Opsoclonus myoclonus syndrome

Opsoclonus-myoclonus syndrome (OMS) also known as opsoclonus-myoclonus-ataxia syndrome (OMAS), ‘Dancing Eye Syndrome’, dancing eyes-dancing feet, Kinsbourne syndrome, myoclonic encephalopathy, paraneoplastic opsoclonus-myoclonus, paraneoplastic opsoclonus-myoclonus-ataxia syndrome; is a rare ocular motor disturbance that causes irregular, rapid eye movements in both horizontal, vertical and diagonal directions (opsoclonus), involuntary muscle twitching in the thorax, abdomen, arms and legs (myoclonus), tremor interfering with hand use that may be accompanied by unsteady gait or loss of ability to stand and walk (ataxia), strabismus (crossed eyes)  ¹, ², ³. Behavioral and sleep disturbances, including extreme irritability, inconsolable crying, reduced and fragmented sleep (insomnia) and rage attacks are common ⁴. Difficulty articulating speech (dysarthria), sometimes with complete loss of speech (mutism) and language (aphasia) may occur. Additional symptoms such as decreased muscle tone (hypotonia) and vomiting are common. The onset is usually abrupt, often severe, and it can become chronic.

Opsoclonus-myoclonus syndrome (OMS) or opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare disorder with an incidence of 1 in a million individuals worldwide. It usually affects infants and young children between 1 and 3 years of age, although it is also known to affect adults too. The peak age in children is about 18 months, with very few diagnosed before 1 year, and a long tail out to about 5 – 6 years ⁵. Occurrence of opsoclonus in infants under 6 months old is quite uncommon, and opsoclonus in that age group, when isolated, is usually from another cause. Opsoclonus-myoclonus-ataxia syndrome (OMAS) occurs in only slightly more girls than boys. Opsoclonus-myoclonus syndrome occurs in about 3% of all children with neuroblastomas. In adults, the age of presentation can vary widely, with reports ranging from adolescence to the eighth decade of life ⁶.

The exact cause of opsoclonus-myoclonus syndrome (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 (paraneoplastic OMS) ⁷, ⁸. It is believed that antibodies are directed against areas of the brain concerned with coordination and with personality and learning.

In young children, opsoclonus-myoclonus syndrome (OMS) commonly presents as a paraneoplastic syndrome secondary to an underlying tumor of embryonic nerve cells (neuroblastoma or ganglioneuroblastoma). While approximately 2% of children with neuroblastoma develop opsoclonus-myoclonus syndrome (OMS), almost 50% to 80% of children with opsoclonus-myoclonus syndrome (OMS) have an underlying neuroblastoma. It has been suggested that it is the immune-based process of rejection of the brain tumor (neuroblastoma) which acts indiscriminately on parts of the brain which are structurally similar to the tumor which is being destroyed. Occasionally, viral infections seem to trigger the illness.

In the adult population, 20% to 40% of opsoclonus-myoclonus syndrome (OMS) cases are paraneoplastic, with small-cell lung cancer (SCLC) and breast cancer (breast adenocarcinoma) being the most common underlying malignancies ⁵. In contrast to paraneoplastic opsoclonus-myoclonus syndrome (OMS) in infants and young children, whose tumors are biologically inactive and often benign, the tumors in adults are commonly malignant, often disseminated.

In other affected individuals, non-paraneoplastic cases of opsoclonus-myoclonus syndrome (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 opsoclonus-myoclonus syndrome (OMS) have been reported following varicella, measles, and diphtheria-pertussis-tetanus vaccine administration  ⁶, ⁸. Also, opsoclonus-myoclonus syndrome (OMS) has been attributed to toxic or metabolite abnormalities including phenytoin overdose, hyperosmolar non-ketotic diabetic coma, and cocaine intoxication ⁸.

The diagnosis of opsoclonus-myoclonus syndrome is clinically driven based on patient presentation as there are no specific laboratory tests or biomarkers to confirm diagnosis. Given its rarity and sometimes atypical presentation, opsoclonus-myoclonus syndrome can often be misdiagnosed. 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 ⁹.

