Opsoclonus-myoclonus-ataxia syndrome

INTRODUCTION — Opsoclonus-myoclonus-ataxia syndrome (OMAS), also known as opsoclonus-myoclonus, is a rare and debilitating acquired nervous system disorder characterized by opsoclonus, diffuse or focal body myoclonus, and truncal titubation with or without ataxia and other cerebellar signs.

OMAS occurs most commonly in young children, either as a paraneoplastic disorder in association with neuroblastoma or as an apparent postviral syndrome. In adults, OMAS can be paraneoplastic or idiopathic. In both children and adults, therapy consists of treatment of the underlying tumor, if present, and immune suppression.

This topic discusses OMAS in children and adults. Approaches to the evaluation and diagnosis of ataxia, myoclonus, and other paraneoplastic disorders of the nervous system are reviewed separately.

●(See "Approach to the child with acute ataxia".)

●(See "Overview of cerebellar ataxia in adults".)

●(See "Classification and evaluation of myoclonus".)

●(See "Overview of paraneoplastic syndromes of the nervous system".)

PEDIATRIC SYNDROME

Epidemiology — OMAS is rare; one prospective study in the United Kingdom estimated an incidence of 0.18 cases per million per year [1]. OMAS affects mainly young children with a mean age of 1.5 to 2 years [1-4].

Pathogenesis — OMAS is thought to be an acquired immune-mediated disorder, although a specific and reproducible biomarker remains elusive.

Approximately half of cases in children are paraneoplastic in association with neuroblastoma, a childhood neoplasm arising from primitive sympathetic ganglion cells. Neural antigens expressed by the tumor cells are the presumed basis for an adaptive immune response in the central nervous system. Overall, only a small minority of patients with neuroblastoma (2 to 3 percent) develop OMAS [5,6]. Rarely, pediatric OMAS has been reported with other tumors, such as ovarian teratoma. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)

A role for antibody-mediated mechanisms is supported by studies showing expansion of CD19+ B cells in the cerebrospinal fluid (CSF) of children with OMAS [7] and the presence of CSF oligoclonal bands in more than one-half of untreated patients [8]. Autoimmune responses to a variety of well-known neuronal autoantigens or uncharacterized neuronal targets have been demonstrated [9-13], but specific pathogenic autoantibodies have yet to be identified.

Nonparaneoplastic OMAS in children is believed to have a para-infectious origin in some cases. Pathogens that have been implicated include hepatitis C [14], Lyme disease [15], Epstein-Barr virus [16,17], poststreptococcal infection [18], human immunodeficiency virus (HIV; possibly with immune reconstitution inflammatory syndrome) [19], Coxsackie B3 [20], mycoplasma pneumoniae [21], and rotavirus [1]. In idiopathic cases of OMAS, a postviral origin is sometimes inferred based upon a suggestive history of a viral prodrome [2].

Clinical features — Children with OMAS usually present with subacute ataxia manifesting as gait imbalance, staggering, falls, and/or a refusal to walk. Symptoms usually progress over days to weeks [2,22,23]. Parents often describe a viral prodrome, even in cases that are found to be paraneoplastic [2,4]. Common prodromal symptoms include crying and irritability, cough, lethargy, fever, and vomiting.

Myoclonus of the limbs and trunk, tremor, and hypotonia may develop at the same time as the ataxia or subsequently [4]. Behavioral changes (often described as irritability, inconsolable crying) and moderate to severe sleep disturbances are common. Many children lose previously acquired speech and language skills [24].

Most patients also have opsoclonus, which is defined as spontaneous, involuntary, arrhythmic, conjugate, multidirectional saccades occurring in all directions of gaze without a saccadic interval. Although opsoclonus is characteristic of the disorder, it may not be present at initial evaluation and can be transient and difficult to see during examination [1]. The absence of this most distinctive finding can delay diagnosis of OMAS, particularly if the patient does not have a known neuroblastoma. Examination of home videos taken by parents or caregivers can be helpful.

Symptoms of OMAS precede the diagnosis of neuroblastoma in approximately one-half of patients. Symptoms usually fluctuate in severity and may have a prolonged course. In a series of 356 children with OMAS seen at a single referral center in the United States, the median time to diagnosis was 2.1 and 3.0 months for children with and without neuroblastoma, respectively [4]. Approximately 50 percent were diagnosed within the first month of symptoms, one-quarter to one-third had symptoms for 1 to 3 months, and the remaining patients had symptoms for greater than 3 months before diagnosis.

