Opsoclonus-myoclonus syndrome

INTRODUCTION — Opsoclonus-myoclonus syndrome (OMS), also known as opsoclonus myoclonus ataxia, is a syndrome that includes opsoclonus along with diffuse or focal body myoclonus and truncal titubation with or without ataxia and other cerebellar signs.

●Opsoclonus is a disorder of ocular motility characterized by spontaneous, arrhythmic, conjugate saccades occurring in all directions of gaze without a saccadic interval.

●Myoclonus is a clinical sign that is characterized by brief, shock-like, involuntary movements caused by muscular contractions or inhibitions.

Patients with OMS are sometimes described as having dancing eyes and feet. Although OMS can be paraneoplastic in origin, it can also result from viral infections, post-streptococcal pharyngitis, metabolic disorders, metastases, and intracranial hemorrhage [1,2].

This topic discusses opsoclonus myoclonus ataxia. An overview of paraneoplastic syndromes and other paraneoplastic disorders are discussed separately. Other disorders causing myoclonus are also discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Classification and evaluation of myoclonus" and "Symptomatic (secondary) myoclonus" and "Treatment of myoclonus".)

PEDIATRIC SYNDROME — OMS is rare; one prospective study in the United Kingdom estimated an incidence of 0.18 cases per million per year [3]. OMS affects mainly young children with a mean age of 1.5 to 2 years [3-5]. Some series, but not others, have found a higher prevalence in girls. A female predominance is characteristic of most, but not all, autoimmune disorders [6].

Pathogenesis — Autoimmunity is believed to underlie paraneoplastic and nonparaneoplastic OMS in children, but specific pathogenic autoantibodies have yet to be identified.

An early pathologic study demonstrated that affected children both with and without neuroblastoma have a high incidence of antibodies that react with central nervous system (CNS) antigens, some of which are directed against cerebellar Purkinje cells [7]. Subsequent studies of the sera of children with OMS demonstrated antibodies against the surface of cerebellar granular neurons; these antibodies also have an antiproliferative and cytotoxic effect on neuroblastoma cells, but their identity remains unknown [8,9]. A variety of other serum antibodies have been described but lack specificity for OMS and require further study before they should be tested clinically [10].

Chemokine abnormalities have been noted in several studies. One report indicates that the chemokine receptor ligand CCL21 is elevated in patients with pediatric OMS and returns to control levels when they are treated with corticosteroids or ACTH, but not other immunosuppressive agents [11]. CCL21 is a ligand for CCL7, a receptor balancing tolerance and immune response. The CCL21 level is positively correlated with the severity and duration of the neurologic abnormality. These findings require further study and validation.

A genetic susceptibility for OMS is suggested by the results of one study that found that the parents of children with OMS were more likely to have autoimmune disease and autoantibodies compared with the parents of healthy controls (16 versus 2 percent, 43 versus 8 percent, respectively) [12]. However, in one large case series of 105 children, none of the several twin siblings in the cohort were affected [4].

The most common malignancy associated with OMS in children is neuroblastoma. Almost 50 percent of children with OMS have an underlying neuroblastoma, and in turn, approximately 2 percent of children with neuroblastoma develop paraneoplastic OMS [13,14]. While neuroblastoma is somewhat more common among boys than girls, the associated OMS is more common in girls [15]. (See "Epidemiology, pathogenesis, and pathology of neuroblastoma".)

Nonparaneoplastic OMS in children is believed to have a parainfectious origin in some cases. Implicated pathogens include hepatitis C [16], Lyme disease [17], Epstein-Barr virus [18,19], post-streptococcal infection [2], HIV (possibly with immune reconstitution inflammatory syndrome) [20], Coxsackie B3 [21], mycoplasma pneumoniae [22], and rotavirus [3]. In idiopathic cases of OMS, a post-viral origin is sometimes inferred based upon a suggestive history of a viral prodrome [4]. One case of OMS has been reported in the setting of celiac disease (an immune-mediated inflammatory disorder of the small intestine) [23].

