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Parkinsonism and Related Disorders 20 (2014) 1309e1310

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Parkinsonism and Related Disorders

journal homepage: www.elsevier .com/locate/parkreldis

Letter to the Editor

Opsoclonus-myoclonus-ataxia syndrome associated with dengue virusinfection

Keywords:DengueOpsoclonus-myoclonus syndromeOpsoclonus-myoclonus-ataxia syndromeOpsoclonusMyoclonus

http://dx.doi.org/10.1016/j.parkreldis.2014.09.0021353-8020/© 2014 Elsevier Ltd. All rights reserved.

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Dengue is a systemic viral infection transmitted betweenhumans by Aedes mosquitoes. It is an important and increasingglobal health threat with fifty million infections occurring annuallyacross 100 countries in tropical and subtropical regions [1,2]. More-over, increasing numbers of travelers return from endemic regionswith dengue, which represents the second leading cause of acutefever in travelers [1,2].

Dengue can manifest with diverse neurological features, mostcommonly encephalopathy or encephalitis [3]. Movement disor-ders are rare with only two cases of parkinsonism (bradykinesia)reported, both from Malaysia; and one report of opsoclonus-myoclonus-ataxia syndrome (OMAS) involving two patients fromIndia [3,4]. However, only one of the two OMAS cases by Vermaet al. was reported in detail [4]. This patient demonstrated neitherleukopenia nor thrombocytopenia (which are seen in the vast ma-jority of patients with symptomatic dengue), and only dengue IgMwas documented, which can remain persistently positive for up to90 days after infection [1,2]. A single positive dengue IgM can onlybe considered a presumptive diagnosis of acute dengue [1,2]. Here,we confirm the association between dengue and OMAS by report-ing two patients with typical clinical features of dengue, and thediagnosis of acute infection was confirmed by IgG seroconversionor the more specific non-structural protein 1 (NS1) antigen test[1,2]. To our knowledge, this also represents the first report of a pe-diatric case of dengue-associated OMAS.

Patient 1. A 30-year-old Syrian man, resident in Malaysia for thepast three years, presented with a three-day history of fever, head-ache, arthralgia, myalgia and generalized petechiae. There was nohistory of recreational drug use or high-risk behaviors. He had amild leukopenia and thrombocytopenia (on day 4 of illness, whitecell count was 3.0 � 109/L, platelet count 132 � 109/L, hematocrit47%). A presumptive diagnosis of dengue fever was made on the ba-sis of a positive serum dengue IgM result. As he was clinically sta-ble, he was discharged and managed as an outpatient. He was welluntil nine days after initial symptom onset, when he was readmit-ted with acute confusion. On examination, there were involuntary,chaotic and rapid multidirectional conjugate saccadic eye move-ments, as well as spontaneous non-rhythmic multifocal myoclonicjerks involving the craniocervical region (with frequent eye

, trunk, and upper and lower limbs, consistent withOMAS (Video). Themyoclonic jerks were aggravated bymovementsand by visual, acoustic and tactile stimuli. He was unable to sit upfor more than several seconds or stand because of truncal myoc-lonus. He had an intense fear and nervousness without apparentexplanation, as well as marked emotional lability with episodesof inappropriate crying and laughing. The remaining neurologicaland physical examinations were normal and there was no neckstiffness.

The diagnosis of dengue was confirmed by paired sera showingIgG seroconversion. Serology for Leptospira, hepatitis A, B and C,HIV, cytomegalovirus and syphilis were negative, as was connectivetissue disease screen. Magnetic resonance imaging (MRI) of thebrain showed pachy- and leptomeningeal enhancement, but nobrain parenchymal changes (Fig. 1). Electroencephalogram (EEG)showed normal alpha rhythmwith focal left temporal slowing. Ce-rebrospinal fluid (CSF) analysis was normal (0 white blood cells,glucose 3.3 mmol/L, protein 0.38 g/L). He was treated symptomat-ically with low-dose clonazepam (1e2 mg daily or bid) with a goodresponse. At one month after illness onset, the opsoclonus hadresolved and gait was normal. He demonstrated only mildmyoclonic jerks of the hands with action. Fear was also 80e90%improved.

Patient 2. A 10-year-old Myanmar boy presented on day 5 of fe-ver with severe hypotension (systolic blood pressure of 70 mmHgand pulse rate of 116 beats per minute). He had leukopenia andthrombocytopenia (white cell count 3.2 � 109/L, platelet count24 � 109/L, hemoglobin 16.2 g/dL). He was resuscitated with intra-venous fluids and recovered from shock after a few hours. The diag-nosis of dengue shock syndromewas confirmed by positive dengueIgM and NS1 antigen on day 5 of illness. On day 7, he became irri-table and developed opsoclonus, subtle myoclonus involving thehead and neck, and cerebellar ataxia (wide-based gait, truncalataxia and scanning speech). The rest of the physical examinationwas unremarkable. Brain computed tomography and EEG werenormal. Lumbar puncture and brain MRI were not performed. Pred-nisolone (2 mg/kg/day for four weeks, then tapered off overanother four weeks) was initiated on day 8 of illness; no othersymptomatic treatments were given. The opsoclonus improvedsignificantly and the ataxia resolved over two weeks, howeverthere was still irritability and aggressiveness at 3 months. He wasnormal at the last review at 6 months.

