebrospinal fluid (CSF) examination revealed 10 cells per microliter (100% lymphocytes), with normal protein and sugar with negative infective panel (including mycobacterium tuberculosis PCR). Neuroimaging studies showed evidence of bi-hemispheric acute-subacute ischemic infarcts involving the anterior circulation (Figure 1A-C). MR Angiography followed by invasive cerebral angiography revealed evidence of bilateral supraclinoid ICA stenosis (approximately 50% on left side and less than 20% on right side) (Figure 2A-C) with normal cervical carotid vasculature. There was no evidence of ulceration or flow limitation across the supraclinoid stenotic lesions bilaterally. MR Vessel wall imaging demonstrated focal eccentric thickening and enhancement of the supraclinoid ICA lesions visualized on luminal vascular studies, suggestive of atherosclerotic disease. No tell-tale evidence of large or medium vessel vasculitis was noted on imaging studies. Cardiac evaluation with transthoracic echocardiogram and 72-hour cardiac telemetry was normal. Nerve conduction study did not show any evidence of neuropathy. Ophthalmology evaluation revealed evidence of severe xerostomia with reduction of tear film break up time to less than 2 seconds. Histopathological evaluation of the lip biopsy specimen showed periductal and periacinar lymphocytic infiltration, with acinar atrophy and interstitial fibrosis of minor salivary glands (Figure 3A-B), consistent with a diagnosis of Sjögren’s syndrome.

Figure 1.

A: Diffusion weighted sequences (DWI) of baseline MRI brain done during the first episode of weakness, at outside facility revealing acute infarct in the anterior right frontal lobe and punctate acute infarct in the left frontal lobe. B: T2 Fluid attenuated inversion recovery images (FLAIR) reveal hyperintensities involving bilateral frontoparietal regions. C: Follow up MRI Brain done 4 weeks later at the time of second episode of focal deficit, revealed acute infarcts of varying ages on the left frontoparietal region on DWI sequences.

Figure 2.

(A) Non-contrast MR Angiography of intracerebral vessels revealed bilateral supraclinoid ICA stenosis (left more than right; white arrow). However invasive cerebral angiography revealed less than 20% narrowing on the coronal projection of right supraclinoid ICA (B). Coronal images of left ICA injection (C) showed approximately 50% narrowing of the left supraclinoid ICA (white arrow). No evidence of vasculitis noted on invasive cerebral angiography studies.

Figure 3.

A: Low power magnification hematoxylin and eosin stained (H & E) image of lip biopsy specimen depicting perivascular as well as periacinar lymphocytic infiltrates (thick arrow), acinar atrophy and interstitial fibrosis (arrow head) of minor salivary glands. B: High power magnification of the same image demonstrating extensive lymphocytic and plasma cell infiltrate (thick arrow).

Discussion

Neurological manifestations occur in about 20% of patients with PSS (range 8%-49%), with central nervous system (CNS) involvement (CNS-SS) rarely being the index event preceding the diagnosis of PSS. ² The spectrum of CNS-SS can encompass ischemic strokes, focal demyelinating lesions mimicking multiple sclerosis/NMO, aseptic meningitis, encephalitis, cerebellar ataxia, cognitive impairment and movement disorders like chorea secondary to involvement of basal ganglia.^1-3 The postulated pathogenic mechanisms for these conditions include an immune mediated vasculopathy, demyelination or less frequently small vessel vasculitis. ² The presence of anti SS-A/Ro antibodies, concomitant pulmonary involvement, low C4 complement levels and long duration of disease increases the risk of CNS-SS.^2,4 Those with anti SS-A/Ro antibodies are likely to have more severe and extensive CNS disease. ⁴ Earliest documentation of PSS presenting as ischemic stroke in literature was in 1994 ³ but subsequent reports have not found an increased risk of ischemic stroke in PSS as compared to age/gender/co-morbidity matched controls. ² However, the presence of atypical antibodies like aPL (including aCL, ab2GP1 and LA) seen in 9%-34% of PSS have been associated, even though infrequently with increased risk of thromboembolic vascular events, with the greatest strength of evidence being for LA.^5-7 Despite the prevalence of aPL antibodies in up to 30% in PSS cohort, many studies have pointed out a much lower incidence of antiphospholipid antibody syndrome (aPS), with less than 1 in 10 PSS subjects with positive aPL antibodies eventually meeting the diagnostic criteria of aPS. This is contrast to other autoimmune diseases like SLE where the prevalence of aPS is much higher. ⁷ Our patient had strongly positive anti SS-A antibodies along with low complement C4 levels contributing to a higher chance for CNS-SS. The presence of positive IgG aCL and IgG ab2GP1 antibodies in very high titres increased the odds of developing recurrent ischemic thromboembolic events. Even though the CSF evaluation revealed evidence of mononuclear pleocytosis, no strong evidence of CNS vasculitis was evident on catheter cerebral angiography, while taking out in to account the limitation of the latter imaging tool in evaluating the small calibre vessels. In addition, imaging features on MR Vessel wall imaging supported intracranial atherosclerotic disease of the supraclinoid ICA stenosis rather than large vessel vasculitis. The patient refused to undergo leptomeningeal biopsy to rule out concomitant CNS Vasculitis. On account of recurrent ischemic strokes in the background of underlying autoimmune disease (PSS), strongly positive IgG aCL and ab2GPI, with high possibility of evolution to aPS, we started the patient on therapeutic anticoagulation with oral Warfarin (therapeutic target INR between 2 and 3), ocular lubricants for xerophthalmia and hydroxychloroquine sulfate (400 mg/day) for PSS. We did not start him on corticosteroids or other immunomodulators given the lack of evidence to corroborate CNS vasculitis or other end organ damage secondary to PSS. Despite the presence of other atypical antibodies ⁸ like IIF-ANA, anti-CCP ⁹ and RF, he did not meet the diagnostic criteria for either Rheumatoid Arthritis ¹⁰ or Mixed Connective Tissue Disorder. ¹¹ The presence of these antibodies in PSS is attributed to B-cell hyperactivation contributing to polyclonal hypergammaglobulinemia, resulting in presence of autoantibodies considered typical of other autoimmune diseases. ⁷ Nevertheless, the latter group of PSS requires closer rheumatological follow up. Ramos-Casals et al reported that about 16% of PSS cohort with atypical antibodies eventually develop other autoimmune disorders after a follow up of 534 patient years. ⁷ Even though anti-CCP antibodies are highly specific for RA, it has been found in up to 5%-10% of PSS as well.^7-9 In one of largest studies till date, 7 out of 16 PSS patients (43.8%) with baseline anti CCP positivity, met the ACR-EULAR diagnostic criteria for RA ¹⁰ after a median follow up of 8 years (range of 5-10 years). ⁹ Acute phase reactants (elevated ESR and CRP) reliably predicted progression to RA, with no correlation observed between RF and anti-CCP titers. ⁹

Our case throws light on a rare etiology of recurrent ischemic strokes in a young male, with subtle systemic symptoms which were not given importance by the patient until he developed focal neurological deficits. This case highlights the protean manifestations of PSS and underlines the importance of extensive diagnostic evaluation which might be required in-order to arrive at the etiology of an index stroke.