A Pediatric Case of Anti-N-methyl-D-aspartate Receptor Encephalitis Associated With Optic Neuritis

We describe a pediatric case of bilateral optic neuritis (ON) as a feature of anti-N-methyl-D-aspartate receptor (NDMAR) antibodies encephalitis. ON in children with N-methyl-D-aspartate receptor (NMDAR) encephalitis is uncommon. Herein, we present a case with literature review and highlight its possible associations with demyelinating syndromes.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD A Pediatric Case of Anti-N-methyl-D-aspartate Receptor Encephalitis Associated With Optic Neuritis Jia Yue You, MD, Caroline Lacroix, MD, Daniela Toffoli, MD W e describe a pediatric case of bilateral optic neuritis (ON) as a feature of anti-N-methyl-D-aspartate receptor (NDMAR) antibodies encephalitis. ON in children with N-methyl-D-aspartate receptor (NMDAR) encephalitis is uncommon. Herein, we present a case with literature review and highlight its possible associations with demyelinating syndromes. A previously healthy 6-year-old-girl developed headaches, fatigue, and fever. She presented to hospital months later following 2 paroxysmal seizures. Brain MRI without contrast showed T2 and fluid-attenuated inversion recovery (FLAIR) sequence hypersignal at the right middle frontal gyrus. Lumbar puncture showed elevated white blood cells (11 · 109/L) and glucose (8 mmol/L), normal protein (0.18 g/L), and negative herpes simplex virus (HSV) polymerase chain reaction (PCR). Following discharge on clobazam, she developed abnormal behaviors, including impulsivity, irritability, and reclusiveness, and had 2 episodes of confusion with disorientation. Five months after symptom onset, she developed acute bilateral vision loss. Emergency room evaluation showed bilateral ataxia with intention tremor. Visual acuity was counting fingers in the right eye and 20/800 in the left eye. Pupils were sluggish with no relative afferent pupillary defect. Extraocular movements were normal. Neither eye could see the Ishihara control plates. Funduscopy (Fig. 1A) showed tortuous enlarged vessels with bilateral optic disc edema. Optical coherence tomography global optic nerve retinal nerve fiber layer (RNFL) thickness was 145 mm in the right eye and 160 mm in the left eye. Goldman visual field was impossible due to poor vision in the right eye and showed a central scotoma in the left eye. Head MRI and MRA showed patchy cortical/subcortical foci of T2/FLAIR hyperintense signal (Fig. 2). Lumbar puncture showed negative oligoclonal bands, slightly low glucose Departments of Ophthalmology and Pediatric Surgery (JYY, DT), Montreal Children’s Hospital, McGill University, Montreal, Canada; Department of Medical Imaging (CL), Montreal Children’s Hospital, McGill University Health Centre, Montreal, Canada; and Department of Ophthalmology (DT), Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montreal, Canada. The authors report no conflicts of interest. Address correspondence to Jia Yue You, MD, Department of Ophthalmology, McGill Academic Eye Centre, 5252 Boulevard de Maisonneuve O, Montréal, QC H4A 0A4, Canada; E-mail: jia.y.you@mail. mcgill.ca You et al: J Neuro-Ophthalmol 2022; 42: e289-e292 (2.9 mmol/L), high protein (0.58 g/L), and mildly elevated white blood cells (25 cells/mL) with opening pressure of 8 mm Hg. Blood and cerebrospinal fluid (CSF) were positive for anti-NMDAR antibodies (type 1/NR1) prompting a diagnosis of anti-NDMAR encephalitis. Other investigations, including anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, were negative (Table 1). Anti-aquaporin 4 (AQP4) antibodies were not requested. Treatment consisted of 2 days of intravenous immunoglobulin (IVIG) and 5 days of intravenous SoluMedrol with oral prednisone taper. During the following 2 weeks, visual acuity, color vision, and optic nerve head swelling improved (Fig. 1B, C). Three months later, the patient showed mild residual memory and behavioral changes with visual acuity of 20/20 in the right eye and left eye and color vision of 17/18 in each eye with Ishihara plates. Exam showed optic nerve pallor bilaterally (Fig. 1D). Optical coherence tomography showed global RNFL thinning with 67 mm in the right eye and 74 mm in the left eye. Goldman visual fields were normal. Anti-NMDAR encephalitis is a rare autoimmune encephalitis affecting 1 