Parkinsonism and Related Disorders 20 (2014) 1309e1310
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Opsoclonus-myoclonus-ataxia syndrome associated with dengue virus infection Keywords: Dengue Opsoclonus-myoclonus syndrome Opsoclonus-myoclonus-ataxia syndrome Opsoclonus Myoclonus
Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. It is an important and increasing global health threat with fifty million infections occurring annually across 100 countries in tropical and subtropical regions [1,2]. Moreover, increasing numbers of travelers return from endemic regions with dengue, which represents the second leading cause of acute fever in travelers [1,2]. Dengue can manifest with diverse neurological features, most commonly encephalopathy or encephalitis [3]. Movement disorders are rare with only two cases of parkinsonism (bradykinesia) reported, both from Malaysia; and one report of opsoclonusmyoclonus-ataxia syndrome (OMAS) involving two patients from India [3,4]. However, only one of the two OMAS cases by Verma et al. was reported in detail [4]. This patient demonstrated neither leukopenia nor thrombocytopenia (which are seen in the vast majority of patients with symptomatic dengue), and only dengue IgM was documented, which can remain persistently positive for up to 90 days after infection [1,2]. A single positive dengue IgM can only be considered a presumptive diagnosis of acute dengue [1,2]. Here, we confirm the association between dengue and OMAS by reporting two patients with typical clinical features of dengue, and the diagnosis of acute infection was confirmed by IgG seroconversion or the more specific non-structural protein 1 (NS1) antigen test [1,2]. To our knowledge, this also represents the first report of a pediatric case of dengue-associated OMAS. Patient 1. A 30-year-old Syrian man, resident in Malaysia for the past three years, presented with a three-day history of fever, headache, arthralgia, myalgia and generalized petechiae. There was no history of recreational drug use or high-risk behaviors. He had a mild leukopenia and thrombocytopenia (on day 4 of illness, white cell count was 3.0 109/L, platelet count 132 109/L, hematocrit 47%). A presumptive diagnosis of dengue fever was made on the basis of a positive serum dengue IgM result. As he was clinically stable, he was discharged and managed as an outpatient. He was well until nine days after initial symptom onset, when he was readmitted with acute confusion. On examination, there were involuntary, chaotic and rapid multidirectional conjugate saccadic eye movements, as well as spontaneous non-rhythmic multifocal myoclonic jerks involving the craniocervical region (with frequent eye http://dx.doi.org/10.1016/j.parkreldis.2014.09.002 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
blinking), trunk, and upper and lower limbs, consistent with OMAS (Video). The myoclonic jerks were aggravated by movements and by visual, acoustic and tactile stimuli. He was unable to sit up for more than several seconds or stand because of truncal myoclonus. He had an intense fear and nervousness without apparent explanation, as well as marked emotional lability with episodes of inappropriate crying and laughing. The remaining neurological and physical examinations were normal and there was no neck stiffness. The diagnosis of dengue was confirmed by paired sera showing IgG seroconversion. Serology for Leptospira, hepatitis A, B and C, HIV, cytomegalovirus and syphilis were negative, as was connective tissue disease screen. Magnetic resonance imaging (MRI) of the brain showed pachy- and leptomeningeal enhancement, but no brain parenchymal changes (Fig. 1). Electroencephalogram (EEG) showed normal alpha rhythm with focal left temporal slowing. Cerebrospinal fluid (CSF) analysis was normal (0 white blood cells, glucose 3.3 mmol/L, protein 0.38 g/L). He was treated symptomatically with low-dose clonazepam (1e2 mg daily or bid) with a good response. At one month after illness onset, the opsoclonus had resolved and gait was normal. He demonstrated only mild myoclonic jerks of the hands with action. Fear was also 80e90% improved. Patient 2. A 10-year-old Myanmar boy presented on day 5 of fever with severe hypotension (systolic blood pressure of 70 mmHg and pulse rate of 116 beats per minute). He had leukopenia and thrombocytopenia (white cell count 3.2 109/L, platelet count 24 109/L, hemoglobin 16.2 g/dL). He was resuscitated with intravenous fluids and recovered from shock after a few hours. The diagnosis of dengue shock syndrome was confirmed by positive dengue IgM and NS1 antigen on day 5 of illness. On day 7, he became irritable and developed opsoclonus, subtle myoclonus involving the head and neck, and cerebellar ataxia (wide-based gait, truncal ataxia and scanning speech). The rest of the physical examination was unremarkable. Brain computed tomography and EEG were normal. Lumbar puncture and brain MRI were not performed. Prednisolone (2 mg/kg/day for four weeks, then tapered off over another four weeks) was initiated on day 8 of illness; no other symptomatic treatments were given. The opsoclonus improved significantly and the ataxia resolved over two weeks, however there was still irritability and aggressiveness at 3 months. He was normal at the last review at 6 months. Our cases highlight several additional points of interest. Irritability and emotional lability are common in OMAS [5], but to our knowledge intense fear (seen in Patient 1) has not been reported previously. This patient was very sensitive to visual stimuli and
1310
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1309e1310
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 leptomeningeal pathology (arrows); B. Post-gadolinium T1-weighted image demonstrating subtle but diffuse pachymeningeal enhancement (arrows).
