Secondary Logo

Journal Logo

Brief Reports

Anti-N-Methyl-D-Aspartate Receptor Encephalitis In A Young Child With Histological Evidence On Brain Biopsy Of Coexistent Herpes Simplex Virus Type 1 Infection

Ellul, Mark A. MRCP(UK); Griffiths, Michael J. MRCPCH; Iyer, Anand MD; Avula, Shivaram FRCR; Defres, Sylviane MB ChB; Baborie, Atik FCRPath; Vincent, Angela FRS; Martin, Natalie G. MB ChB; Sadarangani, Manish Dphil; Pollard, Andrew J. FRCPCH, PhD; Solomon, Tom FRCP, PhD; Kneen, Rachel FRCPCH

Author Information
The Pediatric Infectious Disease Journal: March 2016 - Volume 35 - Issue 3 - p 347-349
doi: 10.1097/INF.0000000000001011


Anti-NMDAR encephalitis is a recently described autoimmune disorder of the central nervous system with a recognizable phenotype consisting of cognitive and psychiatric features, movement disorder and progressively deteriorating encephalopathy. It was first described as a paraneoplastic condition in a series of young women with ovarian teratomas, but more recently has been described in children, who are more likely than adults to have had a prodromal illness before presentation and less likely to have an underlying tumor.1 The outcome is generally good especially if recognized and treated early with immunosuppressant medication.1 In this report, we describe a child who had anti-NMDAR encephalitis with a classical presentation and a good outcome but also had histological evidence of HSV type 1 infection in neurons.


A previously well 3-year-old Caucasian boy presented with a 2 week change in behavior, irritability and altered sleep pattern followed by difficulty swallowing, drooling, encephalopathy and involuntary limb and facial movements. Four weeks earlier, he had a mild encephalopathy, consisting of lethargy and excessive sleepiness, with vomiting lasting 3 days. The parents had sought medical attention, and he was given a course of antibiotics for presumed tonsillitis but had apparently made a full recovery. He had developed a mild fever and coryzal symptoms just before admission. On examination, he was afebrile and encephalopathic with a Glasgow Coma Scale of 9 out of 15 with tachycardia, hyperhidrosis and excessive salivation. He had evidence of right otitis externa but no other signs of infection. He had a florid movement disorder characterized by orofacial dyskinesia and coarse writhing movements of all 4 limbs. He was treated empirically with intravenous aciclovir (total 10 days) and ceftriaxone (total 7 days). His condition deteriorated rapidly over several hours, with periods of agitation alternating with apneic episodes and reduced conscious level with tachycardia and excessive salivation. He was intubated and transferred to a pediatric intensive care unit.

Initial blood workup was normal and blood cultures were negative. Cerebrospinal fluid (CSF) analysis demonstrated 12 white cells/mm3 (100% lymphocytes), protein 58 mg/dL and glucose 38 mg/dL with CSF/plasma glucose ratio of 0.7. CSF microscopy and culture and polymerase chain reaction (PCR) for HSV types 1 and 2, enterovirus, echovirus and parechovirus were negative. Oligoclonal bands were present in serum and CSF with additional bands in CSF, implying a systemic response with an additional central nervous system-restricted response. Magnetic resonance imaging (MRI) of the brain showed evidence of T2 hyperintensity, diffusely involving the right temporal lobe cortex with right hippocampal volume loss and subtle hyperintensity involving the left amygdala (see Figure A–C, Supplemental Digital Content 1, Electroencephalography demonstrated generalized slowing, most marked over the right cerebral hemisphere, consistent with encephalopathy, without epileptiform features.

A clinical diagnosis of anti-NMDAR encephalitis was made and 500 mg of intravenous methylprednisolone was given once daily on days 5–7 of admission followed by intravenous immunoglobulin (IVIg): total dose 2 g/kg. He was extubated after 5 days, but his conscious level continued to be reduced and the florid movement disorder continued.