in 1.5 million people per year. Presenting features include a flu-like prodromal phase followed by neuropsychiatric findings, including headaches, seizures, movement disorders, agitation, and paranoia (1). Associations include tumors, mainly antibody-producing ovarian teratomas. Anti-NMDAR antibody production may also follow viral encephalitis, particularly from HSV (1). First-line treatment includes immunosuppressive therapy with corticosteroids, IVIG, plasmapheresis, and tumor removal (1). Our patient had negative abdominal ultrasonography, paraneoplastic antibodies panel, and CSF HSV PCR. She responded rapidly to corticosteroids and IVIG with only mild residual neuropsychiatric sequelae. Following the recent review of neuro-ophthalmic features of autoimmune encephalitis by Bohm et al, we present a pediatric case of NMDAR encephalitis with complete ophthalmic assessment to highlight one of the suggested associations (1). Pediatric ON in the context of NMDAR encephalitis is uncommon. Literature review has shown that ON may occur before, concurrent with, or following encephalitis onset, may be anterior or retrobulbar, and may be recurrent (2–4). Following treatment, there is often significant improvement in visual function. Our patient presented with bilateral anterior ON 5 months following e289 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Fundus photography of optic nerve of the right eye (top row) and left eye (bottom row) at the initial visit, 1 week, 2 weeks, and 3-months since presentation. Initial optic nerve swelling decreased significantly across visits with optic disc pallor seen at 3-month follow-up. neuropsychiatric symptom onset. Her initial profound bilateral vision loss showed excellent recovery. Although ON in the context of NMDAR encephalitis has been reported as an isolated phenomenon, it can also occur in the context of other demyelinating syndromes. Indeed, both adult and pediatric patients with NMDAR encephalitis can present with so-called overlap syndromes, whereby they may harbor features of neuromyelitis (NMO) spectrum or demyelinating disease, with or without the presence of anti-AQP4 or anti-MOG antibodies. Titulaer et al showed that among 691 patients with anti-NMDAR encephalitis, 23 (3.3%) had clinical and/or MRI findings suggestive of demyelinating disorder, 9 of whom had anti-AQP4 and 9 anti-MOG antibodies. In this study, clinical or radiological features of demyelination occurred sequentially or concurrent with symptoms of NMDAR encephalitis, with demyelinating episodes proving more difficult to treat than encephalitis symptoms and often requiring second-line immunotherapy. Importantly, these second-line treatments sometimes differed from those typically used as second-line agents for NMDAR encephalitis. Fan et al also looked at the rate of overlap between NMDAR encephalitis and demyelinating disorder and treatment response (5). They found that 11.9% of patients with anti-MOG antibodies and 0.6% of patients with NMO spectrum disease also had NMDAR FIG. 2. A–C. T2 axial fluid-attenuated inversion recovery images showing new lesions involving the cortex and subcortical white matter of the bilateral superior frontal gyri, of the mid portion of the right cingulate gyrus, of the right peri-insular frontal and right parietal lobes in comparison to MRI brain done 3 months prior. There was a mixed evolution of the findings between the first different MRIs. These are nonspecific findings, but given the clinical context and the multiphasic course of the disease, diagnostic considerations include notably N-methyl-D-aspartate receptor encephalitis. The distribution of the lesions could have been seen with acute disseminated encephalomyelitis (ADEM). However, the clinical evolution was not consistent with ADEM. Otherwise, the studies were not suggestive of MS, and there were no signs of optic neuritis seen on the orbit section of the brain MRI. e290 You et al: J Neuro-Ophthalmol 2022; 42: e289-e292 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence TABLE 1. Investigations and imaging Negative blood tests CSF Imaging Antineuronal Ab panel (Anti-Hu, RI, YO, amphiphysin, CV2, PNMA2) Anti-PR3 Ab, Anti-MPO Ab Anti-TPO Ab, ACE Anti-MOG Ab Bartonella IgG, CMV IgG/IgM, Mycoplasma IgM Lyme Ab, syphilis EIA EBV, adenovirus, enterovirus PCR HIV Ab/Ag Hepatitis