Opsoclonus Myoclonus Syndrome

1. O P S O C L O N U S - M Y O C L O N U S
S Y N D R O M E
A D E W I J AYA , M D
J U LY 2 0 1 8

2. OUTLINE:
• Introduction
• Pathophysiology
• Epidemiology
• Clinical presentation
• Diagnostic criteria
• Differential diagnosis
• Etiology / risk factors
• Clinical work-up / diagnostic
• Management
• Prognosis
• Summary

3. INTRODUCTION
• Marcel Kinsbourne, 1962
• Opsoclonus + myoclonus (dancing eyes, dancing feet)
• Both children and adults; in children related to neuroblastoma
• Opsoclonus is a form of saccadic intrusion characterized by multidirectional conjugate
eye movements with horizontal, vertical, and torsional directions. The saccades are
rapid, involuntary, lack an intersaccadic interval, and do not follow a rhythmic pattern.
Because of these characteristics, opsoclonus is also often referred to as saccadomania.
• Myoclonus is a rapid, abnormal movement featuring brief, shock-like muscle
contractions (“positive myoclonus”) or muscle tone inhibitions (“negative myoclonus”)
Kinsbourne M. Myoclonic encephalopathy of infants. J Neurol Neurosurg Psychiatry. 1962; 25:271-276.
Espay AJ, Chen R. Myoclonus. Continuum (Minneap Minn). 2013; 19:1264-1286.

4. INTRODUCTION
opsoclonus myoclonus
ataxia
Behavioral
disturbance
Wong AM, Musallam S, Tomlinson RD, Shannon P, Sharpe JA. Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates. J Neurol Sci. 2001; 189:71-81.

5. PATHOPHYSIOLOGY
• Autoimmune, inflammatory triggered by paraneoplastic or infection
• Anti-neuronal and anti-Purkinje cell antibodies have been associated with OMS and
neuroblastoma in some patients
Proposed mechanisms:
• The first is that oculomotor neurons of the caudal fastigial nucleus of the cerebellum
become disinhibited secondary to Purkinje cell dysfunction in the cerebellar vermis
• A second potential mechanism is disinhibition of burst neurons, which are cells that
normally generate saccadic eye movements
Wong AM, Musallam S, Tomlinson RD, Shannon P, Sharpe JA. Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates. J Neurol Sci. 2001; 189:71-81.
Rucker JC, Ying SH, Moore W, et al. Do brainstem omnipause neurons terminate saccades?Ann N Y Acad Sci. 2011; 1233:48-57.

6. EPIDEMIOLOGY
• Rare
• 1/1,000,000 population
• Incidence 1/5,000,000 per year
• No gender / ethnic predilection
• No genetic cause identifiable
• Children 1 & 3 years old of age
• Adults: any age
Pang KK, de Sousa C, Lang B, Pike MG. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom.Eur J Paediatr Neurol. 2010; 14:156-161
Tate ED, Allison TJ, Pranzatelli MR, Verhulst SJ. Neuroepidemiologic trends in 105 US cases of pediatric opsoclonus-myoclonus syndrome. J Pediatr Oncol Nurs. 2005; 22:8-19.
Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol. 2012; 69:1598-1607.

7. CLINICAL PRESENTATION
• Acute or subacute onset of ataxia over a period of days to weeks, resulting in an
inability to walk or sit normally
• Attempts to move or maintain certain postures are often disrupted by myoclonic
jerking movements that may include the head, trunk, or extremities
• Behavioral and sleep disturbances as well as profound irritability, sometimes being
inconsolable
• Sometimes apathy or social withdrawal
• Opsoclonus is generally observed within days after the onset of ataxia, but has been
reported to occur weeks to months later in some cases
Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol. 2012; 69:1598-1607.

8. DIAGNOSTIC CRITERIA
3 of 4 :
• (1) opsoclonus,
• (2) ataxia and/or myoclonus,
• (3) behavioral changes or sleep disturbances, and
• (4) diagnosis of neuroblastoma
Additional signs on examination that may be suggestive of neuroblastoma include periorbital
ecchymoses (“raccoon eyes”)
In adults: dizziness, imbalance, nausea, and vomiting
Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol. 2012; 69:1598-1607.
Matthay KK, Blaes F, Hero B, et al. Opsoclonus myoclonus syndrome in neuroblastoma: a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy,
2004. Cancer Letters. 2005; 228:275-282.