Given the unusual MRI findings, which were consistent with HSV type 1 encephalitis, lesional brain and meningeal biopsies were performed on day 10 after admission (see Figure E–I, Supplemental Digital Content 1, These showed a nonspecific active chronic inflammation with occasional polymorphonuclear cells, epithelioid and CD68-positive foamy macrophages, LCA-positive lymphocytes, a few rod and plasma cells and multinucleated giant cells in meninges, white and cortical type grey matter, consistent with meningoencephalitis. The brain parenchyma had a positive PCR for HSV type 1, confirmed on repeat testing, and immunohistochemistry for HSV type 1 showed occasional very faint cytoplasmic staining in neuronal-type cells (see Figure I, Supplemental Digital Figure 1,, positive control Figure 1J). Aciclovir was recommenced and given intravenously for a further 21 days. Anti-NMDAR antibodies (IgG), drawn on day 3 of admission, were reported on day 11 of admission to be highly positive in serum and CSF. Voltage-gated potassium channel complex antibodies, glutamic acid decarboxylase antibodies and a panel of onconeuronal antibodies were negative. Plasma exchange was commenced on day 12; he received 15 single volume cycles without complications. On day 15, CSF demonstrated 2 white cells/mm3, protein 59 mg/dL, glucose 45 mg/dL, PCR for HSV type 1 was negative and anti-NMDAR antibodies were negative. Anti-NMDAR serum antibodies were still present on day 15 at low levels but were negative at day 33.

Given the severity of his encephalitis, he took a 6-week tapering course of oral prednisolone, infusions of cyclophosphamide every month for 6 months (cumulative dose of 2250 mg/m2) and 2 rituximab cycles, given 6 months apart (375 mg/m2 per day given on 2 consecutive days, 2 weeks apart). A repeat MRI 8 months after presentation revealed atrophy of the right medial temporal lobe with bilateral cerebral parenchymal volume loss and postbiopsy subdural effusions (see Figure D, Supplemental Digital Content 1, He was discharged after 4 months of neurorehabilitation having made a good recovery. At last follow-up, 24 months after presentation, he had no residual physical neurological disability. Formal neuropsychology has not been performed due to his young age but the parents report that his understanding and expression of speech, sleep and behavior are normal. Anti-NMDAR antibodies in serum remain negative.


There is increasing evidence of an association between HSV type 1 encephalitis and the presence of anti-NMDAR antibodies. To date, 33 cases of HSV type 1 encephalitis in adults (n = 18) and children (n = 15) have been reported in close temporal relationship to the identification of anti-NMDAR antibodies in the serum and/or CSF2–9 (see Table, Supplemental Digital Content 2,

Several small case series and case reports have identified patients, primarily children, with clinical relapse following proven HSV type 1 encephalitis. These relapses were associated with development of movement disorders, not seen during the HSV encephalitis, and anti-NMDAR antibodies in the serum, and in CSF when available.2–7,9 In 7 cases, sera and CSF from the original HSV encephalitis period were shown to be negative for anti-NMDAR antibodies, demonstrating that, in these cases at least, anti-NMDAR antibodies developed only during relapse.2,4–6

In another retrospective study, stored acute serum from a cohort of 44 adults diagnosed with HSV type 1 encephalitis (CSF PCR positive) were tested for anti-NMDAR antibodies.8 None had clinical features suggestive of anti-NMDAR encephalitis, but 13 had anti-NMDAR antibodies with a mixture of IgA, IgM and IgG classes. All the anti-NMDAR antibody positive patients had extensive temporal lobe hyperintensity on MRI imaging in keeping with the typical appearances of HSV type 1 encephalitis, and additional imaging features were not reported.

Our patient differs from those in previous reports as he did not have features of severe clinical HSV type 1 encephalitis during his initial illness, 4 weeks before presentation. Also, the CSF PCR for HSV type 1 was negative throughout the time of hospitalization, although no lumbar puncture was undertaken during his initial mild encephalopathy. Nevertheless, PCR of the parenchyma of the temporal lobe lesion was positive for HSV type 1, 25 days from onset of symptoms and there was histological evidence of infection within some of the neurons. Given his age, it seems likely that this was a primary infection, possibly occurring during his earlier mild encephalopathy.

There are several case series reporting positive HSV type 1 PCR on tissue from patients with epilepsy who had undergone temporal lobectomy,10 as well as from patients with Rasmussen’s encephalitis11 who did not have clinical HSV type 1 encephalitis. The significance of these findings is not clear, but they may represent reactivation of latent virus in the setting of seizures and neuronal injury.

The temporal lobe changes seen on the MRI in our patient, including hippocampal volume loss, are also consistent with a previous HSV infection with residual damage. MRI findings in anti-NMDAR encephalitis are usually less florid (or normal) and include abnormalities in the medial temporal lobes or less frequently in the thalamus or occipital cortex.12 Therefore, the evidence of bilateral medial temporal lobe involvement in addition to right-sided diffuse temporal lobe involvement in this case is an important finding that supports features of both HSV type 1 and anti-NMDAR encephalitis. Oedema and T2 hyperintensity on MRI can occur after status epilepticus, with atrophy in severe cases.13 However, our patient had no clinical or neurophysiologic evidence of seizure activity.