Bs Ab, hepatitis C Ab, hepatitis Be Ag Blood bacterial culture Albumin 0.26 g/L (0.14–0.20) Glucose 2.9 mmol/L (3.9–5.0) Protein 0.58 g/L (0.15–0.45) IgG 0.0310 g/L (0.0050–0.0340) Hemorrhagic specimen—total cells 8,775 cells/mL, RBC 8750 cells/mL, WBC 25 cells/mL Negative bacterial culture Negative oligoclonal bands MRI head C+/C2 MRI orbits G+/G2 MRA head C-MRI total spine Abdomen and pelvis ultrasound Whole body 18F—PDG PET/CT Chest x-ray Multiple new patchy cortical/subcortical foci of T2/FLAIR hyperintense signal— with most lesions showing punctate peripheral and central enhancement and one lesion showing focus of central cavitation in right medial frontal region Requested by ophthalmology but decision was made to cancel as MRI brain had already been performed, patient had large number of upcoming tests, and overall medical condition was prohibitive All unremarkable Ab, antibody; ACE, angiotensin-converting enzyme; Ag, antigen, C+/C2, with/without contrast; CMV, cytomegalovirus; CSF, cerebral spinal fluid; CT, computerized tomography; EBV, Epstein–Barr virus; EIA, enzyme immunoassay; FLAIR, fluid attenuated inversion recovery; G+/G2, with/without gadolinium; HIV, human immunodeficiency virus; IgG/M, immunoglobulin G/M; MOG, myelin oligodendrocyte glycoprotein; MPO, myeloperoxidase; MRI/MRA, magnetic resonance imaging/angiography; PCR, polymerase chain reaction; PDG, fluorodeoxyglucose; PET, positron emission tomography; PR3, proteinase 3; RBC, red blood cell; TPO, thyroid peroxidase; WBC, white blood cell. antibodies. In their study, patients with both antiNMDAR and anti-MOG antibodies responded better to steroid and IVIG treatment than those with anti-NMDAR and anti-AQP4 antibodies, with the latter more commonly requiring second-line therapies, including rituximab or cyclophosphamide. This was true for both symptoms related to NMDAR encephalitis and demyelinating disorder, further highlighting the importance of recognizing disease overlap between these entities and obtaining antiMOG and anti-AQP4 antibody testing when suspicion arises. Although our patient developed ON, she never presented with brain or spinal cord lesions typical for acute disseminated encephalomyelitis, multiple sclerosis, or NMO, and anti-MOG testing was negative. Anti-AQP4 You et al: J Neuro-Ophthalmol 2022; 42: e289-e292 antibody testing was not performed in our patient because brain MRI was not typical for NMO, spine MRI was normal, and vision recovery was excellent. Nonetheless, anti-AQP4 antibody testing might have been useful at onset to guide prognosis and treatment. In sum, clinicians should be aware of the possible association of NMDAR encephalitis with ON. Although ON may occur in NMDAR encephalitis as an isolated phenomenon, it may also occur as part of an “overlap syndrome” and in the context of an associated demyelinating syndrome. In all patients with NMDAR encephalitis and concurrent or sequential ON, we recommend anti-MOG and anti-NMO testing because this may help to prognosticate and guide treatment. e291 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Y. You, and D. Toffoli; b. Acquisition of data: J. Y. Yue You, and D. Toffoli; c. Analysis and interpretation of data: J. Y. Yue You, D. Toffoli, and C. Lacroix. Category 2: a. Drafting the manuscript: J. Y. You, and D. Toffoli; b. Revising it for intellectual content: D. Toffoli, and C. Lacroix. Category 3: a. Final approval of the completed manuscript: D. Toffoli. REFERENCES 1. Bohm PE, Chen JJ, Bhatti TM, Eggenberger ER. Neuroophthalmic features of autoimmune encephalitides. J Neuroophthalmol. 2020;40:385–397. e292 2. Yang HK, Kim JH, Park YH, Park KS, Kim JS, Hwang JM. AntiNMDA-receptor optic neuritis in a patient with a history of encephalitis. Can J Ophthalmol. 2017;52:e216–e218. 3. Liu X, Giri M, Ling W, Li T. Optic neuritis associated with antiNMDA receptor antibody in the remission phase of anti-NMDA receptor encephalitis. Neurol India. 2020;68:474. 4. Titulaer MJ, Höftberger R, Iizuka T, Leypoldt F, McCracken L, Cellucci T, Benson LA, Shu H, Irioka T, Hirano M, Singh G, Calvo AC, Kaida K, Morales PS, Wirtz PW, Yamamoto T, Reindl M, Rosenfeld MR, Graus F, Saiz A, Dalmau J. Overlapping demyelinating syndromes and anti-NMDA receptor encephalitis. Ann Neurol. 2014;75:411–428. 5. 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