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Year : 2020  |  Volume : 2  |  Issue : 1  |  Page : 37

Pediatric anti-N-methyl-D-aspartate receptor encephalitis and bilateral optic neuritis: An updated review

Department of Ophthalmology, Hospital Center Entre o Douro e Vouga, Santa Maria da Feira, Portugal

Date of Submission11-Sep-2020
Date of Acceptance22-Oct-2020
Date of Web Publication10-Dec-2020

Correspondence Address:
Dr. Jeniffer Jesus
R. Dr. Cândido Pinho 5, 4520-211, Santa Maria da Feira
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/PAJO.PAJO_49_20

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We present the case report of a 6-year-old girl with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis associated with bilateral optic neuritis. She initially presented with disturbing behaviors and gait impairments and was hospitalized in the context of meningoencephalitis, without agent isolation and with inconclusive laboratory tests. After discharge, she noted a loss of vision with impaired color sensation and returned to the emergency department. Her best-corrected visual acuity was 20/400 in both eyes, and fundoscopy revealed bilateral optic disc edema. She was hospitalized once again. Anti-NMDAR antibodies were detected in serum and cerebrospinal fluid. The patient was successfully treated with a pulse of methylprednisolone, followed by a tapering regimen of prednisolone. She recovered to 20/20 vision in the right eye and left eye. Our report highlights additional aspects of anti-NMDAR encephalitis in children and suggests that the disease could present atypical visual manifestations, which requires multidisciplinary approaches.

Keywords: Anti-N-methyl-D-aspartate receptor encephalitis, autoimmune disturbance, bilateral optic disc edema, neurological deficits, pediatric encephalitis

How to cite this article:
Jesus J, Ruão M, Ferreira CC, Soares R, Matias MJ, Chibante-Pedro J. Pediatric anti-N-methyl-D-aspartate receptor encephalitis and bilateral optic neuritis: An updated review. Pan Am J Ophthalmol 2020;2:37

How to cite this URL:
Jesus J, Ruão M, Ferreira CC, Soares R, Matias MJ, Chibante-Pedro J. Pediatric anti-N-methyl-D-aspartate receptor encephalitis and bilateral optic neuritis: An updated review. Pan Am J Ophthalmol [serial online] 2020 [cited 2021 Nov 27];2:37. Available from: https://www.thepajo.org/text.asp?2020/2/1/37/303003

  Introduction Top

The spectrum of central nervous system autoimmune disorders has recently expanded with the discovery of disorders associated with antibodies directed against the neuronal membrane surface. Autoimmune encephalitis is a group of neuropsychiatric conditions, presenting acutely or subacutely, with a very wide range of neuropsychiatric symptoms. The best example of diffuse autoimmune encephalitis is anti-N-methyl-D-aspartate receptor (NMDAR), which accounts for 40% of all cases in children.[1] This disease was initially described as a paraneoplastic syndrome affecting young women with ovarian teratomas,[2] and later, it has been observed in patients of all ages and both sexes, with or without teratomas.[3],[4] Currently, it is known that this entity develops when autoantibodies attack NMDARs in the brain, provoking neurologic decompensation, personality changes, or autonomic dysfunction.[1],[5]

Nonetheless, considering the latest publications and significant literature increasing, the impairment of visual function associated with anti-NMDAR encephalitis has not been well described in the pediatric population and the disease remains underestimated.

This paper aims to review current knowledge on this topic and to clarify physicians about the possible ophthalmological and neuropsychiatric presentation of the anti-NMDAR encephalitis and their diagnostic approach and current management.