Neuroimaging is normal in most children with acute OMAS [1,25]. Long-term follow-up may demonstrate cerebellar atrophy and cortical volume loss [26].

CSF findings in OMAS are nonspecific. Approximately 15 percent of children have a mild lymphocytic pleocytosis and over half have positive oligoclonal bands [24].

Diagnosis in children — OMAS is a clinical diagnosis based on characteristic clinical features and exclusion of alternative etiologies. There are no biomarkers for the disorder aside from the presence of a peripheral neuroblastic tumor in approximately half of children.

Based on expert panel recommendations, the diagnosis may be made when at least three out of four clinical features are present, in the appropriate clinical context: opsoclonus, ataxia or myoclonus, behavior change or sleep disturbance, and neuroblastoma [24]. (See 'Clinical features' above.)

Clinical evaluation — All children presenting with acute ataxia with or without myoclonus and behavioral changes should have laboratory testing and review of medications to exclude a toxic-metabolic encephalopathy, including a hyperosmolar state, liver disease, and intoxications. Neuroimaging to exclude a structural abnormality and lumbar puncture, unless contraindicated, should also be performed in most patients unless the etiology is readily apparent based on initial evaluation. (See "Acute toxic-metabolic encephalopathy in children", section on 'Diagnostic approach' and "Approach to the child with acute ataxia".)

When OMAS is suspected, testing recommended by an expert consensus panel includes the following [24]:

●Blood tests – Complete blood count, erythrocyte sedimentation rate, electrolytes, blood urea nitrogen, creatinine, uric acid, lactate, C-reactive protein, liver function tests, glucose, clotting studies (international normalized ratio and partial thromboplastin time), quantitative immunoglobulins (paired with CSF for calculation of IgG and albumin synthesis)

●Infection screening – May include testing for herpes viruses (cytomegalovirus [CMV], Epstein-Barr virus [EBV], varicella-zoster virus [VZV], human herpes virus 6 [HHV-6]), West Nile virus, adenovirus, enterovirus, and influenza as clinically indicated

●Neuroimaging – Contrast-enhanced brain magnetic resonance imaging (MRI) to exclude a focal lesion in the posterior fossa and other structural abnormalities

●Cerebrospinal fluid (CSF) – Cell count, protein level, glucose, lactate, IgG and albumin synthesis index (paired with blood sample), oligoclonal bands (paired with serum), and infectious studies as clinically indicated

●Evaluation for neuroblastoma – Laboratories and imaging are reviewed below (see 'Evaluation for neuroblastoma' below)

We do not suggest paraneoplastic antibody panel testing in serum or CSF in most cases, as specific paraneoplastic biomarkers have not been identified for OMAS when associated with neuroblastoma. While children with paraneoplastic OMAS have a higher frequency of other paraneoplastic antibodies (including anti-Hu antibodies) than healthy controls, the sensitivity and specificity are low, and autoantibody screening in this population is not clinically useful [1,6,27].

Evaluation for neuroblastoma — All children presenting with OMAS must be evaluated for neuroblastoma [24,28]. There are no clinical features of OMAS that distinguish children with and without an occult tumor [4,24]. A screening protocol includes:

●Chest, abdominal, and pelvic MRI

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

●¹²³I-metaiodobenzylguanidine (MIBG, iobenguane I-123) scan if MRI results are unrevealing (also used for tumor staging and follow-up if positive)

When negative, the evaluation should be repeated after several months [29]. The evaluation of children with possible neuroblastoma is discussed in detail separately. (See "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma".)

Differential diagnosis — Early in its course, the differential diagnosis of OMAS is the same as that for any child presenting with acute ataxia. Life-threatening causes (eg, posterior fossa tumors, intracranial hemorrhage, stroke, central nervous system infection, acute cerebellitis) should be considered, in addition to more common diagnoses such as acute cerebellar ataxia, drug intoxication, Guillain-Barré syndrome, and migraine-related disorders (algorithm 1 and table 1). This evaluation is reviewed in detail separately. (See "Approach to the child with acute ataxia".)

