View source for Opsoclonus myoclonus syndrome

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{{SK}}dancing eyes-dancing feet, dancing eye syndrome, Kinsbourne syndrome, myoclonic encephalopathy (Kinsbourne type), OMAS (opsoclonus-myoclonus-ataxia syndrome), OMS (opsoclonus myoclonus syndrome), opsoclonic encephalopathy

==Overview==

'''Opsoclonus myoclonus syndrome''' ('''OMS''') is a rare [[neurological]] [[disease|disorder]], which can be very heterogenous, presenting itself with many different [[symptoms]] such as [[opsoclonus]] and/or [[myoclonus]] - which name the [[syndrome]], but also ataxia, [[behavioral]] and/or [[sleep disturbances]]. It is believed to be caused by an [[Immune systems|immune system]] dysfunction, either induced by [[infection]] or [[Paraneoplastic Syndromes|paraneoplastic]] etiologies.

==Historical Perspective==

*Opsoclonus myoclonus syndrome was first described in 1962 by M. [[Kinsbourne Syndrome|Kinsbourne]], who presented a series of six cases of children with [[ataxia]], [[myoclonus]] and [[opsoclonus]].
*The syndrome was named as "myoclonic encephalopathy", but has also been called as "dancing eye syndrome".<ref name="pmid27095464">{{cite journal| author=Blaes F, Dharmalingam B| title=Childhood opsoclonus-myoclonus syndrome: diagnosis and treatment. | journal=Expert Rev Neurother | year= 2016 | volume= 16 | issue= 6 | pages= 641-8 | pmid=27095464 | doi=10.1080/14737175.2016.1176914 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27095464  }}</ref> Recently it has been more often referred to as opsoclonus myoclonus syndrome.

== Classification==

* There is no established system for the classification of opsoclonus myoclonus syndrome.

== Pathophysiology ==

*The pathogenesis of opsoclonus myoclonus syndrome is characterized by neuroinflammation involving dysregulated [[B cells]]. It is believed that loss of tolerance and [[autoantibody]] production causes the neurological damage seen in the disease.
*[[Cerebrospinal fluid]] studies have shown [[B cell]] recruitment to the brain via [[CXCL13]]/[[CXCR5]] and [[CXCL10]]/ [[CXCR3]] ligand/receptor pairs<ref name="pmid22264765">{{cite journal| author=Pranzatelli MR, Tate ED, McGee NR, Travelstead AL, Ransohoff RM, Ness JM | display-authors=etal| title=Key role of CXCL13/CXCR5 axis for cerebrospinal fluid B cell recruitment in pediatric OMS. | journal=J Neuroimmunol | year= 2012 | volume= 243 | issue= 1-2 | pages= 81-8 | pmid=22264765 | doi=10.1016/j.jneuroim.2011.12.014 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22264765  }}</ref><ref name="pmid26786246">{{cite journal| author=Pranzatelli MR, Tate ED| title=Trends and tenets in relapsing and progressive opsoclonus-myoclonus syndrome. | journal=Brain Dev | year= 2016 | volume= 38 | issue= 5 | pages= 439-48 | pmid=26786246 | doi=10.1016/j.braindev.2015.11.007 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26786246  }}</ref>. The [[B cell activating factor]] plays a role increasing [[B cell]] survivability and there may be seen [[intrathecal]] production of [[oligoclonal bands]].<ref name="pmid26786246" />
*There are two theories about the cause of the disease:
**Dysfunction of the [[Purkinje cells]] in the [[cerebellar vermis]] leading to disinhibition of the [[oculomotor]] [[neurons]] of the [[fastigial nucleus]] of the [[cerebellum]].
**Disinhibition of burst [[Neuron|neurons]], which are mostly under inhibition from omnipause cells, causing [[Saccadic movement|saccadic]] eye movements.<ref name=":3">{{Cite web|url=https://www.aao.org/disease-review/opsoclonus-myoclonus-syndrome|title=American Academy of Ophthalmology - Opsoclonus Myoclonus Syndrome|last=|first=|date=07/04/2020|website=American Academy of Ophthalmology|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*It is not known if the triggers that causes opsoclonus myoclonus syndrome and those that causes relapses of the disease are the same or if they affect the same region of the [[brain]].<ref name="pmid26786246" />
*There is no obvious gene/mutation associated with the development of opsoclonus myoclonus syndrome.<ref name=":3" />
*On microscopic histopathological analysis, [[gliosis]] and [[inflammation]] in the [[cerebellar vermis]] are characteristic findings of opsoclonus myoclonus syndrome.<ref name=":3" />

==Causes==

* Opsoclonus myoclonus syndrome is caused by neuroinflammation, though its mechanism is yet unknown. There is evidence supporting the neuroinflammatory theory due to the increase of [[oligoclonal bands]] on [[CSF]]. This theorized pathophysiology is discussed on its own section.