  Case Report Top

A previously healthy 6-year-old girl presented to the pediatric emergency department with a history of disturbing behaviors (agitation, incoherent speech, and difficulties in accepting rules) and gait disturbance for 3 days. Physical examination revealed nuchal rigidity and hyperlordosis, without other alterations. Laboratory investigation showed slight anisocytosis and hypochromia, leukocytosis (72.8% neutrophils), thrombocytosis (561 × 10E9/L), lactate dehydrogenase 229 U/L, C-reactive protein 5.5, and procalcitonin 0.600 ng/mL. Urinalysis revealed a high level of leukocytes (500/μL). Cerebrospinal fluid (CSF) examination showed pleocytosis, with predominance of polymorphonuclear leukocytes (leukocytes 339/uL, 57.5% polymorphonuclear), a protein level of 81.7 mg/dL (normal: 15–40 mg/dL), and glucose of 53 mg/dL (normal: 40–70 mg/dL). Axial tomography was normal. Because the patient's clinical course suggested meningoencephalitis, she was hospitalized to continue the investigation and to initiate the treatment. She was empirically treated with intravenous ceftriaxone (100 mg/kg/day) and acyclovir (30 mg/kg/day). Brain and spinal cord magnetic resonance imaging (MRI) and electroencephalography (EEG) were both normal at this stage. After 3 days, there was no agent isolated in both CSF and uroculture, and ceftriaxone and acyclovir were discontinued. The patient showed gradual clinical improvement, and she was discharged after 7 days with a completely normal physical examination and laboratory tests. Stool parasitological examination, hemocultures, serologies, and immunological study were not conclusive at this point. On the day after discharge, the patient initiated visual symptoms and presented to the ophthalmology emergency department. She explained a history of progressive vision loss in her right eye (RE) and left eye (LE). Her mother noticed that she was unable to recognize faces and colors and intermittently adopted aggressive postures. Her best-corrected visual acuity was 20/400 in both eyes, with relative afferent pupillary defect in the LE. She did not collaborate in monocular vision tests and Ishihara's test because of a sudden repetitive onset of irritability and crying. Biomicroscopy was normal, and fundoscopy revealed bilateral optic disc edema. She was hospitalized once again. Contrast MRI was normal. Laboratory tests were repeated. She was empirically treated with a 5-day pulse of methylprednisolone (30 mg/kg/day) with clinical improvement. Anti-NMDAR autoantibodies were detected in the patient's serum and CSF (ELISA method). No other anti-neuronal antibodies were found, namely anti-AQ4, anti-MOG, anti-LGI1, anti-CASPR2, and anti-GlyR. Abdominopelvic ultrasound was normal with no tumor evidence. After 14 days of hospitalization, physical examination and analytic tests became normal. The patient's visual acuity recovered to 20/20 RE and 20/20 LE, with Ishihara's color vision 17/17 RE and LE. In the fundoscopy, she still presented a minor elevation in both optic discs. Optical coherence tomography (OCT) showed minor peripapillary retinal nerve fiber layer (ppRNFL) edema [Figure 1]. She was discharged with a prednisolone management dose therapy (1.4 mg/kg/day) plus esomeprazole (20 mg/day). The weaning from prednisolone was carried out over 6 months. After 1 year of follow-up, the patient has remained stable and brain MRI findings remain unchanged. She retained 20/20 visual acuity and 17/17 Ishihara's plate color vision. Fundoscopy revealed bilateral optic disc pallor, and OCT showed a decrease of ppRNFL [Figure 2].
Figure 1: Optical coherence tomography images, showing an increase of peripapillary retinal nerve fiber layer thickness

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Figure 2: One year later, optical coherence tomography images, showing a decrease of peripapillary retinal nerve fiber layer thickness

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  Discussion Top

Anti-NMDAR encephalitis is a rare condition first recognized in 2005 in young women with psychiatric illness and occult ovarian teratomas.[6] Although this disease has become increasingly recognized and identified as a significant cause of encephalitis, the medical community continues to learn about the diversity of symptoms presented.[6]

To our knowledge, this is the first reported case of a child experiencing bilateral acute optic neuritis with optic disc swelling in acute presentation of anti-NMDAR encephalitis.

There have been two reported older pediatric cases with anti-NMDAR encephalitis associated with recurrent optic neuritis during a few months, and one reported case with optic neuritis described during a relapse of the encephalitis.[7],[8],[9] In the adult population, four associated cases have been described.[10],[11],[12],[13] The key findings surrounding their presentation are listed in [Table 1].
Table 1: Review of the literature of optic neuritis associated with anti-N-methyl-D-aspartate receptor antibody

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The first step in establishing the diagnosis is to recognize the cardinal clinical manifestations of anti-NMDAR encephalitis, which typically involves neuropsychiatric manifestations.[14] In children, the initial features can be subtle or atypical and the disease can mimic other central nervous system conditions, as we also showed in our case report.[14]

In our patient, due to behavioral changes, gait impairment, and nuchal rigidity, the disease was initially misdiagnosed as viral or bacterial encephalitis and was empirically treated with antibiotics and antiviral agents, with both clinical and laboratorial improvements. After discharge, the beginning of visual symptoms took the patient back to the emergency department. The patient had bilateral acute optic neuritis with optic disc swelling. At this time, we detected the presence of anti-NMDAR autoantibodies in CSF and serum. Brain MRI and EEG were both normal. According to the literature, the diagnosis is clinical, and confirmation is through the demonstration of antibodies in serum or CSF. Brain MRI and EEG changes are nonspecific for the diagnosis.[3]

All suspected patients should be investigated for the presence of a tumor. Our patient did not have an underlying teratoma, which is not surprising, given that this is infrequent in female patients ≤6 years old.[14] In patients with neoplastic disease, tumor removal is proposed.[10] Immunotherapies with combined methylprednisolone and intravenous immunoglobulins have been used as first-line agents, and in patients with a lack of response, additional management options include rituximab, plasmapheresis, and cyclophosphamide.[10],[14],[15] However, experience in children is limited, and treatment is often empirical.[14] Management includes symptomatic treatment with antiepileptic, antipsychotic, and anticholinergic agents or monoamine depletors; benzodiazepines should also be used for insomnia, agitation, and behavioral problems.[11]

Our patient was successfully treated with a pulse of methylprednisolone followed by a management regimen of prednisolone therapy (1.4 mg/kg/day) with gradual tapering. Twelve months after beginning the treatment, she was free of visual and neurological symptoms.