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 opsoclonus-myoclonus syndrome 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 opsoclonus-myoclonus syndrome with neuroblastoma in the pediatric population, all children presenting with opsoclonus-myoclonus syndrome should be considered for neuroblastoma evaluation ⁶, ⁵.

High clinical suspicion and prompt treatment of opsoclonus-myoclonus syndrome is prudent. The mainstay of medical therapy for opsoclonus-myoclonus syndrome remains immunomodulatory. Particularly, corticosteroids and adrenocorticotropic hormone (ACTH) have been both considered the standard treatments of opsoclonus-myoclonus syndrome in children and adults ¹⁰. 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 ⁶, ⁵.

In patients with paraneoplastic opsoclonus-myoclonus syndrome 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 ⁶, ⁹.

Opsoclonus myoclonus syndrome causes

The exact cause of opsoclonus-myoclonus syndrome (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 (paraneoplastic OMS) ⁷, ⁸.

Cell-mediated and humoral mechanisms, including the presence of anti-neuronal and anti-Purkinje cell antibodies have been implicated in opsoclonus-myoclonus syndrome (OMS) ¹⁰. Nevertheless, most patients with opsoclonus-myoclonus syndrome (OMS) are seronegative for currently known antineuronal antibodies ⁶.

In young children, opsoclonus-myoclonus syndrome (OMS) commonly presents as a paraneoplastic syndrome secondary to an underlying tumor of embryonic nerve cells (neuroblastoma or ganglioneuroblastoma). While approximately 2% of children with neuroblastoma develop opsoclonus-myoclonus syndrome (OMS), almost 50% to 80% of children with opsoclonus-myoclonus syndrome (OMS) have an underlying neuroblastoma.

In the adult population, 20% to 40% of opsoclonus-myoclonus syndrome (OMS) cases are paraneoplastic, with small-cell lung cancer (SCLC) and breast cancer (breast adenocarcinoma) being the most common underlying malignancies ⁵. In contrast to paraneoplastic opsoclonus-myoclonus syndrome (OMS) in infants and young children, whose tumors are biologically inactive and often benign, the tumors in adults are commonly malignant, often disseminated.

In other affected individuals, non-paraneoplastic cases of opsoclonus-myoclonus syndrome (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 opsoclonus-myoclonus syndrome (OMS) have been reported following varicella, measles, and diphtheria-pertussis-tetanus vaccine administration  ⁶, ⁸. Also, opsoclonus-myoclonus syndrome (OMS) has been attributed to toxic or metabolite abnormalities including phenytoin overdose, hyperosmolar non-ketotic diabetic coma, and cocaine intoxication ⁸.

Opsoclonus myoclonus syndrome pathophysiology

Although the exact pathophysiology of opsoclonus-myoclonus syndrome 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 ¹¹. 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 ¹¹.

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 ¹². Support for this theory comes from histopathological examination, which has revealed gliosis and inflammation in the cerebellar vermis of patients with opsoclonus ¹¹, ¹².

Opsoclonus myoclonus syndrome symptoms

The diagnostic features of opsoclonus-myoclonus syndrome include: (1) opsoclonus, (2) ataxia and/or myoclonus, (3) behavioral changes or sleep disturbances and for the paraneoplastic syndrome (4) a diagnosis of neuroblastoma ¹³. In the adult population, opsoclonus-myoclonus syndrome presents similarly, with symptoms of dizziness and loss of balance being the most likely presenting complaints ⁶.

Children with opsoclonus-myoclonus syndrome typically present between 12 and 36 months of age with an acute or subacute onset of unsteady gait or loss of ability to stand and walk (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 opsoclonus-myoclonus syndrome, may be absent on initial evaluation and can present as late as a few weeks after onset of motor symptoms, delaying the diagnosis of opsoclonus-myoclonus syndrome. 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 ¹⁴. Additionally, myoclonic jerks in opsoclonus-myoclonus syndrome 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 ¹⁴, ¹³.

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 opsoclonus-myoclonus syndrome (OMS) from other forms of acquired ataxias. Some children with opsoclonus-myoclonus syndrome (OMS) may present with apathy, social withdrawal and lack of engagement in age-appropriate play ¹³.

