Opsoclonus Myoclonus Syndrome

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Disease

In 1962, Marcel Kinsbourne described a rare and heterogeneous neurological syndrome of unknown etiology with clinical features of opsoclonus, myoclonus, cerebellar ataxia, cognitive impairments, and behavioral and sleep disturbances. This syndrome was referred to as Kinsbourne syndrome, or more commonly opsoclonus–myoclonus syndrome (OMS).[1]

Clinical features

Children with OMS typically present between 12 and 36 months of age with an acute or subacute onset of ataxia and falls, interfering with posture and physical activity. This is often accompanied by marked irritability and sleep disturbances. Opsoclonus, the most distinctive feature of OMS, may be absent on initial evaluation and can present as late as a few weeks after onset of motor symptoms, delaying the diagnosis of OMS. Opsoclonus is a form of saccadic intrusion characterized by spontaneous bursts of arrhythmic, back-to-back, conjugate saccades, occurring in multiple planes without an inter-saccadic interval.[2] Additionally, myoclonic jerks in OMS can be variable in quality and affect any part of the body. Although sometimes persistent, they are often exacerbated by emotional stress and attempts of movement.[2][3]

In addition to these motor deficits, personality changes and developmental regression typically occur involving loss of speech and language. The early onset of these behavioral changes can help distinguish OMS from other forms of acquired ataxias. Some children with OMS may present with apathy, social withdrawal and lack of engagement in age-appropriate play.[3]

The diagnostic features of OMS include: (1) opsoclonus, (2) ataxia and/or myoclonus, (3) behavioral changes or sleep disturbances and for the paraneoplastic syndrome (4) a diagnosis of neuroblastoma.[3] In the adult population, OMS presents similarly, with symptoms of dizziness and loss of balance being the most likely presenting complaints.[4]

Etiology

The exact etiology for OMS remains unclear. However, given the clinical response to corticosteroids and other immunosuppressive therapies, the leading hypothesis is that it is an autoimmune, inflammatory phenomenon driven by infectious or paraneoplastic processes. Cell-mediated and humoral mechanisms, including the presence of anti-neuronal and anti-Purkinje cell antibodies have been implicated in OMS. Nevertheless, most patients with OMS are seronegative for currently known antineuronal antibodies. [4][5]

In the pediatric population, OMS commonly presents as a paraneoplastic syndrome secondary to an underlying neuroblastoma. While approximately 2% of children with neuroblastoma develop OMS, almost 50% of children with OMS have an underlying neuroblastoma. In the adult population, 20-40% of OMS cases are paraneoplastic, with small-cell lung carcinoma and breast adenocarcinoma being the most common underlying malignancies.[5]

Non-paraneoplastic cases of OMS, often labelled as “idiopathic,” have been extensively reported in the literature and are thought to be of parainfectious or postinfectious origin in some cases. Some of these associated pathogens include Lyme disease, Epstein-Barr virus, HIV (possibly secondary to reconstitution syndrome), mycoplasma pneumoniae, and rotavirus. Post-immunization associations have been reported following varicella, measles, and diphtheria-pertussis-tetanus vaccine administration.[4][6] Also, OMS has been attributed to toxic or metabolite abnormalities including phenytoin overdose, hyperosmolar non-ketotic diabetic coma, and cocaine intoxication.[6]

Epidemiology

OMS is extremely rare worldwide with an incidence of 1 in 5 million per year and a prevalence of approximately 1 in a million of the worldwide population. There are no clear familial, genetic, sexual or ethnic predilections for OMS. In children, the most common age of presentation is between 1 and 3 years.[5] In adults, the age of presentation can vary widely, with reports ranging from adolescence to the eighth decade of life.[4]

Pathophysiology of opsoclonus

Although the exact pathophysiology of OMS is unclear, there are two proposed theories to explain it: the brainstem and cerebellar theories. The brainstem theory attributes the observed saccadic oscillations in opsoclonus to alterations in the membrane properties of saccadic burst cells. Normally, burst cells are under tonic inhibition from omnipause cells. However, with alterations to their membrane properties, burst cells become prone to increased neuronal excitability or alternatively reduced inhibition from omnipause cells, resulting in the ocular instability or oscillations.[7]

The cerebellar theory attributes the observed opsoclonus to disinhibition of oculomotor neurons of the caudal fastigial nucleus in the cerebellum. Particularly, dysfunctional cerebellar Purkinje cells fail to inhibit the fastigial nucleus, resulting in reinforced inhibition of omnipause neurons and leaving saccadic burst neurons free to oscillate. Support for this theory comes from histopathological examination, which has revealed gliosis and inflammation in the cerebellar vermis of patients with opsoclonus.[7][8]

