Opsoclonus myoclonus syndrome: Difference between revisions

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{{CMG}} {{AE}} {{Jose}}
{{CMG}} {{AE}} {{Jose}}


{{SK}}
{{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==
==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 system dysfunction, either induced by infection or paraneoplastic etiologies.
'''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==
==Historical Perspective==


*Opsoclonus myoclonus syndrome was first described in 1962 by M. Kinsbourne, who presented a series of six cases of children with ataxia, myoclonus and opsoclonus.  
*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=":2">Blaes, Franz, and Backialakshmi Dharmalingam. "Childhood opsoclonus-myoclonus syndrome: diagnosis and treatment." ''Expert review of neurotherapeutics'' 16.6 (2016): 641-648.</ref> Recently it has been more often referred to as opsoclonus myoclonus syndrome.
*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==
== Classification==
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== Pathophysiology ==
== 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.
*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>Pranzatelli MR, Tate ED, McGee NR, Travelstead AL, Ranso- hoff RM, Ness JM, et al. Key role of CXCL13/CXCR5 axis for cerebrospinal fluid B cell recruitment in pediatric OMS. J Neuroimmunol 2012;243:81–8.</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=":0">Pranzatelli, Michael R., and Elizabeth D. Tate. "Trends and tenets in relapsing and progressive opsoclonus-myoclonus syndrome." ''Brain and Development'' 38.5 (2016): 439-448.</ref>
*[[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:
*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.
**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 neurons, which are mostly under inhibition from omnipause cells, causing 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>
**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=":0" />
*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" />
*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" />
*On microscopic histopathological analysis, [[gliosis]] and [[inflammation]] in the [[cerebellar vermis]] are characteristic findings of opsoclonus myoclonus syndrome.<ref name=":3" />


==Clinical Features ==
==Causes==


* Opsoclonus myoclonus syndrome (also often called: “dancing eyes-dancing feet” syndrome) is a rare syndrome of unknown etiology that presents with the following features:<ref name=":3" />
* 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.
** Opsoclonus,
** Myoclonic jerks,  
** Behavioral disturbances
** Ataxia.
* The cause is not yet known but the accepted hypothesis is that it is an autoimmune, inflammatory reaction which damages the central nervous system. It is theorized that I can be triggered by either a paraneoplastic (being associated with neuroblastoma in children) or an infectious etiology.<ref name=":3" />
* 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.<ref name=":0" />
* 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=":0" />
* Children affected by the disease may not be fully asymptomatic between the episodes of the disease, persisting with significant speech and language deficits, sleep and some behavioral changes.<ref name=":0" />
* 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=":2" />


== Differentiating Opsoclonus Myoclonus syndrome from other Diseases==
== Differentiating Opsoclonus Myoclonus syndrome from other Diseases==


*Opsoclonus myoclonus syndrome must be differentiated from acute inflammatory 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>
*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==
== Epidemiology and Demographics==


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


===Age===
===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>
*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>
*Relapses of the disease may affect adults.
*[[Relapse|Relapses]] of the disease may affect adults.


===Gender===
===Gender===
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==Risk Factors==
==Risk Factors==


*There are no risk factors associated with the development of opsoclonus myoclonus syndrome.
*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==
==Natural History, Complications and Prognosis==


*The majority of patients with opsoclonus myoclonus syndrome present with a relapse-remitting form of the disease.
*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=":5">Matthay, Katherine K., 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'' 228.1-2 (2005): 275-282.</ref>
*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=":2" />
*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=":2" />
*[[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=":2" />
*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==
==Diagnosis==
=== Diagnostic Criteria===
===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=":4" />
*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]].
**Rare type of cancer that affects the nerve (neuroblastoma)
**Uncontrolled eye movement (opsoclonus)
**A movement disorder with sudden muscle contractions (myoclonus) and/or lack of coordination (ataxia)
**Behavioral and/or sleep disturbance


===Symptoms===
===History and Symptoms===


* Opsoclonus myoclonus syndrome presents in a relapse-remitting manner.  
*Opsoclonus myoclonus syndrome presents in a relapse-remitting manner.
* There are acute and chronic symptoms.
* There are [[acute]] and [[chronic]] symptoms.
* The classic symptoms are mostly seen in acute disease and they are:<ref name=":1" />
* The classic symptoms are mostly seen in [[acute]] disease and they are: [[myoclonus]], [[opsoclonus]], [[ataxia]].<ref name=":1" />
** Myoclonus,
* 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" />
** Opsoclonus,
*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" />
** Ataxia.
* 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" />
* 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 is generally more affected than receptive language, and cognitive deficits may become more evident in teenagers.<ref name=":5" />
* 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===


