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Classic herpes simplex virus encephalitis (HSVE) is an acute viral infection that usually follows a monophasic disease course; however some patients, mainly children, experience a relapse within weeks or months after the initial event. In a subset of these patients a viral reactivation is unlikely because the CSF PCR for HSV is negative, repeated MRI does not show new necrotic lesions, and the symptoms are refractory to antiviral therapy. These patients often develop choreoathetosis variably accompanied by behavioral changes and seizures, and a postinfectious immune-mechanism has been postulated. Recent studies demonstrated that 7% of patients with HSVE harbor NR1 N-methyl-D-aspartate receptor (NMDAR) IgG antibodies. Moreover, a child with post- HSVE choreoathetosis was found to have NMDAR antibodies; the patient did not improve with antiviral therapy but recovered after aggressive immunotherapy. Based on these findings, evidence is increasing that a subgroup of post-HSVE represents a separate disease entity, which in fact is anti-NMDAR encephalitis. Patients with relapsing HSVE or prolonged atypical symptoms, who have negative CSF PCR for HSV should routinely be tested for NMDAR IgG antibodies in CSF and serum. It is important to be aware of this differential diagnosis because patients respond to immunotherapy.

Clinical Neuropathology practice guide 4-2013: post-herpes simplex encephalitis: N-methyl-Daspartate receptor antibodies are part of the problem