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Table of Contents
Year : 2023  |  Volume : 14  |  Issue : 1  |  Page : 56-59

Anti-N-methyl-D-Aspartate-Receptor encephalitis following herpes simplex virus encephalitis – Presenting as a pediatric patient with abnormal movements and psychiatric manifestation

Department of Pediatrics, Sriramachandra Children's and Dental Hospital, Guntur, Andhra Pradesh, India

Date of Submission05-Nov-2022
Date of Decision13-Dec-2022
Date of Acceptance14-Dec-2022
Date of Web Publication09-Feb-2023

Correspondence Address:
Dr. Sravani Kolla
Sriramachandra Children's and Dental Hospital, Guntur, Andhra Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injms.injms_127_22

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Herpes simplex virus (HSV) encephalitis remains one of the more severe forms of childhood encephalitis. The clinical course of HSV encephalitis is usually monophasic but occasionally complicated by a clinical relapse, causing biphasic illness. Sometimes relapse may be due to secondary immune mechanisms. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an example of immune-mediated relapse following herpes encephalitis. This is still underrecognized, with probable grave consequences if not treated early. Our index case was an 8-year-old male child with severe generalized choreoathetosis and behavioral disturbances, presented 4 weeks after documented HSV encephalitis. Cerebrospinal fluid (CSF) was positive for anti-NMDA receptor antibodies. The diagnosis was confirmed and treated with intravenous (IV) immunoglobulins (2 g/kg) and IV pulse-dose methylprednisolone (30 mg/kg) for 5 days. Other supportive management included tablet revocon 25 mg (tetrabenazine) ¼ tablet BD, clonazepam 0.25 mg one tablet BD, and syrup sizodon (risperidone) 0.5 mg BD. The patient is on regular follow-up and is recovering well but slowly. Patients with relapsing symptoms following HSV encephalitis or prolonged atypical symptoms, with repeat CSF-negative polymerase chain reaction for HSV should routinely be tested for NMDA receptor immunoglobulin G antibodies in CSF and/or serum. It is important to be aware of this differential diagnosis because patients respond well to immunotherapy.

Keywords: Autoimmune encephalitis, cerebrospinal fluid, choreoathetosis

How to cite this article:
Kolla S, Balleda L, Thimmapuram CR. Anti-N-methyl-D-Aspartate-Receptor encephalitis following herpes simplex virus encephalitis – Presenting as a pediatric patient with abnormal movements and psychiatric manifestation. Indian J Med Spec 2023;14:56-9

How to cite this URL:
Kolla S, Balleda L, Thimmapuram CR. Anti-N-methyl-D-Aspartate-Receptor encephalitis following herpes simplex virus encephalitis – Presenting as a pediatric patient with abnormal movements and psychiatric manifestation. Indian J Med Spec [serial online] 2023 [cited 2023 May 29];14:56-9. Available from: http://www.ijms.in/text.asp?2023/14/1/56/369386

  Introduction Top

Anti-N-methyl-D-aspartate (NMDA)-receptor encephalitis is an immune-mediated neuroinflammatory disease characterized by the presence of immunoglobulin G (IgG) antibodies against cell surface epitopes of the NR1 subunit of the NMDA receptor in the hippocampus. Initially, it was diagnosed as a paraneoplastic disease most commonly associated with ovarian teratoma.[1],[2],[3] However, published case reports show evidence of this association in only 31% of children <18 years and 9% of children under the age of 14 years.[2],[3] Another confirmed association has been seen with herpes simplex virus (HSV) encephalitis. Published case reports show 14%–27% of patients with HSV encephalitis developed symptoms of autoimmune encephalitis within 3 months of completing treatment with acyclovir.[4]

Children with autoimmune encephalitis differ from adults in their clinical presentations due to the evolution of neuronal circuits, neuroreceptor densities, and myelination during normal development.[5] Children with anti-NMDA receptor encephalitis are more likely to present with movement abnormalities, agitation, insomnia, seizures, speech deficits, ataxia, and/or hemiparesis, whereas memory deficits, psychiatric manifestations, and central hypoventilation are more common in adults.[6],[7],[8] Here, we are presenting an 8-year-old male child, who presented with gradual onset of agitation, speech, and memory deficits, psychiatric manifestations, and movement abnormalities following HSV encephalitis. Initial presentation is more likely to be nonpsychiatric than in adults, with symptoms including seizures and motor abnormalities. Behavioral symptoms such as temper tantrums, hyperactivity, and irritability are common in children. However, our index case presented with psychiatric, behavioral, and movement abnormalities.