Clinical features — Children with OMS usually present with a subacute onset of ataxia and falls, progressing over days to weeks [4,24,25]. A viral prodrome is common, but in one series was similarly prevalent in patients with paraneoplastic and nonparaneoplastic OMS [4]. Myoclonus of the limbs and trunk, tremor, and hypotonia often develop subsequently. Behavioral changes (often described as irritability) and moderate to severe sleep disturbances are common.

Most patients also have opsoclonus: spontaneous, involuntary, arrhythmic, conjugate, multidirectional saccades occurring in all directions of gaze without a saccadic interval. Opsoclonus may not be present at initial evaluation [3]. The absence of this most distinctive finding can delay diagnosis of OMS, particularly if the patient does not have a known neuroblastoma.

Symptoms precede the diagnosis of neuroblastoma in approximately one-half of patients. Symptoms usually fluctuate in severity and may have a prolonged course.

Evaluation

Differential diagnosis — Myoclonus, encephalopathy, ataxia, and, less commonly, opsoclonus may be features of toxic-metabolic encephalopathy, particularly hyperosmolar coma, liver disease, and intoxications [26,27]. Structural disease (eg, metastasis, inflammation, demyelination, hemorrhage, sarcoidosis) within the pons and/or cerebellum has also been reported to produce some of the neurologic deficits of OMS. Some cases of OMS have been initially misdiagnosed as acute cerebellar ataxia [28]. (See "Acute cerebellar ataxia in children".)

In the setting of fever, opsoclonus and ataxia may be manifestations of acute infectious encephalitis or meningitis. In endemic regions, more rare pathogens to consider in association with opsoclonus include scrub typhus, mumps, and tuberculous meningitis [29]. (See "Acute cerebellar ataxia in children", section on 'Differential diagnosis' and "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)

Testing — There is no laboratory or other test that confirms the diagnosis of OMS, which is a clinical diagnosis. No specific paraneoplastic biomarkers have been identified for OMS associated with neuroblastoma. While children with paraneoplastic OMS have a higher frequency of other paraneoplastic antibodies (including anti-Hu antibodies) than healthy controls, the sensitivity and specificity is low, and autoantibody screening in this population is not clinically useful [3,14,30].

All children presenting with OMS must be evaluated for neuroblastoma [15]. A screening protocol includes:

●Chest, abdominal, and pelvic magnetic resonance imaging (MRI)

●Measurement of urinary vanillylmandelic acid (VMA) and homovanillic (HVA)

●123-I-metaiodobenzylguanidine (MIBG, iobenguane I-123) scan if MRI results are unrevealing

When negative, the evaluation should be repeated after several months [31]. The evaluation of children with possible neuroblastoma is discussed in detail separately. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)

In children without neuroblastoma, brain imaging (MRI with gadolinium) is recommended to rule out structural lesions; this study is usually normal in patients with OMS [3,26]. Laboratory testing and review of medications should be performed to exclude a toxic-metabolic encephalopathy, in particular, hyperosmolar coma, liver disease, and intoxications (see "Acute toxic-metabolic encephalopathy in children", section on 'Diagnostic approach'). If these are negative, evaluation for viral infections is reasonable, including testing for HIV infection [20].

Cerebrospinal fluid analysis should be obtained if there is concern for acute CNS infection; this is typically normal in cases of OMS but may reveal a lymphocytic pleocytosis. Electroencephalography (EEG) in cases of OMS has also been reported to be normal [3].

Treatment and prognosis — Removal of the neuroblastoma, when present, does not appear to improve neurologic symptoms of OMS, and children require additional therapy to achieve sustained improvement [4,32,33]. The treatment of neuroblastoma is discussed separately. (See "Treatment and prognosis of neuroblastoma".)

Based primarily on small observational studies, immunologic treatments (eg, glucocorticoids, ACTH, plasma exchange, intravenous immunoglobulin [IVIG], azathioprine, cyclophosphamide, mycophenolate mofetil) are typically used, often in combinations [4,25,34-42]. Rituximab added to other immunotherapies has been reported effective in small case series [41,43,44].

Although there is no accepted standard, glucocorticoids plus IVIG is a common first-line therapy. The short-term benefit of IVIG was demonstrated by a multicenter open-label trial in which 53 children with neuroblastoma-associated OMS were randomly assigned to receive risk-adapted chemotherapy and prednisolone with or without IVIG [45]. Chemotherapy consisted of cyclophosphamide in the majority of patients. The addition of 12 months of IVIG improved the OMS response rate (81 versus 41 percent).