== Differentiating Opsoclonus Myoclonus syndrome from other Diseases==

*Opsoclonus myoclonus syndrome must be differentiated from [[acute]] [[inflammatory]] [[Cerebellar ataxias|cerebellar ataxia]], which can be differentiated by the type of eye movement, rapid recovery without treatment and absence of [[irritability]].<ref>{{Cite web|url=https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=1183|title=ORPHANET - Opsoclonus-Myoclonus Syndrome|last=|first=|date=07/04/2020|website=ORPHANET|archive-url=|archive-date=|dead-url=|access-date=}}</ref>

== Epidemiology and Demographics==

*The [[prevalence]] of opsoclonus myoclonus syndrome is approximately 1 per 1,000,000 individuals worldwide.

===Age===

*Opsoclonus myoclonus syndrome is more commonly observed among patients aged 18 months old and may occur up to 5-6 years old.<ref name=":1">{{Cite web|url=https://rarediseases.org/rare-diseases/opsoclonus-myoclonus-syndrome/|title=NORD - National Organization for Rare Diseases - Opsoclonus-Myoclonus Syndrome|last=|first=|date=07/04/2020|website=NORD|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*[[Relapse|Relapses]] of the disease may affect adults.

===Gender===

*Girls are slightly more affected with opsoclonus myoclonus syndrome than boys.<ref name=":1" />

=== Race===

* There is no racial predilection for opsoclonus myoclonus syndrome.<ref name=":3" />

==Risk Factors==

*There are no [[risk factors]] associated with the development of opsoclonus myoclonus syndrome.

==Screening==

* There is insufficient evidence to recommend routine screening for opsoclonus myoclonus syndrome as it is a very rare disease.

==Natural History, Complications and Prognosis==

*The majority of patients with opsoclonus myoclonus syndrome present with a [[relapse]]-remitting form of the disease.
*Early clinical features begin mostly at 18 months of age, and include [[myoclonus]], [[opsoclonus]], [[irritability]] and [[ataxia]].<ref name="pmid15922508">{{cite journal| author=Matthay KK, Blaes F, Hero B, Plantaz D, De Alarcon P, Mitchell WG | display-authors=etal| title=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. | journal=Cancer Lett | year= 2005 | volume= 228 | issue= 1-2 | pages= 275-82 | pmid=15922508 | doi=10.1016/j.canlet.2005.01.051 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15922508  }}</ref>
*If left untreated, the neurological deficits of patients with opsoclonus myoclonus syndrome may remain more severe and affect [[neurological]] [[development]] through childhood and teenage years.<ref name="pmid27095464" />
*[[Prognosis]] is generally poor, as the patients with opsoclonus myoclonus syndrome usually remain with [[developmental delays]] and severe [[learning difficulties]].<ref name="pmid27095464" />
*Adult opsoclonus myoclonus syndrome can occur as a [[paraneoplastic syndrome]] in association with [[small cell lung cancer]] or [[breast cancer]], half of the cases being [[idiopathic]] and parainfectious.<ref name="pmid27095464" />

==Diagnosis==
===Diagnostic Study of Choice===

*The diagnosis of opsoclonus myoclonus syndrome is made when at least 3 of the following 4 diagnostic criteria are met:<ref name=":3" /> [[neuroblastoma]]; uncontrolled eye movement ([[opsoclonus]]); movement disorder with sudden muscle contractions ([[myoclonus]]) and/or lack of coordination ([[ataxia]]); behavioral and/or [[sleep disturbance]].