  Case Report Top

An 8-year-old male child previously normal was admitted with fever of high grade, continuous headache, and vomiting for 4 days which was gradually progressing and associated with seizures. The child had three episodes of Generalized tonic clonic seizures (GTCS) over 3 days, associated with loss of consciousness and postictal drowsiness. The child was born out of nonconsanguineous parentage, second in birth order, by cesarean section at term gestation. The prenatal, perinatal, and postnatal periods were uneventful. At the time of admission, the child was febrile and drowsy, with meningeal signs, and no focal deficits. Investigations revealed Hemoglobin 11.5 g/dl, total leukocyte count = 20,500 cells/cumm, (polymorphs = 85%, lymphocytes = 12%, and eosinophils = 03%), platelet count = 317,000 cells/cumm, erythrocyte sedimentation rate = 20 mm/hr, C-reactive protein = 2.2 mg/L, sodium = 128 mmol/L, potassium = 4.2 mmol/L, chloride = 96 mmol/L, and creatinine = 0.5 mg/dl. Liver function tests and kidney function tests were normal. Baseline screening tests for fever such as malaria, typhoid, and viral markers were normal. Echocardiography and ultrasound abdomen were normal. Magnetic resonance imaging (MRI) brain showed areas of altered signal in the cerebrum and suggestive of herpes encephalitis [Figure 1]. Cerebrospinal fluid (CSF) analysis showed six cells, lymphocytes with protein 38 mg/dl and glucose 77 mg/dl. CSF gram's stain was normal. CSF BioFire profile was positive for HSV-1. An electroencephalogram (EEG) revealed diffuse theta-to-delta range slowing with left frontotemporal spikes. With this background, diagnosis of herpes simplex 1 viral encephalitis was made and treated with intravenous (IV) antibiotics, IV antiepileptics, IV acyclovir, and other supportive management. Child recovered gradually and was discharged.
Figure 1: MRI brain: Areas of altered signal in cerebrum Rt > Lt. MRI: Magnetic resonance imaging

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Child was on continuous follow-up. After 4 weeks of initial encephalitis, father observed gradual onset of behavioral disturbances, abusive language, sleep disturbances, and feeding difficulties. Child was gradually not recognizing parents and not opening the eyes. Psychiatric illness was considered and opinion obtained for the same. Child was started on clonazepam 0.25 mg ½ tablet twice daily and syrup risperidone 0.5 mg once at bedtime. However, the child was not improving in due course and symptoms worsened, and developed abnormal movements. Pediatric neurologist's opinion was taken and a probable diagnosis of post-HSV-related autoimmune, anti-NMDA receptor encephalitis was considered. As per the advice of neurologist, CSF anti-NMDA receptor antibodies were sent and investigation revealed positive for anti-NMDA receptor IgG antibodies in CSF. Repeat MRI brain showed residual signal changes in both hemispheres [Figure 2]. Repeat EEG revealed intermittent spike and wave patterns. With this history of neuropsychiatric manifestations, anti-NMDA receptor IgG antibody positivity, and with no new MRI brain changes, anti-NMDA receptor encephalitis was confirmed. Child was treated with IV immunoglobulins 2 g/kg for a span of 2 days and pulse-dose IV methylprednisolone 30 mg/kg for 5 days. Supportive management was also given in the form of IV fluids, IV antibiotics, and IV antiepileptics along with revocon 25 mg (tetrabenazine) ¼ tablet BD, clonazepam 0.25 mg 1 tablet BD, and syrup risperidone 0.5 ml (0.5 mg) BD. Child recovered gradually. Abnormal movements had become passive, gradually child opened eyes, and recognizing their parents. Feeding and sleep disturbances were also decreased. After stabilization and establishment of feeding, child discharged home on oral prednisolone, revocon, clonazepam, and risperidone.
Figure 2: MRI brain: Residual signal changes in both hemispheres. MRI: Magnetic resonance imaging

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  Discussion Top

Kennedy et al. described herpes encephalitis was the most common nonepidemic form of viral encephalitis.[9] According to De Tiège et al., the infection usually affected the limbic structures resulting in seizures, personality change, memory dysfunction, and focal neurological deficits.[5] Ito et al. described that the diagnosis was made by positive HSV polymerase chain reaction (PCR) in the CSF and patients often respond to antiviral treatment.[6] Our index case was also presented with high-grade fever, seizures, and memory dysfunction. CSF HSV PCR was positive and responded well to acyclovir.