9. DIFFERENTIAL DIAGNOSIS
• Square wave jerks, ocular flutter, nystagmus
• Acute cerebellar ataxia/acute cerebellitis spectrum
• Labyrinthitis
• GBS
• Epileptic seizures
Desai J, Mitchell WG. Acute cerebellar ataxia acute cerebellitis and opsoclonus-myoclonus syndrome. J Child Neurol. 2012; 27:1482-1488.
Sivaswamy L. Approach to acute ataxia in childhood: diagnosis and evaluation. Pediatr Ann. 2014; 43:153-159.
Haden SV, McShane MA, Holt CM. Opsoclonus myoclonus: a non-epileptic movement disorder that may present as status epilepticus. Arch Dis Child. 2009; 94:897-899.

10. ASSOCIATION WITH NEUROBLASTOMA
• 48 % children with OMS  have occult neuroblastoma
• 2 % of neuroblastoma patients have OMS
• Paraneoplastic
• Warrant a thorough evaluation to detect an occult neuroblastic tumor
Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr. 2010; 22:745-750.
Aydin GB, Kutluk MT, Buyukpamukcu M, Akyuz C, Yalcin B, Varan A. Neurological complications of neuroblastic tumors: experience of a single center. Childs Nerv Syst. 2010; 26:359-365.

11. OTHER ETIOLOGIES / RISK FACTORS
• Idiopathic
• Post- or parainfectious: influenza, West Nile virus, varicella, cytomegalovirus, human herpes
virus 6, human immunodeficiency virus, and hepatitis C
• Antecedent bacterial infections including Mycoplasma pneumoniae and salmonella.
• Post-immunization
• Toxic-metabolic: phenytoin overdose, hyperosmolar non-ketotic diabetic coma, and
cocaine intoxication
• Post traumatic: severe brain injury
• Other paraneoplastic syndromes, particularly in the setting of small-cell lung carcinoma and
breast adenocarcinoma in adults
Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol. 2012; 69:1598-1607.
Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr. 2010; 22:745-750.
Morita A, Ishihara M, Kamei S, Ishikawa H. Opsoclonus-myoclonus syndrome following influenza A infection. Intern Med. 2012; 51:2429-2431.
Hasegawa S, Matsushige T, Kajimoto M, et al. A nationwide survey of opsoclonus-myoclonus syndrome in Japanese children. Brain Dev. 2015; 37:656-660.
Turazzi S, Alexandre A, Bricolo A, Rizzuto N. Opsoclonus and palatal myoclonus during prolonged post-traumatic coma. A clinico-pathologic study. Eur Neurol. 1977; 15:257-263.

12. CLINICAL WORK-UP/DIAGNOSTICS
• Urine/serum analysis
• Cerebrospinal fluid analysis
• Radiological studies

13. URINE/SERUM ANALYSIS
• Urinary levels of the catecholamine metabolites homovanillic acid (HVA) and
vanillylmandelic acid (VMA) are useful tumor markers for neuroblastoma. These assays
are reportedly elevated in 95% of cases of neuroblastoma and are useful for
confirmatory purposes
• Autoantibodies (?)
Ater JL, Worth LL. Neuroblastoma. In: Chan KW, Raney RB, editors. Pediatric Oncology. New York (NY): Springer. :82-95.
Connolly AM, Pestronk A, Mehta S, Pranzatelli MR 3rd, Noetzel MJ. Serum autoantibodies in childhood opsoclonus-myoclonus syndrome: targets in neural tissues. J Pediatr. 1997; 130:878-884.
Antunes NL, Khakoo Y, Matthay KK, et al. Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus. J Pediatr Hematol Oncol. 2000; 22:315-320.