===History and Symptoms===

*Opsoclonus myoclonus syndrome presents in a relapse-remitting manner.
* There are [[acute]] and [[chronic]] symptoms.
* The classic symptoms are mostly seen in [[acute]] disease and they are: [[myoclonus]], [[opsoclonus]], [[ataxia]].<ref name=":1" />
* The symptoms presenting in the [[chronic]] disease may be a residual opsoclonus and abnormalities of eye movement which may be elicited by re-fixating from near to far or squeezing the [[eyelids]] shut. Hypometric [[saccades]] and smooth eye pursuit movements can remain abnormal for years. Children may also remain not as coordinated as their peers. [[Expressive language disorder|Expressive language]] is generally more affected than receptive language, and cognitive deficits may become more evident in teenagers.<ref name="pmid15922508" />
*In children it is associated [[neuroblastoma]] in approximately half of cases.<ref name=":3" /> In this age group it also presents with [[gait ataxia]], [[dysarthria]], [[drooling]], [[irritability]], [[vomiting]], and [[Insomnia Disorder|insomnia]].<ref name="pmid26786246" />
* It has a [[relapse]]-remitting course. Symptoms may vary in duration during [[relapses]] and the remission period is also variable, but usually the relapses last at least 48-72h.<ref name="pmid26786246" />
* Children affected by the disease may not be fully asymptomatic between the episodes of the disease, persisting with significant [[Speech and language pathology|speech]] and language deficits, [[sleep]] and some [[behavioral]] changes.<ref name="pmid26786246" />
* Most patients have no detectable [[antibody]], but a few patients presenting with [[neuroblastoma]] do have anti-neuronal and anti-Purkinje cell antibodies.<ref name=":3" />
* Children with [[neuroblastoma]] and opsoclonus myoclonus syndrome usually have a better [[prognosis]] for their [[neuroblastomas]] as they are in more differentiated stages.<ref name="pmid27095464" />

===Physical Examination===

*Physical examination may be remarkable for:
**[[Ataxia]]: children present with an [[acute]] or [[subacute]] form of [[ataxia]], losing the ability to walk and/or sit over a period ranging from one day to a few weeks, accompanied by severe [[irritability]] and [[myoclonus]], being the first diagnosis proposed for most children often post-infectious [[acute]] [[Cerebellar ataxias|cerebellar ataxia]] of childhood.<ref name="pmid15922508" />
**[[Opsoclonus]]: must be differentiated from [[nystagmus]], which is present in most [[acute]] [[cerebellar ataxias]]. [[Opsoclonus]] is multidirectional, [[Conjugate gaze|conjugate]], non-phasic and fast in contrast with [[nystagmus]], which is phasic, may be [[Conjugate gaze|conjugated]], unidirectional.<ref name="pmid15922508" />
**[[Myoclonus]]: ranges from polymyoclonia to coarse multifocal [[Jerking|jerks]], and may be persistent and exacerbated by emotional distress and movement.<ref name="pmid15922508" />

===Laboratory Findings===

*There are no specific laboratory markers associated with opsoclonus myoclonus syndrome.<ref name="pmid23622330">{{cite journal| author=Pike M| title=Opsoclonus-myoclonus syndrome. | journal=Handb Clin Neurol | year= 2013 | volume= 112 | issue=  | pages= 1209-11 | pmid=23622330 | doi=10.1016/B978-0-444-52910-7.00042-8 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23622330  }}</ref>
*In adults with opsoclonus myoclonus syndrome, a blood exam may show Hu anti-neuronal nuclear [[antibodies]] ([[anti-Hu]]) but not in children.<ref name=":4">{{Cite web|url=https://rarediseases.info.nih.gov/diseases/10009/opsoclonus-myoclonus-syndrome/cases/24932#ref_7345|title=Genetic and Rare Diseases Information Center - Opsoclonus Myoclonus Syndrome|last=|first=|date=07/04/2020|website=GARD|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
*In some patients [[cerebrospinal fluid]] evaluation is necessary to detect neuroinflammation. These studies should include [[oligoclonal bands]] (with paired [[serum]] sample), aiming to detect [[antibodies]] in the [[CSF]] and [[flow cytometry]] of the [[lymphocytes]] using [[immunophenotyping]], which may find an increased frequency of [[CSF]] [[CD19|CD19+]] [[B cells]], which is a [[biomarker]] of opsoclonus myoclonus disease activity.<ref name=":1" />
*Atypical cases may warrant [[autoantibodies]] tests in some children, but this is not cost-effective.<ref name=":1" />

===Electrocardiogram===

* There are no [[ECG]] findings associated with opsoclonus myoclonus syndrome.

===X-ray===

* There are no specific [[x-ray]] findings associated with opsoclonus myoclonus syndrome.

===Echocardiography or Ultrasound===

* There are no specific echocardiography/ultrasound  findings associated with opsoclonus myoclonus syndrome.

