|Ahead of print publication
An unusual cause of recurrent meningitis in a 17-year-old girl
K Nikitha1, Sachin Sureshbabu2, P Anoof3
1 Department of General Medicine, Aster MIMS, Kozhikode, Kerala, India
2 Department of Neurology, Aster MIMS, Kozhikode, Kerala, India
3 Department of Rheumatology, Aster MIMS, Kozhikode, Kerala, India
|Date of Submission||25-Apr-2020|
|Date of Acceptance||23-Jun-2020|
Department of Neurology, Aster Mims Hospital, Kozhikode, Kerala
Source of Support: None, Conflict of Interest: None
We present the report of a 17-year-old girl, with a history of recurrent headaches, diagnosed as meningitis on two occasions 2 years apart. She was extensively evaluated for all systemic and local causes of the same, which was finally diagnosed as Sjogren's syndrome (SS). SS presenting with recurrent, aseptic meningitis as the only manifestation in the pediatric age group is a very rare occurrence.
Keywords: Aseptic meningitis, headache, Sjogren's syndrome
| Introduction|| |
Sjogren's syndrome (SS), like sarcoidosis, can affect every part of the nervous system and yet may not announce itself with florid manifestations until late. Sicca symptoms are not synonymous with the disorder, and they are conspicuously absent in many patients who present with neurological symptoms. Aseptic meningitis in SS can be recurrent, indolent, and self-limiting, and only a high index of suspicion can help one to establish the diagnosis and initiate prompt treatment.
| Case Report|| |
A 17-year-old girl, with no previous comorbidities, presented with the complaints of low-grade, intermittent fever and headache of 2 days' duration. The headache was holocranial and associated with photo- and phonophobia. There was no history of any visual or auditory aura. There was no history of seizures, diplopia, visual disturbances, or any focal neurological deficit. She also had a history of an evanescent maculopapular rash over her right thigh and forearm. There were no pustules or vesicles. She did not report any features of Raynaud's phenomenon, photosensitivity, arthralgia, uveitis, and orogenital ulcers, dryness of mouth or eyes or any gastrointestinal or urinary symptoms. She had a past history of similar complaints 2 years back, which was diagnosed as meningitis and treated with antibiotics with prompt improvement. However, treatment records were not available for scrutiny.
Systemic examination was within normal limits. Neurological examination was also unremarkable except for subtle neck stiffness and positive Kernig's sign. Complete hemogram was normal except for a mild normocytic anemia. Hepatic and renal biochemistry were also normal. Chest X-ray and ultrasonography abdomen were within normal limits. Thyroid function and serum cortisol levels were normal ruling out endocrinological abnormalities.
Magnetic resonance (MR) imaging brain with contrast showed mild leptomeningeal enhancement, suggestive of an acute meningitis. A MR venogram returned normal findings. Cerebrospinal fluid (CSF) examinations showed modestly elevated protein levels (58 mg/dl) with normal sugar levels. CSF total cell count was high (231) with lymphocytic predominance (L81P19). CSF - Adenosine deaminase was normal and CSF-TB-PCR was negative. CSF-Neuroviral and autoimmune encephalitis panel were also negative.
Investigations for tropical infections including typhoid, dengue fever, malaria, chikungunya, West Nile virus, and rickettsia were negative. Blood and urine cultures were sterile.
Considering her age and persistent fever, a probable autoimmune etiology was considered. Antinuclear antibody (ANA) (enzyme-linked immunosorbent assay [ELISA]) was positive with a titer of 4.8, and the ANA profile (immunoblot) showed strong positivity to SS-A (Ro52) and SS-B (La) antibodies. Anti-PR3 anti-neutrophil cytoplasmic antibody (ANCA) (ELSIA) and antimyeloperoxidase ANCA (ELSIA) were negative. Anti-phospholipid antibody syndrome was ruled out with anti-cardiolipin (IgG and IgM ELISA) and anti-beta-2-glycoprotein antibodies (IgG and IgM ELISA) and lupus anticoagulant (by diluted Russell viper venom test) came out to be negative. Serum ACE levels were normal. Human leukocyte antigen B51 was negative. Schirmer test was not contributory to the diagnosis. Minor salivary gland biopsy was performed which showed lymphoplasmacytic infiltration of the salivary glands, and the FOCUS score was 1. She responded well to a course of pulse steroids followed by oral prednisolone at 1 mg/kg and azathioprine at 100 mg/day. However, it was changed over to mycophenolate mofetil, in view of leukopenia. She was also commenced with hydroxychloroquine at 5 mg/kg/day and oral Vitamin D3 60k units weekly. Now, she is clinically stable and on follow-up for the past 5 months.
| Discussion|| |
SS is a chronic autoimmune disease, characterized by inflammatory infiltration of the exocrine glands. It can be isolated – termed primary SS – or associated with other rheumatological diseases such as systemic lupus erythematosus or rheumatoid arthritis – when it is termed secondary SS.