*Physical examination may be remarkable for:
*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 ataxia of childhood.<ref name=":5" />
**[[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, non-phasic and fast in contrast with nystagmus, which is phasic, may be conjugated, unidirectional.<ref name=":5" />
**[[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 jerks, and may be persistent and exacerbated by emotional distress and movement.<ref name=":5" />
**[[Myoclonus]]: ranges from polymyoclonia to coarse multifocal [[Jerking|jerks]], and may be persistent and exacerbated by emotional distress and movement.<ref name="pmid15922508" />
** Behavioral changes: development regression and personality change may also be seen.<ref name=":5" />


===Laboratory Findings===
===Laboratory Findings===


*There are no specific laboratory markers associated with opsoclonus myoclonus syndrome.<ref>Pike M. Opsoclonus-myoclonus syndrome. Handb Clin Neurol 2013;112:1209–11.</ref>
*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 OMS, 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 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 CD 19+ B cells, which is a biomarker of opsoclonus myoclonus disease activity.<ref name=":1" />
*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" />
*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===


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


* 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=":5" />
===CT scan===
* 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" />
*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" />
* 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" />
* 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 adults, the most associated neoplasms are small cell lung cancer, breast carcinoma, and ovarian teratoma<ref name=":7">Oh, Sun-Young, Ji-Soo Kim, and Marianne Dieterich. "Update on opsoclonus–myoclonus syndrome in adults." ''Journal of neurology'' 266.6 (2019): 1541-1548.</ref>, and PET scans are done to evaluate for occult tumors.<ref name=":1" />
* 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===
===Other Diagnostic Studies===
Line 125: Line 135:
===Medical Therapy===
===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.<ref name=":1" />
* 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=":7" /> 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.
*[[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]].
*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=":7" /> Most patients respond to such initial treatment.<ref>Rudnick, Emily, et al. "Opsoclonus‐myoclonus‐ataxia syndrome in neuroblastoma: Clinical outcome and antineuronal antibodies—a report from the children's cancer group study." ''Medical and Pediatric Oncology: The Official Journal of SIOP—International Society of Pediatric Oncology (Societé Internationale d'Oncologie Pédiatrique'' 36.6 (2001): 612-622.</ref>
*[[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 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=":7" />
*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" />
*Corticosteroids and IVIG alone are insufficient to prevent relapse or disease progression, and multimodal combination imunotherapy with disease modifying agents significantly improve long-term outcome when given early.<ref name=":0" />
*[[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=":0" />
*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=":0" />
*[[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=":7" />
*There are reports that intensive [[immunosuppression]] can be associated with improved long-term neurological outcome.<ref name="pmid30483882" />
*Most children will have relapses with corticosteroid dose tapering.<ref name=":7" />
*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===
===Surgery===


*If opsoclonus myoclonus syndrome is due to a 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).
*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.
*[[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=":5" />
*[[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.


===Prevention===
===Secondary Prevention===


*There are no primary preventive measures available for opsoclonus myoclonus syndrome.
* 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==
==References==

Latest revision as of 14:34, 20 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: José Eduardo Riceto Loyola Junior, M.D.[2]

Synonyms and keywords: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 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 system dysfunction, either induced by infection or paraneoplastic etiologies.

Historical Perspective

  • Opsoclonus myoclonus syndrome was first described in 1962 by M. 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".[1] 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

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

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.[6]
  • Relapses of the disease may affect adults.

Gender

  • Girls are slightly more affected with opsoclonus myoclonus syndrome than boys.[6]

Race

  • There is no racial predilection for opsoclonus myoclonus syndrome.[4]

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

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:[4] 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.[6]
  • 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 is generally more affected than receptive language, and cognitive deficits may become more evident in teenagers.[7]
  • In children it is associated neuroblastoma in approximately half of cases.[4] In this age group it also presents with gait ataxia, dysarthria, drooling, irritability, vomiting, and insomnia.[3]
  • 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.[3]
  • Children affected by the disease may not be fully asymptomatic between the episodes of the disease, persisting with significant speech and language deficits, sleep and some behavioral changes.[3]
  • Most patients have no detectable antibody, but a few patients presenting with neuroblastoma do have anti-neuronal and anti-Purkinje cell antibodies.[4]
  • Children with neuroblastoma and opsoclonus myoclonus syndrome usually have a better prognosis for their neuroblastomas as they are in more differentiated stages.[1]