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 [30]. (See "Acute cerebellar ataxia in children", section on 'Differential diagnosis' and "Acute viral encephalitis in children: Clinical manifestations and diagnosis".)

Among children without evidence of structural disease or acute infection who are subsequently diagnosed with OMAS, the most common misdiagnoses are acute cerebellar ataxia and Guillain-Barré syndrome [1,31]. (See "Acute cerebellar ataxia in children" and "Guillain-Barré syndrome in children: Epidemiology, clinical features, and diagnosis".)

Management — Immune suppression is the primary treatment for OMAS in both paraneoplastic and nonparaneoplastic cases, based on the presumed autoimmune etiology, the rarity of spontaneous remissions, and the disabling nature of the disorder in many children [24]. Early initiation of immunosuppressive therapy (eg, within two weeks of diagnosis) is believed to be associated with improved outcomes [32].

Tumor-directed therapy — Most children with neuroblastoma-associated OMAS have low-risk, nonmetastatic disease, and surgery is the primary oncologic therapy. Risk stratification is based on patient age, stage, pathology, and molecular genetic factors. The treatment and prognosis of neuroblastoma are discussed separately. (See "Treatment and prognosis of neuroblastoma".)

Despite favorable oncologic prognosis, definitive tumor treatment does not appear to improve neurologic outcomes, and children require additional OMAS-directed therapy to achieve sustained improvement [2,33,34]. Immune therapies should be initiated as soon as possible upon recognition of OMAS, in parallel with the oncologic evaluation and in coordination with the surgical team. If a delay in surgery is anticipated, initial doses of immune suppression may be given before tumor resection [24].

Approach to immune suppression — We suggest an initial regimen of glucocorticoids plus intravenous immune globulin (IVIG) in most patients, rather than glucocorticoids alone (algorithm 2). Reasonable alternative agents used at some centers include corticotropin (ACTH) instead of glucocorticoids and plasma exchange instead of IVIG [24]. We suggest add-on therapy with rituximab or cyclophosphamide in children with an insufficient response in the first four to eight weeks of initial therapy; some experts favor even earlier use, at the time of diagnosis [24].

The short-term benefit of IVIG was demonstrated by a multicenter open-label trial in which 53 children with neuroblastoma-associated OMAS were randomly assigned to receive risk-adapted chemotherapy and prednisone with or without IVIG [35]. Chemotherapy consisted of cyclophosphamide in the majority of patients according to the Children’s Oncology Group (COG) protocol. All patients received prednisone 2 mg/kg/day in two divided doses for a minimum of two months; a slow taper could be initiated thereafter based on clinical response. IVIG was given monthly for the first six cycles (1 g/kg/day on two consecutive days for cycle 1, then 1 g/kg on day 1 of cycles 2 through 6), then 1 g/kg on day 1 of cycles 8, 10, and 12. Response was determined using an OMAS severity scale administered at two, six, and 12 months; responders were those with partial or complete improvement and no subsequent progression. Over 12 months of therapy, the proportion of responders was higher when IVIG was added to the treatment regimen (81 versus 41 percent; odds ratio [OR] 6.1, 95% CI 1.5-25.1), and adverse effects were similar between groups. Twelve patients in the standard care arm (44 percent) crossed over and received IVIG due to nonresponse within the first year (median 144 days). Long-term follow-up is ongoing.

There is limited evidence to support the optimal timing and efficacy of other add-on therapies, and treatment decisions should be individualized [24,36-46]. If a stepwise approach is chosen initially, there should be a low threshold for addition of rituximab or cyclophosphamide for patients with an inadequate response to glucocorticoids and IVIG by four to eight weeks (algorithm 2) [24]. In either case, rituximab is generally favored over cyclophosphamide based on toxicity profiles, unless chemotherapy is indicated for oncologic reasons.

The added value of rituximab as initial therapy in all patients is uncertain. A retrospective chart review of children with neuroblastoma-associated OMAS concluded that early use of rituximab (within three months of diagnosis) was associated with decreased risk of relapse [47]. However, another retrospective review of OMAS with and without neuroblastoma suggested that early rituximab permitted a reduction in the duration of glucocorticoid and IVIG therapy but did not appear to impact relapse rate [46].

Administration of specific agents — Dosing and monitoring of immune suppression is individualized and may be influenced by institutional protocols. Reasonable regimens reviewed by the International OMAS Study Group in 2022 are included below [24].