even voluntarily bringing his own hand close to the face exacerbated the myoclonic jerks and opsoclonus. Neurological manifestations can occur with typical dengue fever (Patient 1), or in association with dengue shock syndrome (Patient 2). In fact, it is increasingly recognized that patients can present neurological symptoms in the absence of other typical symptoms of dengue infection (e.g., rash, myalgias, joint or abdominal pain and diarrhea) [3]. Although direct viral invasion of the brain cannot be excluded, a post-infectious immune-mediated mechanism is proposed to underlie dengue-associated OMAS. This is supported by the delayed onset of OMAS in Patient 1, and the response to corticosteroid treatment in Patient 2. Early initiation of immunotherapy (corticosteroid, intravenous immunoglobulin and/or plasma exchange) has been advocated by some authors to ensure an optimal neurologic outcome of OMAS [5], but as exemplified by Patient 1, a good recovery without immunotherapy can also be seen. Immunotherapy was not instituted for this patient because he showed early signs of improvement. Finally, meningeal enhancement, seen in Patient 1, has only rarely been reported previously in association with dengue encephalitis [3]. Although dysfunction of neurons in the pontine tegmentum is implicated in the pathogenesis of OMAS, brain MRI typically does not demonstrate a parenchymal lesion in this condition [5]. Acknowledgments We gratefully acknowledge the patients for their consent and participation in this report, including publication of the video. The study was supported by the Malaysian Ministry of Higher Education 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: a continuing global threat. Nat Rev Microbiol 2010;8(12 Suppl.):S7e16. n J. Neurological complications of [3] Carod-Artal FJ, Wichmann O, Farrar J, Gasco dengue virus infection. Lancet Neurol 2013;12:906e19.
[4] Verma R, Sharma P, Garg RK, Atam V, Singh MK, Mehrotra HS. Neurological complications 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 Tan Division of Neurology and the Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, University of Malaya, Kuala Lumpur, Malaysia Kyaw Linn Pediatric Neurology Unit, Yangon Children's Hospital, Yangon, Myanmar Norlisah Mohd Ramli University of Malaya Research Imaging Centre and Department of Biomedical Imaging, University of Malaya, Kuala Lumpur, Malaysia Chaw Su Hlaing, Aye Mya Min Aye Pediatric Neurology Unit, Yangon Children's Hospital, Yangon, Myanmar I-Ching Sam Department of Medical Microbiology, University of Malaya, Kuala Lumpur, Malaysia Chong Guan Ng Department 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 Centre for Parkinson's & Related Disorders, University of Malaya, Kuala Lumpur, Malaysia * Corresponding author. Neurology Laboratory, Level 5 (Main block), University of Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia. Tel.: þ60 16 3518009; fax: þ60 03 79494613. E-mail address: [email protected] (S.-Y. Lim).
