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Brain & Development 29 (2007) 254–256

Case report

Acute cerebellar ataxia and consecutive cerebellitisproduced by glutamate receptor d2 autoantibody

Takashi Shiihara a,b,*, Mitsuhiro Kato a, Akihiro Konno c,Yukitoshi Takahashi d, Kiyoshi Hayasaka a

a Department of Pediatrics, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japanb Department of Neurology, Gunma Children’s Medical Center, 779 Shimohakoda, Hokkitsu-machi, Shibukawa, Gunma 377-8577, Japan

c Department of Pediatrics, Yamagata Prefectural Central Hospital, 1800 Aoyagi, Yamagata 990-2292, Japand National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka 420-8688, Japan

Received 15 June 2006; received in revised form 6 September 2006; accepted 7 September 2006

Abstract

Acute cerebellar ataxia is usually a self-limited benign disease, which may develop in children after certain viral infections or vac-cinations. There are several reports of acute cerebellar ataxia associated with autoantibodies. Glutamate receptor d2, a member ofthe glutamate receptor family, is predominantly expressed in cerebellar Purkinje cells and plays a crucial role in cerebellar functions.To date anti-GluRd2 autoantibody was detected in a patient with chronic cerebellitis. Herein, an 18-month-old boy presented withcerebellar ataxia 9 days following a mild respiratory tract infection. Although cerebellar ataxia gradually improved, it worsened yetagain following mumps and varicella virus infection. Cerebro-spinal fluid examination and magnetic resonance imaging of the braindemonstrated pleocytosis and meningeal enhancement, respectively. Furthermore, glutamate receptor d2 autoantibody was detectedin serum and cerebro-spinal fluid. Thus, we believe that the glutamate receptor d2 autoantibody may play a role in cerebellar ataxiaand consecutive cerebellitis.� 2006 Elsevier B.V. All rights reserved.

Keywords: Acute cerebellar ataxia; Cerebellitis; Glutamate receptor d2 autoantibody

1. Introduction

Acute cerebellar ataxia (ACA) is usually a self-limitedbenign disease, showing temporary cerebellar signs suchas gait disturbance and action tremor, which may devel-op in children after certain viral infections or vaccina-tions [1]. As a prodromal illness causing ACA,varicella is the primary cause, followed by mumps,mycoplasma and the Epstein-Barr virus [2]. Glutamatereceptor d2 (GluRd2), a member of the glutamate recep-tor family, is predominantly expressed in cerebellar Pur-

0387-7604/$ - see front matter � 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.braindev.2006.09.004

* Corresponding author. Tel.: +81 279 52 3551; fax: +81 279 522045.

E-mail address: shiihara-ind@umin.net (T. Shiihara).

kinje cells and plays a crucial role in cerebellar functions[3]. Herein, we describe a patient with ACA and consec-utive cerebellitis associated with anti-GluRd2autoantibody.

2. Case report

An 18-month-old boy exhibited gait instability (day 0of illness) and hand tremor 9 days following a mildrespiratory tract infection. Perinatal history and devel-opmental stages prior to this illness were normal. Gaitdisturbance worsened and the infant was admitted tohospital on day 7. Routine laboratory tests, cerebro-spinal fluid (CSF) examination and magnetic resonance

T. Shiihara et al. / Brain & Development 29 (2007) 254–256 255

imaging (MRI) of the brain and spinal cord demonstrat-ed normal findings. Gait disturbance and hand tremorgradually improved and the patient was discharged.On day 13, varicella skin lesions appeared and thepatient was administered acyclovir (800 mg/day for 5days). However, gait disturbance and hand tremor wors-ened on day 14, and the patient was unable to walk onday 16. The child was re-admitted to hospital on day 18.The patient’s sister demonstrated apparent parotitis onthe same day. CSF examination on day 18 demonstratedpleocytosis (144 mononuclear cells and 6 polynuclearcells/ll), protein 28 mg/dl and glucose 50 mg/dl. Themumps virus was detected in CSF by the polymerasechain reaction (PCR), while the varicella and herpessimplex virus were not. A brain MRI, on day 22, dem-onstrated normal findings except for meningealenhancement (Fig. 1). The patient was referred to ourhospital on that day. On examination, the child wasawake and alert. The patient could sit without assistancebut was unable to walk. Mild tremor of the hands andmuscular hypotonia were noted. CSF examination, onday 22 of illness, demonstrated 27 mononuclear cells/ll, protein 41 mg/dl, glucose 41 mg/dl, lactate 12.6 mg/dl, pyruvate 0.86 mg/dl, myelin basic protein 45.5 pg/ml and negative oligoclonal band. CSF cytokines werenormal except for a mild elevation of interleukin-2(15.9 pg/ml, normal < 4.6). Autoantibody to GluRd2(only IgM without IgG) was positive in serum andCSF. The patient was able to walk with support and