Our cases highlight several additional points of interest. Irrita-bility and emotional lability are common in OMAS [5], but to ourknowledge intense fear (seen in Patient 1) has not been reportedpreviously. This patient was very sensitive to visual stimuli and

Fig. 1. 3-Tesla brain magnetic resonance imaging. A. Coronal pre-contrast T2-weighted FLAIR image demonstrating high signal within the sulci in keeping with leptomeningealpathology (arrows); B. Post-gadolinium T1-weighted image demonstrating subtle but diffuse pachymeningeal enhancement (arrows).

Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1309e13101310

even voluntarily bringing his own hand close to the face exacer-bated the myoclonic jerks and opsoclonus. Neurological manifesta-tions can occur with typical dengue fever (Patient 1), or inassociation with dengue shock syndrome (Patient 2). In fact, it isincreasingly recognized that patients can present neurologicalsymptoms in the absence of other typical symptoms of dengueinfection (e.g., rash, myalgias, joint or abdominal pain and diarrhea)[3]. Although direct viral invasion of the brain cannot be excluded, apost-infectious immune-mediated mechanism is proposed to un-derlie dengue-associated OMAS. This is supported by the delayedonset of OMAS in Patient 1, and the response to corticosteroid treat-ment in Patient 2. Early initiation of immunotherapy (corticoste-roid, intravenous immunoglobulin and/or plasma exchange) hasbeen advocated by some authors to ensure an optimal neurologicoutcome of OMAS [5], but as exemplified by Patient 1, a good recov-ery without immunotherapy can also be seen. Immunotherapy wasnot instituted for this patient because he showed early signs ofimprovement. Finally, meningeal enhancement, seen in Patient 1,has only rarely been reported previously in associationwith dengueencephalitis [3]. Although dysfunction of neurons in the pontinetegmentum is implicated in the pathogenesis of OMAS, brain MRItypically does not demonstrate a parenchymal lesion in this condi-tion [5].

Acknowledgments

We gratefully acknowledge the patients for their consent andparticipation in this report, including publication of the video.The study was supported by the Malaysian Ministry of Higher Edu-cation grants for High-Impact Research (HIR), E000033 and UM.C/625/1/HIR/MOHE/CHAN/11-H-50001-00-A000025.

References

[1] Simmons CP, Farrar JJ, Chau NVV, Wills B. Dengue. N Engl J Med 2012;366:1423e32.

[2] Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, et al. Dengue: acontinuing global threat. Nat Rev Microbiol 2010;8(12 Suppl.):S7e16.

[3] Carod-Artal FJ, Wichmann O, Farrar J, Gasc�on J. Neurological complications ofdengue virus infection. Lancet Neurol 2013;12:906e19.

[4] Verma R, Sharma P, Garg RK, Atam V, Singh MK, Mehrotra HS. Neurologicalcomplications of dengue fever: experience from a tertiary center of north India.Ann Indian Acad Neurol 2011;14:272e8.

[5] Klaas JP, Ahlskog JE, Pittock SJ, Matsumoto JY, Aksamit AJ, Bartleson JD, et al.Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol 2012;69:1598e607.

Ai Huey TanDivision of Neurology and the Mah Pooi Soo & Tan Chin Nam Centre

for Parkinson's & Related Disorders, University of Malaya,Kuala Lumpur, Malaysia

Kyaw LinnPediatric Neurology Unit, Yangon Children's Hospital,

Yangon, Myanmar

Norlisah Mohd RamliUniversity of Malaya Research Imaging Centre and Department of

Biomedical Imaging, University of Malaya, Kuala Lumpur, Malaysia

Chaw Su Hlaing, Aye Mya Min AyePediatric Neurology Unit, Yangon Children's Hospital,

Yangon, Myanmar

I-Ching SamDepartment of Medical Microbiology, University of Malaya,

Kuala Lumpur, Malaysia

Chong Guan NgDepartment of Psychological Medicine, University of Malaya,

Kuala Lumpur, Malaysia

Khean Jin Goh, Chong Tin Tan, Shen-Yang Lim*

Division of Neurology and the Mah Pooi Soo & Tan Chin Nam Centrefor Parkinson's & Related Disorders, University of Malaya,

Kuala Lumpur, Malaysia

* Corresponding author. Neurology Laboratory, Level 5 (Mainblock), University of Malaya Medical Centre, 50603 Kuala Lumpur,

Malaysia. Tel.: þ60 16 3518009; fax: þ60 03 79494613.E-mail address: limshenyang@ymail.com (S.-Y. Lim).

13 July 2014