===CT scan===

*Opsoclonus myoclonus syndrome may present with [[neuroblastoma]] in half of the cases (one author reported 80% of the cases), though only 2-3% of [[neuroblastoma]] present with opsoclonus myoclonus syndrome.<ref name="pmid159225082">{{cite journal| author=Matthay KK, Blaes F, Hero B, Plantaz D, De Alarcon P, Mitchell WG | display-authors=etal| title=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. | journal=Cancer Lett | year= 2005 | volume= 228 | issue= 1-2 | pages= 275-82 | pmid=15922508 | doi=10.1016/j.canlet.2005.01.051 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15922508  }}</ref><ref name="pmid15922508" />
* In the evaluation of a child with opsoclonus myoclonus syndrome, it is usually performed either a [[CT scan]] with contrast or [[MRI]] with [[gadolinium]] of the [[neck]], [[chest]], [[abdomen]], and [[pelvis]]<ref name=":1" /> as [[neuroblastomas]] can arise from [[sympathetic nervous system]], being most frequent in the [[abdomen]] (2/3 of the cases) and [[thorax]] (20% of the cases)<ref name=":6">{{Cite web|url=https://radiopaedia.org/articles/neuroblastoma?lang=us|title=Radiopaedia - Neuroblastomas|last=|first=|date=07/04/2020|website=Radiopaedia.org|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* On [[CT scans]], the [[neuroblastoma]] is [[heterogeneous]] with [[calcifications]] being commonly seen. Usually the [[tumor]] insinuates itself beneath the [[aorta]] and lifting it off the [[vertebral column]].<ref name=":6" />

===MRI===

* In the evaluation of a child with opsoclonus myoclonus syndrome, it is usually performed either a [[CT scan]] with contrast or [[MRI]] with [[gadolinium]] of the [[neck]], [[chest]], [[abdomen]], and [[pelvis]]<ref name=":1" /> as [[neuroblastomas]] can arise from [[sympathetic nervous system]], being most frequent in the [[abdomen]] (2/3 of the cases) and [[thorax]] (20% of the cases)<ref name=":6" />
*[[Magnetic resonance imaging|MRIs]] are superior to all other exams on detecting [[neuroblastomas]] and shows the tumor being heterogenous and iso to hypo intense on T1, and hyper intense on T2, with [[cystic]]/[[necrotic]] areas being easily identifiable.<ref name=":1" />. Usually the [[tumor]] insinuates itself beneath the [[aorta]] and lifting it off the [[vertebral column]].<ref name=":6" />

===Other Imaging Findings===

* On adults, the most associated [[neoplasms]] are [[small cell lung cancer]], [[breast carcinoma]], and [[ovarian teratoma]]<ref name="pmid30483882">{{cite journal| author=Oh SY, Kim JS, Dieterich M| title=Update on opsoclonus-myoclonus syndrome in adults. | journal=J Neurol | year= 2019 | volume= 266 | issue= 6 | pages= 1541-1548 | pmid=30483882 | doi=10.1007/s00415-018-9138-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30483882  }}</ref>, and [[Positron emission tomography|PET scans]] are done to evaluate for occult [[tumors]].<ref name=":1" />

===Other Diagnostic Studies===

*There are no other diagnostic studies that may be used to diagnose opsoclonus myoclonus syndrome.

==Treatment==
===Medical Therapy===

* The mainstay of therapy for opsoclonus myoclonus syndrome is rule it out as a [[paraneoplastic syndrome]] and then early and aggressive [[immunotherapy]] to obtain a durable and complete neurological [[Remission (medicine)|remission]].<ref name=":1" />
*[[Corticosteroids]] ([[prednisolone]] at 2mg/kg/day and tapered slowly or [[dexamethasone]] 20mg/m2/day for 3 days) and [[ACTH]] are the gold standard<ref name="pmid30483882" /> and they act by [[binding]] to [[intracellular]] [[receptors]] which then act to modulate [[gene transcription]] in target tissues, decreasing the production of pro-[[inflammatory]] [[cytokines]].
*[[Intravenous immunoglobulin|IVIG]] (1gr/kg for 12 cycles) may also be used alone or in combination with [[corticosteroids]], and recent studies suggests that the combination is indeed more effective.<ref name="pmid30483882" /> Most patients respond to such initial treatment.<ref name="pmidhttps://doi.org/10.1038/nrdp.2016.78">{{cite journal| author=Schmoldt A, Benthe HF, Haberland G| title=Digitoxin metabolism by rat liver microsomes. | journal=Biochem Pharmacol | year= 1975 | volume= 24 | issue= 17 | pages= 1639-41 | pmid=https://doi.org/10.1038/nrdp.2016.78 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10  }}</ref>
*There have been reports of [[dexamethasone]] being used with [[cyclophosphamide]], [[rituximab]] ([[Chimeric protein|chimeric]] anti-[[CD20]] [[monoclonal antibody]] that depletes circulating [[B cells]]) in moderately severe opsoclonus myoclonus syndrome, but such associations as also plasma exchange should be reserved for severe cases or cases refractory to [[IVIG]], [[corticosteroids]] or a combination of both.<ref name="pmid30483882" />
*[[Corticosteroid|Corticosteroids]] and [[IVIG]] alone are insufficient to prevent [[relapse]] or disease progression, and multimodal combination [[immunotherapy]] with disease modifying agents significantly improve long-term outcome when given early.<ref name="pmid26786246" />
*Some studies show that combining imunotherapy with [[rituximab]], [[ACTH]] and [[IVIG]], adhering to a more aggressive approach can significantly reduce the [[cognitive impairment]] and [[morbidity]] on opsoclonus myoclonus syndrome.<ref name="pmid26786246" />
*[[Ofatumumab]] can be used in children [[allergic]] to [[rituximab]]. [[Rituximab]] should be avoided in the absence of [[B lymphocytes]] on the [[CSF]].<ref name="pmid26786246" />
*There are reports that intensive [[immunosuppression]] can be associated with improved long-term neurological outcome.<ref name="pmid30483882" />
*Most children will have relapses with [[Corticosteroids|corticosteroid]] dose tapering.<ref name="pmid30483882" />
*Patients should be assessed for treatment following the flowchart below as proposed by Pranzatelli:<ref name="pmid26786246" />