The disease usually follows a monophasic course, but 14%–27% of the patients, often children, develop a recurrent encephalitic episode after successful treatment of the initial infection.[2],[4] The pathogenesis of these relapses is heterogeneous, some cases represent true relapses of viral encephalitis, with positive HSV PCR in the CSF, new necrotic lesions in the MRI, and response to antiviral treatment.[4] Garg et al. described an unusual relapsing course of HSV encephalitis. The CSF PCR for HSV was no longer positive, the MRI did not show new necrotic lesions, and symptoms did not respond to antiviral therapy. The exact etiology of this disorder is unknown, but reports of patients who responded to immunotherapy suggested an immune-mediated pathogenic mechanism.[8] Our index case was also showed unusual relapsing course with gradual onset of agitation, speech, and memory deficits, psychiatric manifestations, and movement abnormalities.

Since the first report of pediatric anti-NMDAR encephalitis in China in 2010, it has become more common in the pediatric population. NMDA receptors are found throughout the brain, including the hippocampus, brain stem, and neocortex. Anti-NMDAR antibodies produced by peripheral plasma cells cross the blood–brain barrier. Anti-NMDAR antibodies bind to synaptic and extrasynaptic NMDA receptors with high specificity. As a result, anti-NMDAR antibodies cause a specific, titer-dependent, and reversible decrease in NMDA receptors on postsynaptic dendrites, resulting in neuronal hypoactivity. First-line therapy is IV immunoglobulins (0.4 g/kg) plus methylprednisolone (30 mg/kg) for 5 days or plasma exchange. Second-line therapy is rituximab (375 mg/mt2) weekly for 4 weeks plus cyclophosphamide (750 mg/mt2) monthly along with other symptomatic therapy.

A study by Armangue et al. suggested that some atypical symptoms following HSV encephalitis, including prolonged abnormal movements such as choreoathetosis with positive serum and CSF IgG antibodies against the NMDAR and responded to intensive immunotherapy could be related to anti-NMDAR encephalitis.[7] Our index case was also positive for CSF IgG antibodies against the NMDA receptors that responded well to immunotherapy.

This case report raises awareness for anti-NMDAR encephalitis triggered by HSV encephalitis and reveals a predictable time frame of approximately 4 weeks. Detection of NMDAR antibodies is confirmatory of this condition, and response to immunotherapy is favorable. The challenges are now to determine the mechanisms involved, whether there are predisposing genetic factors, whether anti-inflammatory or immunotherapy prophylaxis during HSV encephalitis prevents autoimmunity, whether earlier diagnosis and treatment may improve outcome, and whether there is any need for continuation of immune therapy.

  Conclusion Top

Anti-NMDA receptor encephalitis can be easily diagnosed using serum and/or CSF sample testing for IgG. High index of suspicion of anti-NMDA receptor encephalitis is to be considered following HSV-1 encephalitis, especially when the course is biphasic and recovery is slow and associated with movement disorder and psychiatric illness. Early institution of immunotherapy may result in better outcomes. Further follow-up studies are needed to document the need for continued immunotherapy to prevent relapses of HSV encephalitis. Also, further studies may be needed to document if systematic use of anti-inflammatory and immune therapies during the acute viral phase (acute HSV encephalitis) could prevent the development of autoimmune anti-NMDAR encephalitis as well.

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.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies. Lancet Neurol 2008;7:1091-8.  Back to cited text no. 1
Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009;66:11-8.  Back to cited text no. 2
Florance-Ryan N, Dalmau J. Update on anti-N-methyl-D-aspartate receptor encephalitis in children and adolescents. Curr Opin Pediatr 2010;22:739-44.  Back to cited text no. 3
Nosadini M, Mohammad SS, Corazza F, Ruga EM, Kothur K, Perilongo G, et al. Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: A systematic literature review with analysis of 43 cases. Dev Med Child Neurol 2017;59:796-805.  Back to cited text no. 4
De Tiège X, Rozenberg F, Des Portes V, Lobut JB, Lebon P, Ponsot G, et al. Herpes simplex encephalitis relapses in children: Differentiation of two neurologic entities. Neurology 2003;61:241-3.  Back to cited text no. 5
Ito Y, Kimura H, Yabuta Y, Ando Y, Murakami T, Shiomi M, et al. Exacerbation of herpes simplex encephalitis after successful treatment with acyclovir. Clin Infect Dis 2000;30:185-7.  Back to cited text no. 6
Armangue T, Titulaer MJ, Málaga I, Bataller L, Gabilondo I, Graus F, et al. Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 2013;162:850-6.e2.  Back to cited text no. 7
Garg D, Mohammad SS, Sharma S. Autoimmune encephalitis in children: An update. Indian Pediatr 2020;57:662-70.  Back to cited text no. 8
Steiner I, Kennedy PG, Pachner AR. The neurotropic herpes viruses: Herpes simplex and varicella-zoster. Lancet Neurol 2007;6:1015-28.  Back to cited text no. 9


  [Figure 1], [Figure 2]


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