A case of anti- N-methyl-D-aspartate (NMDA) receptor encephalitis possibly triggered by an episode of Japanese B encephalitis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_340_16
Source of Support: None, Conflict of Interest: None
The recent emergence of potentially treatable disease entities resulting from antibodies against neuronal cell surface or synaptic proteins has led to a dramatic shift in the approach to the management of encephalitis. The landmark California Encephalitis Project focusing on the epidemiology of encephalitis showed that the frequency of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis surpassed that of any individual viral etiology, especially in young individuals. Recent studies have also shown that autoimmune encephalitis such as anti-NMDAR encephalitis can be triggered by infections such as herpes simplex encephalitis (HSE)., A case of Japanese B (Jap B) encephalitis is described, which possibly triggered an episode of anti-NMDAR encephalitis.
A premorbid, normal, 7-year-old boy developed an episode of febrile encephalopathy with significant recovery within the next 2 weeks. The illness started with fever, followed by generalized seizure on day 2 and rapidly progressing encephalopathy by the next day. He was admitted to a hospital where he received antibiotics including acyclovir and symptomatic therapy. On day 15, at the time of discharge, he had improved remarkably and could carry out his activities of daily living with minimal support. For the next 10 days, he remained status quo. Then, he developed a progressive twisting posture, beginning in the right leg, which involved the entire body over the next 2 days with appearance of abnormal orofacial movements at the same time. In the next 2 days, he became mute with generalized paucity of his body movements. With these complaints, he was admitted to the current center.
On examination, his vital parameters were stable with no abnormality being detected on general physical and ophthalmoscopic examination. He was in a state of akinetic mutism with generalized rigidity. Intermittently, he had generalized dystonia and oromotor dyskinesia. Rest of the systemic examination was normal.
Magnetic resonance imaging (MRI) of the brain done at the current centre revealed symmetrical bilateral substantia nigra, caudate nucleus, putamen, and globus pallidus signal changes with asymmetric thalamic signal changes (left > right) [Figure 1]. Cerebrospinal fluid (CSF) analysis including Herpes simplex virus (HSE) and tuberculosis polymerase chain reaction (PCR) was negative. Japanese B encephalitis virus serology was positive.
The ratio of apparent to unapparent infection was 200:1 to 300:1. This child came from Japanese B encephalitis endemic area of India. In view of the positive serology in an acute encephalitis syndrome-like scenario in a relevant epidemiological setting with suggestive MRI changes, Japanese B encephalitis was diagnosed. The serological test used was IgM capture enzyme-linked immunosorbent assay (ELISA) with a sensitivity and specificity of >95%. This was confirmatory of Japanese B encephalitis presenting as an acute encephalitis syndrome in a relevant clinicoepidemiological scenario, as per the World Health Organisation's guidelines.,
The work up for Wilson's disease in the form of detection of Kayser–Fleischer rings, serum ceruloplasmin levels and 24-h urinary copper estimation did not reveal any abnormality. His serum ammonia, arterial lactate, blood pH, tandem mass spectrometry and urinary gas chromatography mass spectrophotometry were normal. Anti-NMDA receptor antibody was tested in both serum and cerebrospinal fluid (CSF) using a semi-quantitative indirect immunofluorescence-based test. The sensitivity and specificity of CSF positivity was >99.5%.
In view of the asymptomatic period between the febrile illness and the rapidly progressive extrapyramidal disorder, a possibility of anti-NMDAR encephalitis was also considered. CSF and serum anti-NMDA antibody tested positive. Hence, he was treated with immunotherapy in the form of simultaneous intravenous immunoglobulin (IVIG, 2 g/kg over 5 days) and methylprednisolone (30 mg/kg/day for 5 days). He was discharged on oral steroids (prednisolone 2 mg/kg/day) for 2 weeks followed by its tapering over the next 1 week. At discharge, his rigidity and dystonia had marginally improved, dyskinesias and pseudobulbar palsy were still evident, and he had mutism [Video 1]. One week post-tapering, he showed significant improvement and attained an independent ambulation [Video 2]. At a 3-month follow up, he regained his premorbid developmental state, became independent in activities of daily living, and started attending school. His repeat CSF anti-NMDA antibody was negative. Repeat MRI brain showed minimal bilateral caudate signal changes without any other abnormality [Figure 2].
Recent reports have shown that Herpes simplex virus (HSV) encephalitis can trigger autoimmunity against neuronal surface proteins such as NMDAR and can result in prolonged or atypical neurological symptoms such as relapsing choreoathetosis after completion of treatment., In the current case, the biphasic nature of the illness and the presence of rapidly progressive movement disorder prompted the workup for anti-NMDAR encephalitis.
In Japanese B encephalitis, movement disorders have been observed in up to 60% of patients after 1–4 weeks of onset of illness as consciousness starts improving. Both hypo- and hyperkinetic disorders have been described. Up to 40% mortality is reported in the acute stage with 50% of the survivors having minimal functional impairment. In the current case, the child recovered significantly from the acute stage but developed a debilitating movement disorder later on. Although he developed a movement disorder within 4 weeks of the acute phase, the biphasic nature of the disease and the relatively symptom-free interval in between, made the possibility of autoimmune encephalitis likely.
The biological plausibility proposed in the case of anti-NMDAR encephalitis associated with herpes infection is twofold; molecular mimicry and/or breakdown of immunological tolerance toward NMDAR expressed in diseased neurons. Current evidence also indicates that direct neuronal injury or immune-mediated mechanisms or a combination of both contributed to the pathogenesis of movement disorders related to the Japanese B encephalitis. Thus, it can be speculated that a similar mechanism could have acted in the current case. However, further research is needed to establish this hypothesis.
To best of our knowledge, this is the first report of Japanese B encephalitis triggering an episode of anti-NMDAR encephalitis. Secondary worsening after significant recovery from the acute phase; and, the presence of a predominant movement disorder with absence of new MRI lesions were important clues that initiated a hunt for autoimmune encephalitis in the current patient. In relevant clinical and epidemiological settings, it is imperative to consider post- or parainfectious autoimmune processes, as it has important treatment related implications.
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[Figure 1], [Figure 2]