Physical Examination

Laboratory Findings

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

MRI

Other Imaging Findings

Other Diagnostic Studies

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

Treatment

Medical Therapy


 
 
 
 
 
 
 
 
 
 
 
 
 
TREATMENT
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mitigate Trigger
 
 
 
 
 
 
 
 
Treat/Retreat Neuroinflammation
 
 
 
 
 
 
 
 
 
Reassess for high risk
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treat Infections with antimicrobials
 
Escalate or restart steroids or ACTH
 
Retest for neuroinflammation as needed
 
 
Review previous drug responses
 
Add or change modifying disease drugs
 
Formal IQ testing
 
Treat comorbid neuropsychiatric problems
 
Avoid potential pitfalls
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Give IVIG as needed
 
 
 
 
 
 
 
 
 
 
 
Select tapering method
 
 
Multimodal combination immunotherapy
 
 
 
Intensify speech therapy, PT, OT
 
 
 
 
 
 
 


Surgery

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.[3]

References

  1. 1.0 1.1 1.2 1.3 1.4 Blaes F, Dharmalingam B (2016). "Childhood opsoclonus-myoclonus syndrome: diagnosis and treatment". Expert Rev Neurother. 16 (6): 641–8. doi:10.1080/14737175.2016.1176914. PMID 27095464.
  2. Pranzatelli MR, Tate ED, McGee NR, Travelstead AL, Ransohoff RM, Ness JM; et al. (2012). "Key role of CXCL13/CXCR5 axis for cerebrospinal fluid B cell recruitment in pediatric OMS". J Neuroimmunol. 243 (1–2): 81–8. doi:10.1016/j.jneuroim.2011.12.014. PMID 22264765.
  3. 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 Pranzatelli MR, Tate ED (2016). "Trends and tenets in relapsing and progressive opsoclonus-myoclonus syndrome". Brain Dev. 38 (5): 439–48. doi:10.1016/j.braindev.2015.11.007. PMID 26786246.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "American Academy of Ophthalmology - Opsoclonus Myoclonus Syndrome". American Academy of Ophthalmology. 07/04/2020. Check date values in: |date= (help)
  5. "ORPHANET - Opsoclonus-Myoclonus Syndrome". ORPHANET. 07/04/2020. Check date values in: |date= (help)
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 "NORD - National Organization for Rare Diseases - Opsoclonus-Myoclonus Syndrome". NORD. 07/04/2020. Check date values in: |date= (help)
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Matthay KK, Blaes F, Hero B, Plantaz D, De Alarcon P, Mitchell WG; et al. (2005). "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. 228 (1–2): 275–82. doi:10.1016/j.canlet.2005.01.051. PMID 15922508.
  8. Pike M (2013). "Opsoclonus-myoclonus syndrome". Handb Clin Neurol. 112: 1209–11. doi:10.1016/B978-0-444-52910-7.00042-8. PMID 23622330.
  9. "Genetic and Rare Diseases Information Center - Opsoclonus Myoclonus Syndrome". GARD. 07/04/2020. Check date values in: |date= (help)
  10. Matthay KK, Blaes F, Hero B, Plantaz D, De Alarcon P, Mitchell WG; et al. (2005). "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. 228 (1–2): 275–82. doi:10.1016/j.canlet.2005.01.051. PMID 15922508.
  11. 11.0 11.1 11.2 11.3 "Radiopaedia - Neuroblastomas". Radiopaedia.org. 07/04/2020. Check date values in: |date= (help)
  12. 12.0 12.1 12.2 12.3 12.4 12.5 Oh SY, Kim JS, Dieterich M (2019). "Update on opsoclonus-myoclonus syndrome in adults". J Neurol. 266 (6): 1541–1548. doi:10.1007/s00415-018-9138-7. PMID 30483882.
  13. Schmoldt A, Benthe HF, Haberland G (1975). "Digitoxin metabolism by rat liver microsomes". Biochem Pharmacol. 24 (17): 1639–41. PMID https://doi.org/10.1038/nrdp.2016.78 Check |pmid= value (help).


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