Opsoclonus-Myoclonus Syndrome in Anti–N-Methyl-D-Aspartate Receptor Encephalitis

OBSERVATION Opsoclonus-Myoclonus Syndrome in Anti–N-Methyl-D-Aspartate Receptor Encephalitis

Mary Kurian, MD; Patrice H. Lalive, MD; Josep O. Dalmau, MD; Judit Horvath, MD

Background: Anti–N-methyl-D-aspartate receptor (anti- bility, and opsoclonus-myoclonus. Cerebrospinal fluid NMDAR) encephalitis has been recently reported as au- examination showed mild lymphocytic pleocytosis and toimmune/paraneoplastic encephalitis, affecting mostly intrathecal IgG synthesis with oligoclonal bands. The pa- young females. tient’s condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hal- Objective: To describe opsoclonus-myoclonus syn- lucinations. These gradually subsided; however, a frontal drome in association with anti-NMDAR antibodies. behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti- Design: Case report. NMDAR antibodies were found in the cerebrospinal fluid. Setting: Geneva University Hospital. Conclusions: Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagno- Patient: A 23-year-old woman with opsoclonus- myoclonus syndrome. sis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively Results: Two weeks after an episode of gastroenteritis, good prognosis. the patient developed symptoms of depression associated with psychomotor slowing, progressive gait insta- Arch Neurol. 2010;67(1):118-121

NTI–N-METHYL-D-ASPAR- therapies. However, some patients may de- tate receptor (anti- velop a chronic autoimmune disease.1 NMDAR) encephalitis, ini- The etiologies of opsoclonus-myoclo- tially described in 2007, is nus syndrome include paraneoplastic, para- characterized by a well- infectious, toxic, and metabolic causes. As definedA set of clinical and immunologic far as immunologic mechanisms are con- characteristics. According to a recently cerned, no single antibody marker has been published series of 100 patients, it affects identified.2 Anti-Ri antibodies have been re- mostly young females, and in approxi- ported in several cases of paraneoplastic op- mately half of them, an ovarian teratoma soclonus-myoclonus, and anti–glutamic is found. Typically, after a viral-like pro- acid decarboxylase antibodies have been dromal event, prominent psychiatric found in the serum and CSF of 1 patient with idiopathic opsoclonus-myoclonus- ataxia syndrome.3 Two cases of opsoclonus- Video available online at myoclonus syndrome have been reported www.archneurol.com with benign ovarian teratoma, but anti- Author Affiliations: NMDAR antibodies were not found (I.T.Y. Department of Neurosciences, symptoms develop, followed by a Kawachi, MD, PhD, et al, unpublished data, Clinic of Neurology decreased level of consciousness (usu- 2009).4 Herein we describe a patient who (Drs Kurian, Lalive, and ally in association with abnormal move- developed opsoclonus-myoclonus syn- Horvath), and Department of ments and autonomic instability) and drome and ataxia along with an otherwise Genetic Medicine and finally a gradual recovery phase. Anti- typical presentation of anti-NMDAR Laboratory, Laboratory NMDAR antibodies can be detected in se- encephalitis. Medicine Service (Dr Lalive), rum or cerebrospinal fluid (CSF). De- Faculty of Medicine, University spite the severity of the illness, which of Geneva, Geneva, REPORT OF A CASE Switzerland; and Department of might include central hypoventilation ne- Neurology, University of cessitating ventilatory support, many cases Pennsylvania, Philadelphia are self-limited and respond well to tu- A 23-year-old female patient had an un- (Dr Dalmau). mor removal and/or immunomodulatory complicated episode of gastroenteritis with