Glucocorticoids — Both intravenous (IV) and oral steroids as well as pulsed and daily regimens have been studied. ACTH is generally reserved for second-line therapy because it is less convenient and often more expensive. The most common regimens are:

●Pulsed oral dexamethasone – Dexamethasone 20 mg/m²/day orally in two divided doses on three consecutive days, defined as one pulse. Pulses are repeated every three to four weeks for 12 pulses.

●Pulsed IV methylprednisolone – Methylprednisolone IV 30 mg/kg/day for three to five days, defined as one pulse. Pulses are repeated monthly for 6 to 12 months. Alternatively, the first pulse is followed by oral prednisone or prednisolone starting at 1 to 2 mg/kg/day and gradually tapered over 6 to 12 months.

High-dose glucocorticoids have multiple potential side effects including irritability, hypertension, hyperglycemia, weight gain, infections, osteopenia, and an adverse impact on growth and stature. Growth impairment and other effects may be lessened by pulsed dosing. Side effects, safety monitoring, and growth implications are reviewed separately. (See "Major adverse effects of systemic glucocorticoids" and "Causes of short stature", section on 'Glucocorticoid therapy'.)

Intravenous immune globulin (IVIG) — A typical regimen of IVIG is 2 g/kg over two to five days followed by 1 to 2 g/kg every four weeks for up to 12 months [24]. Administration and toxicities of IVIG are reviewed separately. (See "Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous immune globulin: Adverse effects".)

Rituximab — Rituximab is a chimeric anti-CD20 monoclonal antibody that depletes B cell lymphocytes. Specific rituximab regimens vary by center, and there is no evidence of differences in efficacy or toxicity. Example regimens include [24]:

●Rituximab 375 mg/m²/dose for four weekly doses

●Rituximab 500 mg/m²/dose for two doses, 10 to 14 days apart

●Rituximab 750 mg/m²/dose for 2 doses, 14 days apart

Rituximab is usually well tolerated but carries risks of hypersensitivity, leukopenia, and hypogammaglobulinemia resulting in serious infections. Allergic or infusion reactions may occur, and clinicians should follow institutional protocols for premedication, administration, and monitoring. Serologic testing for hepatitis B, hepatitis C, and HIV should be done prior to treatment due to risk of reactivation. Prophylaxis against pneumocystis pneumonia is usually recommended in children, although practice varies. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

Cyclophosphamide — When used upfront or as escalating add-on therapy, cyclophosphamide is typically given as pulsed IV therapy (500 to 750 mg/m² for patients weighing ≥10 kg) once every four weeks for three to six doses [24]. Important side effects and risks include nausea, vomiting, hair loss, myelosuppression, infections, hemorrhagic cystitis, infertility, and secondary malignancies. Patients require close monitoring of kidney function and blood counts, cystitis prophylaxis, pneumocystis pneumonia prophylaxis, and appropriate immunizations and other precautionary measures.

Monitoring and relapse — The goal of initial immune suppression is to achieve maximal clinical response and sustained remission. Function should be assessed serially in multiple domains, including stance and gait, arm/hand function, opsoclonus, mood/behavior, and speech. Clinicians should have a low threshold to start add-on therapy at four to eight weeks if symptoms have not improved significantly with initial therapy or in patients who develop steroid toxicities. (See 'Approach to immune suppression' above.)

Optimal duration of initial treatment is not known, but expert consensus favors a goal of clinical remission and up to a year of immune suppression before de-escalation of therapy [24]. Clinical remission is defined as normalization of walking and arm/hand function and resolution of opsoclonus; any residual abnormalities in mood, behavior, and speech should be mild.

Neurologic relapses may occur in up to half of patients. Worsening may be seen during steroid withdrawal or with intercurrent infections [2,39]. Patients with suspected relapse should be re-evaluated for acute and reversible causes as well as for tumor recurrence if clinically indicated. (See 'Clinical evaluation' above.)

Treatment of relapse is individualized based on severity of symptoms and treatment history. Patients who worsen during glucocorticoid tapering may respond to higher doses or reinstitution of pulsed therapies for several months. For patients who relapse after previously receiving rituximab, some experts suggest checking a B cell (CD19) count to inform decisions about restarting rituximab; if B cells are fully suppressed at the time of relapse, additional rituximab is unlikely to be helpful [24].