Fig. 1. An axial gadolinium-enhanced T1-weighted MRI, on day 21,shows meningeal enhancement (arrow).

was discharged on day 37. On day 60, the patient couldwalk with a wide-base gait. On the same day, IgM anti-GluRd2 antibody was weakly positive, however, IgGanti-GluRd2 antibody remained negative in serum.Anti-varicella and mumps virus IgG antibodies weremeasured by enzyme-linked immunosorbent assay,showing a more than fourfold rise in antibody titerbetween day 22 and 60, 500 and 2100 and <230 to3800, respectively. Six months after the onset, lympho-cyte stimulation tests (LST) were conducted usinghomogenate of D33 (cell line expressing GluRd2 sub-units) [4]. Cell proliferation was measured by 3H-thymi-dine uptake, and the ratio of the counts of thestimulated samples to the control counts was evaluatedas the stimulation index (SI), with an SI > 2 regardedas positive [4,5]. SI with D33 homogenate stimulationwas 3.8.

3. Discussion

ACA is diagnosed on clinical grounds with CSFpleocytosis (>5/ll) present in approximately one halfof ACA children, ranging from 0 to 107/ll. Theabsence of neuroimaging abnormalities is not a prere-quisite of ACA diagnosis [1,2]. Several authors report-ed acute ataxic cases with MRI abnormalities,involving the cerebellum and/or brain stem, as ACA[6]. Others reported such cases as acute cerebellitis(AC). Sawaishi et al. reviewed case reports of AC;all had cerebellar lesions, and meningeal enhancementwas detected in 3 out of 18 cases and CSF pleocytosiswas present in 14 out of 18 cases, ranging from 0 to1450/ll [7]. However, the distinction between ACAand AC is somewhat obscure; meningeal enhancementcould suggest that the re-exacerbation of ataxiaobserved in this patient was due to consecutive cere-bellitis. Thus, the characterization of ACA and ACmust be established more precisely.

GluRd2 is predominantly expressed in cerebellar Pur-kinje cells [3]. In previous studies, GluRd2 gene knock-out or mutated mice displayed ataxia and injection ofthe antibody, specific for the ligand-binding region ofGluRd2, into the subarachinoidal supracerebellar spaceof adult mice caused transient cerebellar dysfunction,including ataxia [3]. Anti-GluRd2 autoantibody has alsobeen reported in a patient with chronic cerebellitis,showing fluctuation of cerebellar ataxia for 2 years [8].In that case, anti-GluRd2 IgM and IgG antibodies wereboth positive during the first episode of ataxia. In ourpatient, anti-GluRd2 IgM antibody was positive notonly in plasma but also CSF, and the level decreasedwith clinical improvement. However, lymphocytes stim-ulated by LST are usually T cells, thus a positive LSTresult with homogenate of D33, a cell line expressingGluRd2 subunits, could comprise T cell activation

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[4,5]. We estimated that these GluRd2 autoantibodiesand a positive LST result were produced by cross-reac-tion as a result of molecular mimicry following viralinfection, and played an important role in consecutivecerebellitis in the present case.

To date, there have been several reports of ACA orAC associated with autoantibodies, such as anti-centro-some antibody post-varicella and anti-triosephosphateisomerase antibody after Epstein-Barr viral infection[9,10]. However, these reports did not contain detailedclinical descriptions, thus, it is difficult to say whetherthere are any clinical differences, including CSF andbrain MRI findings, in ACA/AC with or without relatedautoantibodies. Follow-up of cerebellar ataxia and anti-GluRd2 autoantibody in our patient could further clar-ify this relationship. Moreover, humoral or cytologicalimmunologic examinations in ACA/AC patients mightclarify their pathogenesis.

Acknowledgment

We thank Dr. Takashi Ichiyama (Department ofPediatrics, Yamaguchi University School of Medicine,Yamaguchi, Japan) for CSF cytokine measurement.

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