Neurologic relapses may occur during steroid withdrawal or with intercurrent infections requiring prolonged treatment in some cases [4,37]. A retrospective chart review of children with neuroblastoma-associated OMS suggests that the early addition of rituximab to the treatment regimen may decrease the risk of relapses [46]. However, another retrospective review of OMS with and without neuroblastoma suggested that the early addition of rituximab permitted a reduction in the duration of corticosteroid and IVIG therapy but did not appear to impact relapse rate [47].

The neurologic prognosis is guarded. Among different case series, motor symptoms appear to improve or resolve in approximately 60 percent during initial treatment [5,34,36]. However, regardless of pathogenesis, approximately 60 to 80 percent of patients have residual behavioral abnormalities or psychomotor retardation that sometimes become increasingly problematic later in life [4,5,34,38,48-50]. Early and more intensive treatment does not clearly improve neuropsychiatric disability, which can occur even while motor symptoms have resolved [49,51]. Sleep problems and associated rage attacks may respond to trazodone [52].

Tumors in children with paraneoplastic OMS appear to have a better prognosis than tumors in patients without paraneoplastic symptoms [34].

ADULT SYNDROME

Pathogenesis — OMS in adults may be paraneoplastic or idiopathic in origin. An underlying cancer is found in approximately 20 to 40 percent of cases [1,53-55]. Patients with idiopathic OMS tend to be younger than patients with paraneoplastic OMS (mean age 40 versus 55 years) [53,55]. An exception is patients with ovarian teratoma, who often present before age 30 years [55].

The most frequent tumor associated with OMS in adults is small cell lung cancer (SCLC) [55,56]. Other tumors have been reported, including non-small cell lung cancer, breast cancer, ovarian teratoma and other gynecologic cancers, gastric adenocarcinoma, malignant melanoma, and bladder cancer [53,55,57-63].

Most cases of paraneoplastic OMS in adults are not associated with well-characterized antibodies [55]. An exception is a small subgroup of women with OMS who have of anti-Ri (antineuronal nuclear autoantibody type 2 [ANNA-2]) antibodies, usually in association with breast cancer (sometimes gynecologic, lung, or bladder cancers) [53,57,58,64-66]. The target antigens of anti-Ri antibodies are the Nova proteins that play a role in the regulation of synaptic proteins [58,67]. A few patients with paraneoplastic OMS have had anti-Hu or other paraneoplastic antibodies; in such cases, these are probably nonspecific markers of underlying cancers rather than linked to OMS [53,56].

Antibodies to neuronal surface antigens have also been reported in association with OMS, including a small number of patients with antibodies to N-methyl-D-aspartate receptor (NMDAR), gamma-aminobutyric acid type A (GABA-A) and type B (GABA-B) receptors, dipeptidyl-peptidase-like protein-6 (DPPX), glutamic acid decarboxylase (GAD), and human natural killer 1 (HNK-1), a novel epitope contained within myelin-associated glycoprotein (MAG) as well as several other brain proteins [55,68-70]. Antibodies to the glycine receptor (GlyR) have been found in up to 20 percent of patients with lung cancer and OMS but do not appear to be sensitive or specific for the disorder [55].

Nonparaneoplastic OMS has been reported in adults in association with various infections, including Lyme disease [71], enterovirus [72], West Nile virus [73], Epstein-Barr virus [74], HIV [75-77], salmonella [78], cytomegalovirus [79], after anti-Rubella vaccination [80], and post-streptococcal infection [81]. Many cases of nonparaneoplastic OMS are idiopathic and often assumed to be parainfectious in origin [53].

Clinical features — In adults, paraneoplastic OMS often develops with truncal ataxia, resulting in gait difficulty and frequent falls [53,54,82]. Most patients have both myoclonus and opsoclonus on presentation; some complain of nausea and/or vomiting. Limb ataxia, tremor, and dysarthria are less frequently present. Symptoms progress rapidly, leading to substantive disability within weeks. Brainstem and cerebellar signs may also be present [57,82]. Encephalopathy accompanies ocular and motor signs in 30 to 60 percent of patients with paraneoplastic OMS and is a less frequent finding in nonparaneoplastic OMS (10 percent) [53,55,82]. In patients with anti-Ri antibodies, opsoclonus is a frequent but not invariable finding.