14. CEREBROSPINAL FLUID ANALYSIS
• Higher amounts of B cells in their CSF
• Unspecified pleocytosis
• CSF lymphocytosis
Pang KK, de Sousa C, Lang B, Pike MG. A prospective study of the presentation and management of dancing eye syndrome/opsoclonus-myoclonus syndrome in the United Kingdom.Eur J Paediatr Neurol.
2010; 14:156-161.
Pranzatelli MR, Travelstead AL, Tate ED, Allison TJ, Verhulst SJ. CSF B-cell expansion in opsoclonus-myoclonus syndrome: a biomarker of disease activity. Mov Disord. 2004; 19:770-777.

15. RADIOLOGICAL STUDIES
• MRI / CT scan
• 123I-metaiodobenzylguanidine (MIBG) scintigraphy  monitor disease course
Matthay KK, Blaes F, Hero B, et al. Opsoclonus myoclonus syndrome in neuroblastoma: a report from a workshop on the dancing eyes syndrome at the advances in neuroblastoma meeting in Genoa, Italy,
2004. Cancer Letters. 2005; 228:275-282.
Ater JL, Worth LL. Neuroblastoma. In: Chan KW, Raney RB, editors. Pediatric Oncology. New York (NY): Springer. :82-95.

16. MANAGEMENT
MEDICAL TREATMENT
• Corticosteroids / ACTH combined with immunotherapy
• Immunotherapy: intravenous immunoglobulin (IVIG), rituximab, cyclophosphamide,
azathioprine, or plasmapheresis
• Rituximab
De Grandis E, Parodi S, Conte M, et al. Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome. Neuropediatrics. 2009; 40:103-111
Tate ED, Pranzatelli MR, Verhulst SJ, et al. Active comparator-controlled rater-blinded study of corticotropin-based immunotherapies for opsoclonus-myoclonus syndrome. J Child Neurol. 2012; 27:875-884.
Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol. 2006; 28:585-593.

17. MANAGEMENT
• Addressing underlying neuroblastoma  surgical
• Rehabilitation
Rudnick E, Khakoo Y, Antunes NL, et al. Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies – a report from the Children’s Cancer Group Study. Med Pediatr Oncol.
2001; 36:612-622.
Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features – a report from the Children’s Cancer Group. Med Pediatr Oncol. 2001; 36:623-629.
Pranzatelli MR, Tate ED, Dukart WS, Flint MJ,video 2 Hoffman MT, Oksa AE. Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone. J Pediatr. 2005; 147:372-378.

18. PROGNOSIS
• The survival prognosis of children with OMS secondary to neuroblastoma is very
favorable better than neuroblastoma without OMS
• A monophasic course and that those patients generally had a more favorable
neurologic prognosis than patients who followed a more chronic, relapsing course
• Approximately 70% of patients are estimated to have some form of motor, speech,
cognitive, or behavioral disturbance
• Early-stage neuroblastoma may correlate with a higher rate of neurological sequelae,
suggesting that more differentiated tumors may elicit a stronger inflammatory reaction
to CNS tissues
• More intense immunosuppression with chemotherapy may help improve neurological
outcomes in OMS patients
Rudnick E, Khakoo Y, Antunes NL, et al. Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: clinical outcome and antineuronal antibodies – a report from the Children’s Cancer Group Study. Med Pediatr
Oncol. 2001; 36:612-622.
Cooper R, Khakoo Y, Matthay KK, et al. Opsoclonus-myoclonus-ataxia syndrome in neuroblastoma: histopathologic features – a report from the Children’s Cancer Group. Med Pediatr Oncol. 2001; 36:623-629.
Mitchell WG, Brumm VL, Azen CG, Patterson KE, Aller SK, Rodriguez J. Longitudinal neurodevelopmental evaluation of children with opsoclonus-ataxia. Pediatrics. 2005; 116:901-917.

19. SUMMARY
• Rare autoimmune, inflammatory
• Paraneoplastic / parainfectious
• Clinical presentation
(1) opsoclonus,
(2) ataxia and/or myoclonus,
(3) behavioral changes or sleep disturbances, and
(4) diagnosis of neuroblastoma
• Corticosteroids/ACTH + immunomodulatory agents + (rituximab)
• Favorable prognosis with neurological sequele