13 July 2014
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Letter to the Editor
Opsoclonus-myoclonus-ataxia syndrome associated with dengue virus infection Keywords: Dengue Opsoclonus-myoclonus syndrome Opsoclonus-myoclonus-ataxia syndrome Opsoclonus Myoclonus
Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. It is an important and increasing global health threat with fifty million infections occurring annually across 100 countries in tropical and subtropical regions [1,2]. Moreover, increasing numbers of travelers return from endemic regions with dengue, which represents the second leading cause of acute fever in travelers [1,2]. Dengue can manifest with diverse neurological features, most commonly encephalopathy or encephalitis [3]. Movement disorders are rare with only two cases of parkinsonism (bradykinesia) reported, both from Malaysia; and one report of opsoclonusmyoclonus-ataxia syndrome (OMAS) involving two patients from India [3,4]. However, only one of the two OMAS cases by Verma et al. was reported in detail [4]. This patient demonstrated neither leukopenia nor thrombocytopenia (which are seen in the vast majority of patients with symptomatic dengue), and only dengue IgM was documented, which can remain persistently positive for up to 90 days after infection [1,2]. A single positive dengue IgM can only be considered a presumptive diagnosis of acute dengue [1,2]. Here, we confirm the association between dengue and OMAS by reporting two patients with typical clinical features of dengue, and the diagnosis of acute infection was confirmed by IgG seroconversion or the more specific non-structural protein 1 (NS1) antigen test [1,2]. To our knowledge, this also represents the first report of a pediatric case of dengue-associated OMAS. Patient 1. A 30-year-old Syrian man, resident in Malaysia for the past three years, presented with a three-day history of fever, headache, arthralgia, myalgia and generalized petechiae. There was no history of recreational drug use or high-risk behaviors. He had a mild leukopenia and thrombocytopenia (on day 4 of illness, white cell count was 3.0 109/L, platelet count 132 109/L, hematocrit 47%). A presumptive diagnosis of dengue fever was made on the basis of a positive serum dengue IgM result. As he was clinically stable, he was discharged and managed as an outpatient. He was well until nine days after initial symptom onset, when he was readmitted with acute confusion. On examination, there were involuntary, chaotic and rapid multidirectional conjugate saccadic eye movements, as well as spontaneous non-rhythmic multifocal myoclonic jerks involving the craniocervical region (with frequent eye http://dx.doi.org/10.1016/j.parkreldis.2014.09.002 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
blinking), trunk, and upper and lower limbs, consistent with OMAS (Video). The myoclonic jerks were aggravated by movements and by visual, acoustic and tactile stimuli. He was unable to sit up for more than several seconds or stand because of truncal myoclonus. He had an intense fear and nervousness without apparent explanation, as well as marked emotional lability with episodes of inappropriate crying and laughing. The remaining neurological and physical examinations were normal and there was no neck stiffness. The diagnosis of dengue was confirmed by paired sera showing IgG seroconversion. Serology for Leptospira, hepatitis A, B and C, HIV, cytomegalovirus and syphilis were negative, as was connective tissue disease screen. Magnetic resonance imaging (MRI) of the brain showed pachy- and leptomeningeal enhancement, but no brain parenchymal changes (Fig. 1). Electroencephalogram (EEG) showed normal alpha rhythm with focal left temporal slowing. Cerebrospinal fluid (CSF) analysis was normal (0 white blood cells, glucose 3.3 mmol/L, protein 0.38 g/L). He was treated symptomatically with low-dose clonazepam (1e2 mg daily or bid) with a good response. At one month after illness onset, the opsoclonus had resolved and gait was normal. He demonstrated only mild myoclonic jerks of the hands with action. Fear was also 80e90% improved. Patient 2. A 10-year-old Myanmar boy presented on day 5 of fever with severe hypotension (systolic blood pressure of 70 mmHg and pulse rate of 116 beats per minute). He had leukopenia and thrombocytopenia (white cell count 3.2 109/L, platelet count 24 109/L, hemoglobin 16.2 g/dL). He was