Diagnosis — OMS should be distinguished from other disorders that can cause similar neurologic symptoms (see 'Differential diagnosis' above):

●Brain imaging (magnetic resonance imaging [MRI] with gadolinium) is recommended to rule out structural lesions that can produce symptoms that may be similar to OMS [26]. This is usually normal in OMS, but occasionally shows hyperintensity in the dorsal pons or midbrain on T2-weighted images [83].

●Laboratory testing and review of medications should be performed to exclude a toxic-metabolic encephalopathy, particularly hyperosmolar coma, liver disease, and intoxications. (See "Acute toxic-metabolic encephalopathy in adults", section on 'Diagnosis'.)

Cerebrospinal fluid should be obtained if there is concern for acute central nervous system (CNS) infection; in OMS this may be normal or show mild elevations of protein or mild lymphocytic pleocytosis [53,82].

Patients with OMS who are over the age of 50 years and those with associated encephalopathy should be rigorously assessed for occult malignancy [1] (see "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'). One study identified a subset of young women (ages 15 to 32 years) who developed OMS in association with systemic teratoma; no autoantibodies were identified, and 74 percent had a full recovery after tumor removal and immunotherapy [84].

While it is reasonable to test for paraneoplastic biomarkers, most adult patients with paraneoplastic OMS will not test positive [53,85].

Testing for HIV should be performed if risk factors are present, as OMS can be the initial manifestation of HIV infection or may occur during immune reconstitution at the onset of antiretroviral therapy [75-77].

Treatment and prognosis — Some adults with paraneoplastic OMS have resolution of neurologic symptoms with treatment of the underlying neoplasm [53,63].

Adults may be less likely to respond to immunotherapy compared with children. Nonetheless, in uncontrolled observations, clinical responses have been reported with corticosteroids, cyclophosphamide, and intravenous immunoglobulin (IVIG). In two cases, patients responded to treatment with high doses of clonazepam (8 to 12 mg daily) after no response to immunotherapy [86]. Another case report describes a therapeutic response to topiramate in a patient with OMS [87].

The neurologic prognosis is better for those patients without underlying cancer and for those whose tumor is promptly diagnosed and treated, than for those with untreated tumors [53]. Older adults appear to be more likely to have relapses of symptoms and residual gait ataxia [26].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paraneoplastic neurologic disorders".)

SUMMARY AND RECOMMENDATIONS — Opsoclonus-myoclonus syndrome (OMS) is a rare syndrome, believed to have an autoimmune pathogenesis that may be paraneoplastic or nonparaneoplastic. Many nonparaneoplastic cases are believed to be parainfectious in origin.

●Ataxia of trunk and limbs with falling is often the first symptom. Patients subsequently develop myoclonus and opsoclonus (spontaneous, involuntary, arrhythmic, conjugate, multidirectional saccades occurring in all directions of gaze without a saccadic interval). Encephalopathy of varying severity can accompany motor symptoms. In children, a moderate to severe sleep disturbance is common. (See 'Clinical features' above.)

●All children with OMS should be evaluated for neuroblastoma. Almost 50 percent of children with OMS have an underlying neuroblastoma; symptoms of OMS precede the diagnosis of neuroblastoma in approximately one-half of patients. (See 'Testing' above.)

●All adults over the age of 50 years and those with associated encephalopathy should be rigorously evaluated for occult malignancy. The most frequent tumor associated with OMS in adults is small cell lung cancer (SCLC). Breast cancer, non-small cell lung cancer, ovarian teratoma and other gynecologic cancers, and bladder tumors are also associated with OMS. (See 'Diagnosis' above.)

●OMS may respond, at least in part, to antitumor treatment and/or immunosuppression. In children, however, the neurologic prognosis is guarded. Most will have long-term neuropsychiatric disability regardless of pathogenesis and treatment. (See 'Treatment and prognosis' above.)