Opsoclonus myoclonus syndrome

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.

• 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.

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

• 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^[2][3]. The B cell activating factor plays a role increasing B cell survivability and there may be seen intrathecal production of oligoclonal bands.^[3]
• 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 neurons, which are mostly under inhibition from omnipause cells, causing saccadic eye movements.^[4]
• 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.^[3]
• There is no obvious gene/mutation associated with the development of opsoclonus myoclonus syndrome.^[4]
• On microscopic histopathological analysis, gliosis and inflammation in the cerebellar vermis are characteristic findings of opsoclonus myoclonus syndrome.^[4]

• 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 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.^[5]

• The prevalence of opsoclonus myoclonus syndrome is approximately 1 per 1,000,000 individuals worldwide.

• 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.

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

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

• There are no risk factors associated with the development of opsoclonus myoclonus syndrome.

• There is insufficient evidence to recommend routine screening for opsoclonus myoclonus syndrome as it is a very rare 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.^[7]
• 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.^[1]
• Prognosis is generally poor, as the patients with opsoclonus myoclonus syndrome usually remain with developmental delays and severe learning difficulties.^[1]
• 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.^[1]

• 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.

• 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 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.^[7]
  • 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.^[7]
  • Myoclonus: ranges from polymyoclonia to coarse multifocal jerks, and may be persistent and exacerbated by emotional distress and movement.^[7]

• There are no specific laboratory markers associated with opsoclonus myoclonus syndrome.^[8]
• In adults with opsoclonus myoclonus syndrome, a blood exam may show Hu anti-neuronal nuclear antibodies (anti-Hu) but not in children.^[9]
• 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+ B cells, which is a biomarker of opsoclonus myoclonus disease activity.^[6]
• Atypical cases may warrant autoantibodies tests in some children, but this is not cost-effective.^[6]

• There are no ECG findings associated with opsoclonus myoclonus syndrome.

• There are no specific x-ray findings associated with opsoclonus myoclonus syndrome.

• 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.^[10][7]
• 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^[6] 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)^[11]
• 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.^[11]

• 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^[6] 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)^[11]
• 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.^[6]. Usually the tumor insinuates itself beneath the aorta and lifting it off the vertebral column.^[11]

• On adults, the most associated neoplasms are small cell lung cancer, breast carcinoma, and ovarian teratoma^[12], and PET scans are done to evaluate for occult tumors.^[6]

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

• 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.^[6]
• Corticosteroids (prednisolone at 2mg/kg/day and tapered slowly or dexamethasone 20mg/m2/day for 3 days) and ACTH are the gold standard^[12] 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.^[12] Most patients respond to such initial treatment.^[13]
• 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.^[12]
• 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.^[3]
• 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.^[3]
• Ofatumumab can be used in children allergic to rituximab. Rituximab should be avoided in the absence of B lymphocytes on the CSF.^[3]
• There are reports that intensive immunosuppression can be associated with improved long-term neurological outcome.^[12]
• Most children will have relapses with corticosteroid dose tapering.^[12]
• Patients should be assessed for treatment following the flowchart below as proposed by Pranzatelli:^[3]

• 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).
• 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.^[7]
• Most children with 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.^[4]

• There are no established measures for the primary prevention of 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.^[3]

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