Although the association between anti-NMDAR encephalitis and optic neuritis has not been widely reported, it should be included in the differential diagnosis of all children presenting with optic neuritis findings, and evaluation of those patients should include laboratory testing for anti-NMDAR autoantibodies. Our report provides additional evidence of the possible link between optic neuritis and anti-NMDAR encephalitis and documents additional potential presentation scenarios in children. This case suggests that we have to be aware of atypical signs in the diagnosis of anti-NMDAR encephalitis, such as visual abnormalities, especially in pediatric patients who are unable to explain changes in their vision.

Literature search PubMed

Last search in Pubmed in August 2020, without date restriction using the terms “Anti NMDAR encephalitis”, “Anti NMDAR encephalitis treatment”, “Optic Neuritis AND anti NMDAR encephalitis”, and “pediatric anti NMDAR encephalitis AND Optic Neuritis”.

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

Day GS, High SM, Cot B, Tang-Wai DF. Anti-NMDA-receptor encephalitis: Case report and literature review of an under-recognized condition. J Gen Intern Med 2011;26:811-6.  Back to cited text no. 1
Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005;58:594-604.  Back to cited text no. 2
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. 3
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 Jul;66(1):11-8. doi: 10.1002/ana.21756. PMID: 19670433; PMCID: PMC2826225.  Back to cited text no. 4
Bhat P, Ahmed A, Jolepalem P, Sittambalam C. A case report: Anti-NMDA receptor encephalitis. J Community Hosp Intern Med Perspect 2018;8:158-60.  Back to cited text no. 5
Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25-36. doi: 10.1002/ana.21050. PMID: 17262855; PMCID: PMC2430743.  Back to cited text no. 6
Ishikawa N, Tajima G, Hyodo S, Takahashi Y, Kobayashi M. Detection of autoantibodies against NMDA-type glutamate receptor in a patient with recurrent optic neuritis and transient cerebral lesions. Neuropediatrics 2007;38:257-60.  Back to cited text no. 7
Motoyama R, Shiraishi K, Tanaka K, Kinoshita M, Tanaka M. Anti-NMDA receptor antibody encephalitis with recurrent optic neuritis and epilepsy. Rinsho Shinkeigaku 2010;50:585-8.  Back to cited text no. 8
Kruer MC, Koch TK, Bourdette DN, Chabas D, Waubant E, Mueller S, et al. NMDA receptor encephalitis mimicking seronegative neuromyelitis optica. Neurology 2010;74:1473-5.  Back to cited text no. 9
Zoccarato M, Saddi MV, Serra G, Pelizza MF, Rosellini I, Peddone L, et al. Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis. J Neurol 2013;260:3185-7.  Back to cited text no. 10
Colley S, Smith J; Sore eyes and psychosis; Case Reports 2014; 2014:bcr2013201956. DOI: 10.1136/bcr-2013-201956.  Back to cited text no. 11
Mugavin M, Mueller BH 2nd, Desai M, Golnik KC. Optic neuropathy as the initial presenting sign of N-methyl-d-aspartate (NMDA) Encephalitis. Neuroophthalmology 2017;41:90-3.  Back to cited text no. 12
Yang HK, Kim JH, Park YH, Park KS, Kim JS, Hwang JM. Anti-NMDA-receptor optic neuritis in a patient with a history of encephalitis. Can J Ophthalmol 2017;52:e216-8.  Back to cited text no. 13
John CM, Mathew DE, Abdelaziz M, Mahmoud AA, AlOtaibi AD, Sohal AP. Anti-N-methyl-d-aspartate receptor encephalitis: A case series and review of the literature. J Pediatr Neurosci 2019;14:180-5.  Back to cited text no. 14
[PUBMED]  [Full text]  
Suthar R, Saini AG, Sankhyan N, Sahu JK, Singhi P. Childhood anti-NMDA receptor encephalitis. Indian J Pediatr 2016;83:628-33.  Back to cited text no. 15


  [Figure 1], [Figure 2]

  [Table 1]


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