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Neurol Neuroimmunol Neuroinflamm. 2018 Apr 5;5(4):e458. doi: 10.1212/NXI.0000000000000458. eCollection 2018 Jul.

Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection.

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Division of Neurology (A.S., J.G., K.R., D.R.L., J.A.P.), Department of Pediatrics, Children's Hospital of Philadelphia, PA; Clinical and Experimental Neuroimmunology Program (T.A.), August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital ClĂ­nic, University of Barcelona; Pediatric Neuroimmunology Unit (T.A.), Department of Neurology, Sant Joan de Deu Childrens Hospital, University of Barcelona, Spain; and Department of Neurology (D.R.L., J.A.P.), Perelman School of Medicine, University of Pennsylvania, PA.



To determine whether there is an association between nonencephalitic herpes simplex virus 1 (HSV-1) infection and anti-NMDA receptor encephalitis (anti-NMDARE).


Antibody testing was performed using samples from 2 cohorts in a case-control observational study. The cohort "Philadelphia" included 16 serum samples of pediatric anti-NMDARE cases and 42 age-matched controls with other neuroinflammatory disorders studied at the Children's Hospital of Philadelphia and University of Pennsylvania. The cohort "Barcelona" contained 23 anti-NMDARE patient samples and 26 age-matched participants with other neuroinflammatory disorders studied at IDIBAPS-Hospital Clinic, University of Barcelona. The presence of HSV-1 IgG antibodies was examined by ELISA. As an additional control, IgG antibodies to cytomegalovirus (CMV) and Epstein-Barr virus viral capsid antigen (EBV-VCA) were determined.


In each cohort, more participants with anti-NMDARE than controls had anti-HSV-1 IgG antibodies. In the Philadelphia cohort (58 participants), 44% of anti-NMDARE cases had antibodies to HSV-1 compared with 14% controls (OR 4.67, 95% CI 1.3-17.3, p = 0.031). In the Barcelona cohort (49 participants), 52% of participants with anti-NMDARE had antibodies to HSV-1 compared with 31% of controls (OR 2.45, 95% CI 0.7-7.9, p = 0.155). Overall, 49% of anti-NMDARE cases have antibodies to HSV-1 in these 2 combined cohorts compared with 21% of controls (Mantel-Haenszel OR 3.21, 95% CI 1.3-7.7, p = 0.007).


Past HSV-1 infection was found in significantly more anti-NMDARE cases than controls. This suggests a meaningful association between nonencephalitic HSV-1 infection and development of anti-NMDARE.

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