resuscitated with intravenous fluids and recovered from shock after a few hours. The diagnosis of dengue shock syndrome was confirmed by positive dengue IgM and NS1 antigen on day 5 of illness. On day 7, he became irritable and developed opsoclonus, subtle myoclonus involving the head and neck, and cerebellar ataxia (wide-based gait, truncal ataxia and scanning speech). The rest of the physical examination was unremarkable. Brain computed tomography and EEG were normal. Lumbar puncture and brain MRI were not performed. Prednisolone (2 mg/kg/day for four weeks, then tapered off over another four weeks) was initiated on day 8 of illness; no other symptomatic treatments were given. The opsoclonus improved significantly and the ataxia resolved over two weeks, however there was still irritability and aggressiveness at 3 months. He was normal at the last review at 6 months. Our cases highlight several additional points of interest. Irritability and emotional lability are common in OMAS [5], but to our knowledge intense fear (seen in Patient 1) has not been reported previously. This patient was very sensitive to visual stimuli and
1310
Letter to the Editor / Parkinsonism and Related Disorders 20 (2014) 1309e1310
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 leptomeningeal pathology (arrows); B. Post-gadolinium T1-weighted image demonstrating subtle but diffuse pachymeningeal enhancement (arrows).
even voluntarily bringing his own hand close to the face exacerbated the myoclonic jerks and opsoclonus. Neurological manifestations can occur with typical dengue fever (Patient 1), or in association with dengue shock syndrome (Patient 2). In fact, it is increasingly recognized that patients can present neurological symptoms in the absence of other typical symptoms of dengue infection (e.g., rash, myalgias, joint or abdominal pain and diarrhea) [3]. Although direct viral invasion of the brain cannot be excluded, a post-infectious immune-mediated mechanism is proposed to underlie dengue-associated OMAS. This is supported by the delayed onset of OMAS in Patient 1, and the response to corticosteroid treatment in Patient 2. Early initiation of immunotherapy (corticosteroid, intravenous immunoglobulin and/or plasma exchange) has been advocated by some authors to ensure an optimal neurologic outcome of OMAS [5], but as exemplified by Patient 1, a good recovery without immunotherapy can also be seen. Immunotherapy was not instituted for this patient because he showed early signs of improvement. Finally, meningeal enhancement, seen in Patient 1, has only rarely been reported previously in association with dengue encephalitis [3]. Although dysfunction of neurons in the pontine tegmentum is implicated in the pathogenesis of OMAS, brain MRI typically does not demonstrate a parenchymal lesion in this condition [5]. Acknowledgments We gratefully acknowledge the patients for their consent and participation in this report, including publication of the video. The study was supported by the Malaysian Ministry of Higher Education 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: a continuing global threat. Nat Rev Microbiol 2010;8(12 Suppl.):S7e16. n J. Neurological complications of [3] Carod-Artal FJ, Wichmann O, Farrar J, Gasco dengue virus infection. Lancet Neurol 2013;12:906e19.
[4] Verma R, Sharma P, Garg RK, Atam V, Singh MK, Mehrotra HS. Neurological complications 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 Tan Division of Neurology and the Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, University of Malaya, Kuala Lumpur, Malaysia Kyaw Linn Pediatric Neurology Unit, Yangon Children's Hospital, Yangon, Myanmar Norlisah Mohd Ramli University of Malaya Research Imaging Centre and Department of Biomedical Imaging, University of Malaya, Kuala Lumpur, Malaysia Chaw Su Hlaing, Aye Mya Min Aye Pediatric Neurology Unit, Yangon Children's Hospital, Yangon, Myanmar I-Ching Sam Department of Medical Microbiology, University of Malaya, Kuala Lumpur, Malaysia Chong Guan Ng Department 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 Centre for Parkinson's & Related Disorders, University of Malaya, Kuala Lumpur, Malaysia * Corresponding author. Neurology Laboratory, Level 5 (Main block), University of Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia. Tel.: þ60 16 3518009; fax: þ60 03 79494613. E-mail address: [email protected] (S.-Y. Lim).
13 July 2014