Prognosis — The neurologic prognosis of OMAS is guarded. Among different case series, motor symptoms appear to improve or resolve in approximately 60 percent of patients during initial treatment [3,36,38]. 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 [2,3,32,36,40,48,49].

Early and more intensive treatment does not clearly improve neuropsychiatric disability, which can occur even while motor symptoms have resolved [48,50]. Sleep problems and associated rage attacks may respond to trazodone [51].

ADULT SYNDROME

Pathogenesis — OMAS in adults may be paraneoplastic or idiopathic in origin. An underlying cancer is found in approximately 20 to 40 percent of cases [11,52-54]. Patients with idiopathic OMAS tend to be younger than patients with paraneoplastic OMAS (mean age 40 versus 55 years) [11,53]. An exception is patients with ovarian teratoma, who often present before age 30 years [11].

The most frequent tumor associated with OMAS in adults is small cell lung cancer (SCLC) [11,12]. 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 [11,53,55-61].

Most cases of paraneoplastic OMAS in adults are not associated with well-characterized antibodies [11]. An exception is a small subgroup of females with OMAS who have anti-Ri (antineuronal nuclear autoantibody type 2 [ANNA-2]) antibodies, usually in association with breast cancer (sometimes gynecologic, lung, or bladder cancers) [53,55,56,62-64]. The target antigens of anti-Ri antibodies are the Nova proteins that play a role in the regulation of synaptic proteins [56,65]. A few patients with paraneoplastic OMAS have had anti-Hu or other paraneoplastic antibodies; in such cases, these are probably nonspecific markers of underlying cancers rather than linked to OMAS [12,53].

Antibodies to neuronal surface antigens have also been reported in association with OMAS, 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 [11,66-68]. Antibodies to the glycine receptor (GlyR) have been found in up to 20 percent of patients with lung cancer and OMAS but do not appear to be sensitive or specific for the disorder [11].

Nonparaneoplastic OMAS has been reported in adults in association with various infections, including Lyme disease [69], enterovirus [70], West Nile virus [71], Epstein-Barr virus [72], HIV [73-75], salmonella [76], cytomegalovirus [77], after anti-Rubella vaccination [78], and poststreptococcal infection [79]. Many cases of nonparaneoplastic OMAS are idiopathic and are often assumed to be para-infectious in origin [53].

Clinical features — In adults, paraneoplastic OMAS often develops with truncal ataxia, resulting in gait difficulty and frequent falls [53,54,80]. Symptoms progress rapidly, leading to substantive disability within weeks.

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. Brainstem and cerebellar signs may also be present [55,80]. Encephalopathy accompanies ocular and motor signs in 30 to 60 percent of patients with paraneoplastic OMAS and is a less frequent finding in nonparaneoplastic OMAS (10 percent) [11,53,80]. In patients with anti-Ri antibodies, opsoclonus is a frequent but not invariable finding.

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

●Brain imaging (MRI with gadolinium) is recommended to rule out structural lesions that can produce symptoms that may be similar to OMAS [25]. This is usually normal in OMAS, but occasionally shows hyperintensity in the dorsal pons or midbrain on T2-weighted images [81].

●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 (CSF) should be obtained if there is concern for acute central nervous system infection; in OMAS, this may be normal or show mild elevations of protein or mild lymphocytic pleocytosis [53,80].

Patients with OMAS who are over the age of 50 years and those with associated encephalopathy should be rigorously assessed for occult malignancy [52] (see "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'). One study identified a subset of young females (ages 15 to 32 years) who developed OMAS in association with systemic teratoma; no autoantibodies were identified, and 74 percent had a full recovery after tumor removal and immunotherapy [82].

While it is reasonable to test for paraneoplastic biomarkers, most adult patients with paraneoplastic OMAS will not test positive [53,83].

Testing for HIV should be performed if risk factors are present, as OMAS can be the initial manifestation of HIV infection or may occur during immune reconstitution at the onset of antiretroviral therapy [73-75].

Treatment and prognosis — Some adults with paraneoplastic OMAS have resolution of neurologic symptoms with treatment of the underlying neoplasm [53,61].