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 fever, which resolved spontaneously. Two weeks later, nance imaging, pelvic ultrasonography and whole-body she presented with speech difficulties, hypophonia, positron-emission tomography, there was no evidence of anxiety, and tremulous eye and head movement fol- tumor. The patient was also negative for tumor markers lowed by increasing gait instability. She was diagnosed and other antineuronal antibodies. with depression and initially hospitalized in the psychi- Although the patient showed a remarkable improve- atric division. Neurological examination revealed se- ment, the cognitive and behavioral abnormalities and ataxia vere psychomotor slowing, apathy, hypomimia, bifacial persisted and she was treated with a second course of im- paresis, opsoclonus, myoclonic head and trunk move- munoglobulins 6 weeks after symptom presentation. The ments, static and kinetic ataxia, as well as a right-sided opsoclonus remained discrete and a continuous improve- hemiparesis (video, day 1, available at http://www ment of the cerebellar symptoms as well as of the frontal .archneurol.com). Results of initial CSF examination behavior was observed. On the seventh week, she was able showed mild lymphocytic pleocytosis (29 leuko- to use a computer and walk without assistance. Speech, cytes/µL [to convert to ϫ109 L, multiply by 0.001), 4% gait, and behavior continued to improve gradually dur- plasmocytes, normal protein and glucose concentra- ing the following weeks. Results of electroencephalogra- tions, and intrathecal IgG synthesis with oligoclonal bands. phy and the routine CSF examination became normal Infectious, toxic, and metabolic workup results were nega- (Figure, B). She received 2 more courses of immunoglobu- tive. Brain magnetic resonance imaging results were nor- lins on the 10th and 14th week, after which she returned mal; electroencephalography showed generalized slow- home. At the last follow-up 5 months after symptom pre- ing of activity with left-sided predominance and no sentation, most symptoms had resolved, but she had per- epileptiform discharges. sistent frontal behavioral abnormalities. The patient’s condition worsened rapidly with devel- opment of tetraparesis and a pseudobulbar paresis. A second electroencephalography showed more marked dif- COMMENT fuse slowing (Figure, A). A pulmonary embolism was discovered on chest computed tomography and a per- Our patient’s clinical features are similar to those re- sistent sinus tachycardia, probably due to dysautono- ported in association with anti-NMDAR encephalitis. In mia, required treatment with ␤-blockers. The patient was addition, she developed opsoclonus-myoclonus syn- initially treated for probable viral or autoimmune en- drome and cerebellar symptoms, which have not been cephalitis with acyclovir and a high dose of intravenous previously reported in this disorder. Interestingly, using methylprednisolone. Her condition continued to worsen rat brain and cerebellum immunohistochemistry, our pa- to almost an akinetic mutism; she became incontinent tient’s CSF and serum did not show any additional re- and needed tube feeding, but she had no respiratory dif- activity to that observed with anti–NR1/NR2 antibodies ficulties (video, day 8). Plasma exchange was started, but (mainly involving neuropil of hippocampus, and to a lesser the second session was complicated by a systemic hypo- degree other areas of brain and granular layer of cerebel- tension, and it was decided to switch to intravenous im- lum; data not shown), suggesting that the opsoclonus was munoglobulins. A slow improvement was observed in the related to dysfunction of the NMDARs and/or to the pres- first days she was treated with intravenous immuno- ence of a yet uncharacterized additional antibody. globulins. She started moving and speaking, albeit with In a series of 21 patients with opsoclonus-myoclonus dysarthria, stammer, and palilalia, and her opsoclonus syndrome, potential target autoantigens localized to the diminished. The next 10 days were characterized by a postsynaptic density.2 The postsynaptic density is a com- delusional state associated with agitation, hyperventila- plex of proteins associated with the glutamate NMDAR. tion, akathisia, obsessions, and hallucinations. These This observation suggests that NMDAR dysfunction might symptoms subsided, leaving a severe frontal dysfunc- be involved, at least in these cases, in the generation of tion characterized by disinhibition, familiarity, logor- opsoclonus. rhea, emotional lability, and executive deficit. The pa- Opsoclonus-myoclonus syndrome is often associated tient’s speech, opsoclonus, and ataxia continued to with infection or cancer. Despite extensive investigations, improve. She was able to sit up by the end of the third including whole-body positron-emission tomography, we week, and by the fifth week she was able to walk with did not find any evidence of tumor in our patient. She re- support. sponded well to immunotherapy and has had a good clini- Results of repeated magnetic resonance imaging 1 cal outcome. From the available literature, it is under- month after the initial study were normal. Immuno- stood, however, that relapses can occur, especially if a tumor logic workup revealed the presence of antibodies to NR1/ is not removed or detected. It should be noted that in 40% NR2 heteromers of NMDAR, confirming the diagnosis of patients in the Dalmau et al case series,1 oncologic as- of anti-NMDAR encephalitis. Using immunocytochem- sessment did not reveal the presence of any tumor. In 6 istry on HEK293 cells transfected with NR1 and NR2 sub- patients, the tumor was diagnosed (56 months to 3 years) units of NMDAR and equally diluted (1:10) CSF and se- after recovery from the encephalitis. rum obtained at symptom presentation, antibodies were The strategies for long-term management of NMDAR only identified in the CSF. Cerebrospinal fluid antibody encephalitis are limited. Because our patient had an ex- titer by enzyme-linked immunosorbent assay was 2890 cellent response to intravenous immunoglobulin therapy, relative fluorescence units (normal reference value Ͻ200). we did not opt for a more aggressive immunosuppres- Despite an extensive oncologic workup, including ab- sion. In the case series of Dalmau et al, after discharge, dominal computed tomography and magnetic reso- 85% of patients who were left with mild deficits or even-