Opsoclonus myoclonus syndrome diagnosis

The diagnosis of opsoclonus-myoclonus syndrome is clinically driven based on patient presentation as there are no specific laboratory tests or biomarkers to confirm diagnosis. Given its rarity and sometimes atypical presentation, opsoclonus-myoclonus syndrome can often be misdiagnosed. Nevertheless, opsoclonus remains the most distinctive feature of opsoclonus-myoclonus syndrome 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 ¹⁵, ⁵.

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 opsoclonus-myoclonus syndrome 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 opsoclonus-myoclonus syndrome with neuroblastoma in the pediatric population, all children presenting with opsoclonus-myoclonus syndrome should be considered for neuroblastoma evaluation ⁶, ⁵.

Opsoclonus myoclonus syndrome treatment

The goal of treatment of opsoclonus-myoclonus syndrome is early and aggressive immunotherapy with the goal of gaining a durable complete neurological remission. If a tumor is present, surgical resection is standard. The tumors in young children are usually low stage neuroblastomas or ganglioneuroblastomas (stage 1 or 2), and tumor chemotherapy or radiation therapy are not generally indicated. Tumor resection does not usually provide sufficient clinical benefit for opsoclonus-myoclonus syndrome, however.

Opsoclonus-myoclonus syndrome treatment, which is usually continued over at least 1-2 years, should involve combined immunotherapies as soon as possible after diagnosis. A three-agent protocol involving initial use of high-dose ACTH (corticotropin), intravenous immunoglobulin (IVIG), and rituximab has the best-documented outcomes for moderately severe and severe cases. Rituximab is a monoclonal antibody against B cells (anti-CD20). Almost all patients (80-90%) show improvement with this treatment, but maintaining sustained improvement may require additional treatment and very gradual weaning. Over time, treatment with ACTH may have substantial cortisol-related adverse effects that must be monitored carefully, particularly weight gain, hypertension, and reductions in bone density. Monthly pulse dose dexamethasone instead of ACTH is an option in mild and more moderate cases. The use of prednisone-type oral steroids is not recommended, because they are the least effective of the steroids for pediatric opsoclonus-myoclonus syndrome. For opsoclonus-myoclonus syndrome relapse, low-dose IV cyclophosphamide (3-6 cycles) or repeated courses of rituximab (1-2 cycles) are given. Oral weekly methotrexate may be a useful steroid sparer in chronic relapse.

Opsoclonus myoclonus syndrome prognosis

Almost all children with neuroblastoma and opsoclonus-myoclonus syndrome survive their tumor, which usually does not behave aggressively, though some tumors may be large and pose difficulties for resection. In contrast, the tumors that are associated with opsoclonus-myoclonus syndrome in adults are often aggressive and are sometimes fatal ⁴. The opsoclonus-myoclonus syndrome relapse rate in children treated with only conventional agents is 50-75%. Increased immunosuppression has improved neurodevelopmental outcomes in opsoclonus-myoclonus syndrome (OMS) ⁴. With more aggressive initial therapies in children, the relapse rate appears to be much lower. Opsoclonus-myoclonus syndrome (OMS) onset in the first two years of life is particularly damaging to expressive speech and language development, and may result in a higher incidence of residual cognitive impairment. The best responders appear to be those who received early combination therapy and were only of mild to moderate severity. Failure to achieve complete neurological remission and multiple relapses may result in chronic-progressive opsoclonus-myoclonus syndrome, with permanent deficits, such as attention deficient disorder (ADD), attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and irreversible cognitive impairment (low IQ). Children in the chronic sick role can become oppositional, depressed, and aggressive, and attention to these issues often helps to improve quality of life. Parents with a severely ill infant or child may develop “fragile child syndrome” and have difficulty ever seeing their child as a normal, thriving individual, with “ordinary” behavioral issues of childhood. These parents may benefit from counseling to gradually adjust their management of their child’s ongoing behavioral and developmental issues.

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 ¹³. Furthermore, it is estimated that 60 to 80 percent of patients have residual behavioral or psychomotor disturbances that can progress later in life ¹⁶.

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