<br />{{familytree/start}}
{{familytree | | | | | | | | | | | | | | A01 | | |A01=TREATMENT}}
{{familytree | | | | | | | | | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | }}
{{familytree | | | |,|-|-|-|-|-|-|-|-|-|-|+|-|-|-|-|-|-|-|-|-|-|-|.| | | | | | | | | | | | | | }}
{{familytree | | | B01 | | | | | | | | | B02 | | | | | | | | | | B03 | | | |B01=Mitigate Trigger|B02=Treat/Retreat Neuroinflammation|B03=Reassess for high risk}}
{{familytree | | | |!| | | | | | | | | | |!| | | | | | | | | | | |!| | | | | | | | | | | | | | }}
{{familytree | |,|-|^|-|.| | | |,|-|-|-|-|+|-|-|-|.| | | |,|-|-|-|+|-|-|-|.| }}
{{familytree | |!| | | |!| | | |!| | | | |!| | | |!| | | |!| | | |!| | | |!| }}
{{familytree | C01 | | C02 | | C03 | | | C04 | | C05 | | C06 | | C07 | | C08| |C01=Treat Infections with antimicrobials|C02=Escalate or restart steroids or ACTH|C03=Retest for neuroinflammation as needed|C04=Review previous drug responses|C05=Add or change modifying disease drugs|C06=Formal IQ testing|C07=Treat comorbid neuropsychiatric problems|C08= Avoid potential pitfalls}}
{{familytree | |!| | | | | | | | | | | | | | |,|-|^|-|.| | | | | |!| | | | | | | }}
{{familytree | D01 | | | | | | | | | | | |  D02 | | | D03 | | | | D04 | | | | | | | |D01=Give IVIG as needed|D02=Select tapering method|D03=Multimodal combination immunotherapy|D04=Intensify speech therapy, PT, OT}}
{{familytree/end}}
<br />

===Surgery===

*If opsoclonus myoclonus syndrome is due to a [[Paraneoplastic syndrome|paraneoplastic]] etiology, then [[surgical resection]] of the [[tumor]] is needed (in children, [[neuroblastoma]] is the most common, in adults there are many such as [[small cell lung cancer]] and [[breast cancer]]).
*[[Surgery]] may be performed to treat such [[tumors]] along other methods of treatments such as [[chemotherapy]] and/or [[radiation]].
*[[Resection]] and treatment of the [[neuroblastoma]] improves the [[acute]] [[symptoms]], but only rarely prevents neurologic [[sequelae]].<ref name="pmid15922508" />
*Most children with [[Paraneoplastic Syndromes|paraneoplastic]] opsoclonus myoclonus syndrome have localized disease which makes [[surgical resection]] more feasible. They also are likely to have tumors with favorable [[cytogenetic]] and [[histopathologic]] traits, with a better [[prognosis]] of their oncologic disease.<ref name=":3" />

===Primary Prevention===

* There are no established measures for the primary prevention of opsoclonus myoclonus syndrome.

===Secondary Prevention===

* Effective measures for the secondary prevention of opsoclonus myoclonus syndrome are not yet established, but chronic [[immunotherapy]] with disease modifying agents is being studied with positive results.<ref name="pmid26786246" />

==References==
{{Reflist|2}}

[[Category:Rheumatology]]
[[Category:Neurology]]

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