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Figure. Electroencephalography of a 23-year-old woman with opsoclonus-myoclonus syndrome. A, Recording on day 10 shows bursts of diffuse delta activity on a background of theta rhythm. The first marker indicates eye closure; the second marker, eye opening. B, Recording on day 60 shows a normal alpha activity with ocular artifacts in the frontopolar leads; the electrocardiogram shows tachycardia (100 beats/min). The marker indicates eye closure.

tually attained full recovery had signs of frontal lobe dys- adults) described by Dalmau et al,1 15had1to3re- function, including poor attention, impulsivity, and be- lapses of encephalitis. A more recent series indicated a havioral disinhibition. Our patient still had features of 25% rate of relapses and slower improvement, particu- frontal lobe dysfunction 5 months after symptom pre- larly in patients without a tumor.6 On the other hand, sentation. In 1 case of reversible anti-NMDAR encepha- disappearance of autoantibodies may indicate a remis- litis, serum antibodies were not detected at the 1-year fol- sion. Besides clinical follow-up, repeated antibody mea- low-up, though the tumor was not removed.5 surements in serum and CSF might be helpful in early Interpretation of these anecdotal cases should be cau- detection of a relapse. tious because relapses may occur several years after ini- Recent reports indicate that patients with ovarian tera- tial presentation. In the series of 100 patients (mostly toma and isolated or classic opsoclonus-myoclonus syn-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 drome do not develop NMDAR antibodies (I.T.Y. Kawa- Online-Only Material: The video is available at http: chi, MD, PhD, et al, unpublished data, 2009).4 Our study //www.archneurol.com. shows that opsoclonus-myoclonus may overlap with the Additional Contributions: Sabina Catalano, Dr Blaise syndrome described in anti-NMDAR encephalitis in which Christ, Alessandra Coeytaux, MD, Olga Delaspre, Adrian case patients do have NMDAR antibodies. Guggisberg, MD, Jean Paul Guyot, Dr Robert Weissert, Andre Zacharia, MD, and Theodore Landis performed the clinical follow-up of the patient. Accepted for Publication: July 25, 2009. Correspondence: Patrice H. Lalive, MD, Department of Neurology, University Hospital of Geneva, Rue Gabri- REFERENCES elle Perret-Gentil 4, GE-1211 Geneva, Switzerland (patrice [email protected]). 1. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti NMDA-receptor encephalitis: case Author Contributions: Study concept and design: Kurian, series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):1091- 1098. Lalive, and Horvath. Acquisition of data: Kurian and Hor- 2. Bataller L, Rosenfeld MR, Graus F, Vilchez JJ, Cheung NK, Dalmau J. Autoantigen di- vath. Analysis and interpretation of data: Kurian, Lalive, versity in the opsoclonus-myoclonus syndrome. Ann Neurol. 2003;53(3):347-353. Dalmau, and Horvath. Drafting of the manuscript: Kurian, 3. Markakis I, Alexiou E, Xifaras M, Gekas G, Rombos A. Opsoclonus-myoclonus- Lalive, and Horvath. Critical revision of the manuscript for ataxia syndrome with autoantibodies to glutamic acid decarboxylase. Clin Neurol important intellectual content: Kurian, Dalmau, and Hor- Neurosurg. 2008;110(6):619-621. 4. Fitzpatrick AS, Gray OM, McConville J, McDonnell GV. Opsoclonus myoclonus syn- vath. Obtained funding: Dalmau. Administrative, techni- drome associated with benign ovarian teratoma. Neurology. 2008;70(15):1292- cal, and material support: Kurian, Dalmau, and Horvath. 1293. Study supervision: Lalive and Horvath. 5. Shindo A, Kagawa K, Ii Y, Sasaki R, Kokubo Y, Kuzuhara S. Anti-N-methyl-D- Financial Disclosure: None reported. aspartate receptor-related grave but reversible encephalitis with ovarian teratoma in 2 Japanese women presenting with excellent recovery without tumor Funding/Support: This study was supported in part by resection. Eur Neurol. 2009;61(1):50-51. grant 2RO1CA89054-06A2 from the National Institutes 6. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate receptor (NMDAR) of Health (Dr Dalmau). encephalitis in children and adolescents. Ann Neurol. 2009;66(1):11-18.

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