Adults may be less likely to respond to immunotherapy compared with children. Nonetheless, in uncontrolled observations, clinical responses have been reported with glucocorticoids, cyclophosphamide, rituximab, and intravenous immune globulin (IVIG). A reasonable initial approach based largely on data in children and the knowledge that adults are at higher risk for poor outcomes is to use rituximab upfront, along with methylprednisolone with IVIG, followed by monthly pulses of steroids and IVIG while symptoms remain active. All patients should undergo appropriate tumor screening based on age and sex.

In two cases, patients responded to treatment with high doses of clonazepam (8 to 12 mg daily) after no response to immunotherapy [84]. Another case report describes a therapeutic response to topiramate in a patient with OMAS [85].

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 [25].

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

●Definition – Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare and debilitating acquired nervous system disorder characterized by opsoclonus, myoclonus, ataxia, and behavioral and sleep disturbances. Evidence supports an immune-mediated etiology, although pathogenic autoantibodies have not been identified in the majority of cases. (See 'Introduction' above and 'Pathogenesis' above.)

●Epidemiology – OMAS usually affects young children with a mean age of 1.5 to 2 years, either as a paraneoplastic disorder in association with neuroblastoma (approximately half of cases) or as an apparent postviral syndrome. Paraneoplastic and idiopathic cases occur rarely in adults. (See 'Epidemiology' above and 'Adult syndrome' above.)

●Clinical features – Patients usually present with subacute ataxia manifesting as gait imbalance, staggering, and falls. Myoclonus of the limbs and trunk may appear at the same time or subsequently. Behavioral changes (irritability, crying), regression of speech and language skills, and sleep disturbances are common in children; adults may have encephalopathy.

Although opsoclonus is characteristic of the disorder, it may not be present at initial evaluation in children and can be transient and difficult to see during examination. There are no characteristic MRI or cerebrospinal fluid (CSF) findings. (See 'Clinical features' above.)

●Evaluation and diagnosis – OMAS is a clinical diagnosis based on characteristic features and exclusion of alternative etiologies through laboratories, MRI of the brain, and lumbar puncture. All children with OMAS should be evaluated for neuroblastoma; symptoms of OMAS precede the diagnosis of neuroblastoma in approximately one-half of patients. (See 'Diagnosis in children' above.)

Adults over the age of 50 years and those with associated encephalopathy should be evaluated for occult malignancy. The most frequent tumors associated with OMAS in adults are small cell lung cancer (SCLC) and breast cancer. (See 'Diagnosis in adults' above.)

●Treatment and prognosis in children – Immune suppression is the primary treatment for OMAS, based on the presumed autoimmune etiology, the rarity of spontaneous remissions with antitumor therapy alone, and the disabling nature of the disorder. Early initiation of therapy (eg, within two weeks of diagnosis) is believed to be associated with improved outcomes (algorithm 2). (See 'Management' above and 'Tumor-directed therapy' above.)

•Initial therapy – In children with OMAS, we suggest an initial regimen of glucocorticoids plus intravenous immune globulin (IVIG), rather than glucocorticoids alone (Grade 2C). Reasonable alternative agents used at some centers include corticotropin (ACTH) instead of glucocorticoids and plasma exchange instead of IVIG. (See 'Approach to immune suppression' above and 'Glucocorticoids' above and 'Intravenous immune globulin (IVIG)' above.)

•Escalation – In children who do not show clinical improvement in the first four to eight weeks of initial therapy, we suggest adding rituximab (Grade 2C). Cyclophosphamide has been commonly used in the past but has greater potential toxicities. Some experts favor using rituximab or cyclophosphamide even earlier, as first-line therapy in combination with glucocorticoids and IVIG. (See 'Approach to immune suppression' above and 'Rituximab' above and 'Cyclophosphamide' above.)

•Duration of therapy – Optimal duration of initial treatment is not known, but expert consensus favors a goal of complete symptom resolution and up to a year of immune suppression before de-escalation of therapy. (See 'Monitoring and relapse' above.)

•Prognosis – The neurologic prognosis of OMAS is guarded. Although many patients achieve partial or complete recovery of motor function with initial treatment, long-term behavioral and neurocognitive disability is common. (See 'Prognosis' above.)

●Treatment and prognosis in adults – Optimal treatment for adults with OMAS is unknown. It is reasonable to try multiagent immune suppression, based largely on experience in children with neuroblastoma, in addition to anticancer therapy, as indicated. (See 'Treatment and prognosis' above.)