Primary SS can have various neurological manifestations. Primarily affecting the peripheral nervous system, it can also affect the central nervous system. Different mechanisms have been described to contribute to the clinical picture. While antibody-mediated ganglionitis is believed to be the pathology behind sensory ataxic, small fiber, autonomic and trigeminal neuropathy; mononeuropathy; and cranial neuropathy are due to the underlying immune-mediated vasculitis. Some role of anti-muscarinic (M3) receptor antibodies in the autonomic dysfunction is also identified.
Many a times, the diagnosis of SS is preceded by the neurological involvement. The spectrum of involvement is diverse with peripheral nervous system involvement in majority and central nervous system involvement in 2%–5% of the individuals. Cognitive dysfunction with hypoperfusion of the frontal and temporal lobes as seen in single-photon emission computed tomography, manifests as attention and memory deficits. Meningitis can often be presented with focal or systemic symptoms and lymphocytic pleocytosis in CSF. There can also be lesions simulating multiple sclerosis, with a chronic relapsing-remitting course, in which CSF shows an elevated IgG index and oligoclonal band synthesis. Optic neuritis due to ischemic vasculitis or demyelination is yet another association, which can present with blindness. Spinal cord involvement in the form of transverse myelitis can present in various forms, depending on the site involved.
Peripheral neuropathy, commonly associated with SS, can manifest as sensory-motor neuropathy, small-fiber neuropathy, mononeuritis multiples, multiple cranial neuropathies, or autonomic dysfunction. Of all, distal axonal polyneuropathy being the most common has an indolent course with symmetric paresthesia and sensory deficits, more in the lower limbs. Various mechanisms involved are axonal degeneration with remyelination and T cell and macrophage infiltration leading to necrotic vascular inflammation. Infiltration in the anterior horn cells can cause motor neuron disease, which is yet another manifestation of the same. Myositis and channelopathies such as hypokalemic periodic paralysis are also reported in SS.
Autonomic dysfunction in SS can be due to various mechanisms. Apart from infiltration of the autonomic neurons, there can be interference with the neurotransmitter release by the cytokines, which can result in the clinical manifestation.
Anti-Ro positivity is found to be associated with a more severe form of the disease, as is witnessed by the angiographic evidence of small-vessel vasculitis in these patients. The association with CNS manifestations is also found to be more in these patients, though seronegativity does not exclude the possibility. Hence, anti-Ro serves as an important marker both for diagnosis and prognostication of disease. Specific antibodies targeting meninges and brain parenchyma have been identified in SS.
Once diagnosed, immunomodulation, with the main objective of a stable dose of steroid-sparing agent, is the primary strategy. Immunomodulators such as cyclophosphamide, cyclosporine, methotrexate, and Rituximab are used with varying benefits. Axonal neuropathies and ganglionopathies if not responding to high-dose corticosteroids and immunomodulators, a trial of IVIg (intravenous immunoglobulin) may be tried. Some role of plasmapheresis is also contended for.
| Conclusion|| |
Neurological manifestations can precede the classical sicca symptoms in SS. Although very mild, it can be the only presentation which can lead to misdiagnosis and complications. Hence, SS should always be considered in the differential diagnosis of recurrent aseptic meningitis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Soliotis FC, Mavragani CP, Moutsopoulos HM. Central nervous system involvement in Sjögren's syndrome. Ann Rheumatic Dis 2004;63:616-20.
Chai J, Logigian EL. Neurological manifestations of primary Sjogren's syndrome. Curr Opinion Neurol 2010;23:509-13.
Perzyńska-Mazan J, Maślińska M, Gasik R. Neurological manifestations of primary Sjögren's syndrome. Reumatologia 2018;56:99.
Alexander EL, Ranzenbach MR, Kumar AJ, Kozachuk WE, Rosenbaum AE, Patronas N, et al
. Anti-Ro (SS-A) autoantibodies in central nervous system disease associated with Sjögren's syndrome (CNS-SS): Clinical, neuroimaging, and angiographic correlates. Neurology 1994;44:899.
McCoy SS, Baer AN. Neurological complications of Sjögren's Syndrome: Diagnosis and management. Curr Treatm Opt Rheumatol 2017;3:275-88.