Our patient had a mild and brief encephalopathy 4 weeks before presentation; we therefore hypothesize that he had mild HSV type 1 encephalitis at this point but by admission he was displaying a secondary anti-NMDAR encephalitis syndrome. The clinical features of HSV type 1 infection may have been less severe because the nondominant temporal lobe was most affected. The response to immunotherapy observed and the correlation between the fall in anti-NMDAR antibody titers and clinical improvement suggest that the pathological process at the time of presentation was primarily antibody mediated rather than as a result of viral infection.

The mechanism by which viral infection leads to the production of autoantibodies is not clear. Inflammation and viral neuronal lysis caused by HSV type 1 infection may result in the exposure of neuronal surface proteins, leading to antibody production directed against antigens to which tolerance is normally preserved.2 Alternatively, a process of molecular mimicry between virus-associated antigens and the NMDA receptor may occur.8 However, the existence of other infections co-incident with anti-NMDAR encephalitis argues against specific molecular mimicry involving HSV type 1. For example, adenovirus was identified in the CSF of 1 child, and there is 1 case report of anti-NMDAR encephalitis occurring after varicella zoster virus encephalitis.9,14 Further studies are needed to characterize the role of anti-NMDAR antibodies in HSV type 1 encephalitis, as well as to establish the prevalence of active infection with HSV type 1 or other viruses in patients with anti-NMDAR encephalitis.

Our findings suggest that some patients with anti-NMDAR encephalitis may have had a preceding subtle HSV type 1 infection which may be the precipitant for an autoimmune process, and that more cases of anti-NMDAR encephalitis may be associated with HSV type 1 than currently recognized using CSF PCR only.


We are grateful to the patient and his parents for allowing us to report his case; the laboratory staff at the Pathology Department at the Walton Centre NHS Foundation Trust and to Dr. Anuradha Chawla and the Virology Department at the Royal Liverpool University Hospital for their help with PCR results. We are also grateful to Drs. Eileen Baildam, Gavin Cleary, Lisa McCann, Claire Pain, Andrew Riordan, Therese Callaghan and Miss Sasha Burn for their role with clinical management of the case.


1. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009;66:11–18
2. Armangue T, Leypoldt F, Málaga I, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75:317–323
3. Mohammad SS, Sinclair K, Pillai S, et al. Herpes simplex encephalitis relapse with chorea is associated with autoantibodies to N-Methyl-D-aspartate receptor or dopamine-2 receptor. Mov Disord. 2014;29:117–122
4. Hacohen Y, Deiva K, Pettingill P, et al. N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse. Mov Disord. 2014;29:90–96
5. Wickström R, Fowler A, Cooray G, et al. Viral triggering of anti-NMDA receptor encephalitis in a child - an important cause for disease relapse. Eur J Paediatr Neurol. 2014;18:543–546
6. Hacohen Y, Absoud M, Hemingway C, et al. NMDA receptor antibodies associated with distinct white matter syndromes. Neurol Neuroimmunol Neuroinflamm. 2014;1:e2
7. Desena A, Graves D, Warnack W, et al. Herpes simplex encephalitis as a potential cause of anti-N-methyl-D-aspartate receptor antibody encephalitis: report of 2 cases. JAMA Neurol. 2014;71:344–346
8. Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72:902–911
9. Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013;84:748–755
10. Karatas H, Gurer G, Pinar A, et al. Investigation of HSV-1, HSV-2, CMV, HHV-6 and HHV-8 DNA by real-time PCR in surgical resection materials of epilepsy patients with mesial temporal lobe sclerosis. J Neurol Sci. 2008;264:151–156
11. Jay V, Becker LE, Otsubo H, et al. Chronic encephalitis and epilepsy (Rasmussen’s encephalitis): detection of cytomegalovirus and herpes simplex virus 1 by the polymerase chain reaction and in situ hybridization. Neurology. 1995;45:108–117
12. Baumgartner A, Rauer S, Mader I, et al. Cerebral FDG-PET and MRI findings in autoimmune limbic encephalitis: correlation with autoantibody types. J Neurol. 2013;260:2744–2753
13. Huang YC, Weng HH, Tsai YT, et al. Periictal magnetic resonance imaging in status epilepticus. Epilepsy Res. 2009;86:72–81
14. Schäbitz WR, Rogalewski A, Hagemeister C, et al. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology. 2014;83:2309–2311

encephalitis; encephalopathy; autoantibody; N-methyl-D- aspartate receptor; herpes simplex virus

Supplemental Digital Content

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.