Differential diagnosis

Given its rarity and sometimes atypical presentation, OMS can often be misdiagnosed. Nevertheless, opsoclonus remains the most distinctive feature of OMS and should be distinguished from other ocular movement disorders such as nystagmus, square eye jerks and ocular flutter. Unlike nystagmus, saccadic intrusions, including opsoclonus, do not contain a slow phase and consist entirely of rapid movements. Square-wave jerks are rapid involuntary saccadic movements that disrupt fixation but maintain a normal intersaccadic interval. Similar to opsoclonus, ocular flutter consists of rapid, conjugate saccadic movements and does not have an intersaccadic interval. However, the saccadic movements of ocular flutter are purely horizontal while those of opsoclonus are multidirectional.[5][9]

Diagnostic procedures

The diagnosis of OMS is clinically driven based on patient presentation and there are no specific laboratory tests or biomarkers to confirm diagnosis. Nevertheless, exclusion of primary central nervous system pathology through neuroimaging and cerebrospinal fluid analysis is typical as part of the diagnostic workup. Screening for infectious causes, given association with infections as listed above, could also be considered. Since OMS can often present as a paraneoplastic syndrome, workup for an underlying malignancy should be considered, as the syndrome can antedate the diagnosis of an unknown cancer. Particularly, given the high association of OMS with neuroblastoma in the pediatric population, all children presenting with OMS should be considered for neuroblastoma evaluation.[4][5]

Management

High clinical suspicion and prompt treatment of OMS is prudent. However delays in diagnosis are common, with an average delay in diagnosis of more than two months. Prolonged time to diagnosis has been associated with worse neurological, psychological, and behavioral outcomes.[10]

The mainstay of medical therapy for OMS remains immunomodulatory. Particularly, corticosteroids and adrenocorticotropic hormone (ACTH) have been both considered the standard treatments of OMS in children and adults. More recently, other immunomodulatory therapies, including intravenous immunoglobulin (IVIG), rituximab and azathioprine, have been associated with significant neurological improvement, suggesting that a multimodal immunosuppressive approach may yield greater therapeutic effects.[4][5]

In patients with paraneoplastic OMS in the setting of neuroblastoma or other tumors, malignancy-targeted treatments such as surgery, chemotherapy, and radiation should be considered either alone or in combination with other immunotherapies. However, tumor resection does not always lead to neurologic improvement and patients may require recurring treatment to control their symptoms.[4][10]

Prognosis

Regardless of treatment, opsoclonus usually resolves. Residual opsoclonus may relapse after apparent remission with adjustments to immunotherapy, or with new illnesses. Even with the resolution of opsoclonus, abnormalities of smooth pursuit eye movements can be commonly seen even years after treatment.[3] Furthermore, it is estimated that 60 to 80 percent of patients have residual behavioral or psychomotor disturbances that can progress later in life.[11]

Summary

OMS is a rare ocular motor disturbance characterized by multivectorial, bilateral, conjugate back to back saccades without intersaccadic interval. OMS is commonly post-infectious or paraneoplastic (especially neuroblastoma in children). A thorough search for underlying neoplasm is warranted. In addition to treating the underlying etiology, immunosuppressive therapy may be helpful.

References

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  1. Kinsbourne M. Myoclonic encephalopathy of infants. J Neurol Neurosurg Psychiatry. 1962; 25:271-276.
  2. 2.0 2.1 Sahu JK, Prasad K. The opsoclonus–myoclonus syndrome. Pract Neurol. 2011;11(3):160-166. doi:10.1136/practneurol-2011-000017
  3. 3.0 3.1 3.2 3.3 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 Lett. 2005;228(1-2):275-282. doi:10.1016/j.canlet.2005.01.051
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 Oh SY, Kim JS, Dieterich M. Update on opsoclonus-myoclonus syndrome in adults. J Neurol. 2019;266(6):1541-1548. doi:10.1007/s00415-018-9138-7
  5. 5.0 5.1 5.2 5.3 5.4 5.5 Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr. 2010; 22:745-750
  6. 6.0 6.1 Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-onset opsoclonus-myoclonus syndrome. Arch Neurol. 2012; 69:1598-1607.
  7. 7.0 7.1 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.
  8. Rucker JC, Ying SH, Moore W, et al. Do brainstem omnipause neurons terminate saccades? Ann N Y Acad Sci. 2011; 1233:48-57.
  9. Desai J, Mitchell WG. Acute cerebellar ataxia acute cerebellitis and opsoclonus-myoclonus syndrome. J Child Neurol. 2012; 27:1482-1488.
  10. 10.0 10.1 De Grandis E, Parodi S, Conte M, et al. Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome. Neuropediatrics. 2009;40(3):103-111. doi:10.1055/s-0029-123772
  11. Pike M. Opsoclonus-myoclonus syndrome. Handb Clin Neurol. 2013;112:1209-1211. doi:10.1016/B978-0-444-52910-7.00042-8
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