Paraneoplastic Opsoclonus-Myoclonus

Paraneoplastic opsoclonus myoclonus syndrome is a rare immune mediated disorder of the brainstem and cerebellum characterised by chaotic multidirectional saccadic eye movements (opsoclonus), myoclonus, ataxia and behavioural change, triggered by an underlying tumour. In children it is commonly linked with neuroblastoma, and in adults with breast cancer, small cell lung cancer and gynaecological cancers.

It is very rare, with an incidence of about 1 case in 5,000,000 people each year. In children it presents at a median age of 18 months (range 6 to 36 months) and about 40% to 50% have a neuroblastic tumour (often low stage with a good oncological prognosis). In adults the median age is 40 to 60 and about 20% to 40% are paraneoplastic.

Associated antibodies in adults are anti-Ri (ANNA-2) with breast and gynaecological cancer, anti-Hu with small cell lung cancer, and anti-Yo, with antibody negative cases being the commonest. Non-paraneoplastic causes include infection (post-viral), toxic or metabolic causes and autoimmune disease.

Pathophysiology. It is immune mediated, with B-cell and T-cell activation against cerebellar and brainstem circuits (omnipause neurons, cerebellar vermis and fastigial nucleus). The disease can follow a tumour found within the following months to years.

Prognosis. In children, tumour outcome is usually good, but neurological sequelae (cognitive, behavioural, motor and speech deficits) persist in 60% to 80%, so immunotherapy is aimed at reducing the chance of relapse and deficit. In adults, outcome depends on the cancer, and neurological recovery is partial.

• Opsoclonus: involuntary, rapid, conjugate multidirectional eye movements without an intersaccadic interval, persisting during sleep and eye closure.
• Myoclonus of the limbs, trunk and head, tremor, ataxia of gait and limbs, and dysarthria.
• Children: irritability, sleep disturbance, regression of speech, developmental delay ("dancing eyes, dancing feet").
• Adults: nausea, vertigo, oscillopsia, encephalopathy.

Red flags.

• Inability to walk, sit or feed and severe sleep disturbance.
• Rapid progression with encephalopathy or reduced consciousness.

• Clinical diagnosis on the triad of opsoclonus, myoclonus and ataxia or behavioural change.
• MRI of the brain (normal in most) to exclude structural causes. CSF (lymphocytic pleocytosis, oligoclonal bands, B-cell expansion) and exclusion of infection.
• Antibodies in serum and CSF: anti-Ri, anti-Hu, anti-Yo, anti-Ma and others (negative in most children).
• Children: urinary catecholamine metabolites, MRI or CT of the neck, chest, abdomen and pelvis, and MIBG scintigraphy (to find a neuroblastic tumour). Thoracic and abdominal tumours are often small.
• Adults: CT of the chest, abdomen and pelvis, whole body FDG-PET-CT, mammography or breast MRI, pelvic imaging and testicular ultrasound. Repeat every 3 to 6 months for 2 to 4 years if negative.

Differential diagnosis.

• Para infectious or post-viral opsoclonus (including Epstein-Barr virus and others)
• Drug toxicity (lithium, phenytoin, cocaine) and metabolic encephalopathy
• Brainstem and cerebellar encephalitis, multiple sclerosis and stroke
• Ocular flutter, voluntary nystagmus and functional disorders

Treat the tumour, and start immunotherapy early with combination treatment.

Tumour treatment. Surgical resection (neuroblastoma, breast, lung, ovarian or other tumours), with chemotherapy and radiotherapy by tumour type. Many low risk paediatric neuroblastic tumours are managed with surgery alone.

Immunotherapy in adults.

• Methylprednisolone: methylprednisolone 1 g IV over 1 to 2 hours once daily for 3 to 5 days, then oral prednisolone 1 mg/kg daily (maximum 60 mg daily) tapered over 4 to 8 weeks in line with response; maximum 1 g daily for pulse therapy; monitoring: glucose, blood pressure, potassium, mood, infection, gastric symptoms, bone health; adjustment: give gastric protection, calcium and vitamin D, pneumocystis prophylaxis when over 20 mg prednisolone daily is expected for more than 4 weeks, reduce for psychiatric toxicity
• Immunoglobulin: immunoglobulin (human normal) 0.4 g/kg IV daily for 5 days (total 2 g/kg), started at 0.5 mL/kg/h and increased every 15 to 30 minutes to a maximum of 4 mL/kg/h as tolerated; maximum 2 g/kg in one course; monitoring: creatinine, blood pressure and heart rate during the infusion, headache, aseptic meningitis, haemolysis, thromboembolic events; adjustment: use a slower rate and a sucrose free product in renal impairment, hydrate beforehand, check IgA level (anaphylaxis in IgA deficiency), reduce the rate or avoid in patients at high thrombotic risk
• Plasma exchange (5 to 7 exchanges) is used when the response is poor.
• Rituximab: rituximab 375 mg/m2 IV once weekly for 4 doses (or 1000 mg IV on days 1 and 15), with hydrocortisone 100 mg IV, an antihistamine and paracetamol before each dose; maximum 1000 mg in one dose; monitoring: hepatitis B serology before the first dose, FBC, immunoglobulins, CD19 counts, infusion reactions, infection; adjustment: start the first infusion at 50 mg/h and increase by 50 mg/h every 30 minutes to a maximum of 400 mg/h, give antiviral prophylaxis for hepatitis B core antibody positivity, defer live vaccines, repeat at 6 months if relapse occurs and B cells have returned
• Cyclophosphamide for refractory disease: cyclophosphamide 750 mg/m2 IV once monthly for 6 months; maximum 1000 mg/m2 in one dose; monitoring: FBC (nadir at 10 to 14 days), creatinine, hydration with mesna cover for haemorrhagic cystitis, urine dipstick, pregnancy test; adjustment: reduce by 25% when creatinine clearance is under 30 mL/min, hold for neutrophils under 1.0 x 10^9/L or platelets under 100 x 10^9/L, discuss fertility preservation before the first dose

Symptomatic control.

• Myoclonus: clonazepam 0.5 mg orally at night, increased by 0.5 mg every 3 to 7 days to 1 to 2 mg three times daily in response to myoclonus; maximum 8 mg daily in this use; monitoring: sedation, ataxia, respiratory depression (especially with opioids), mood, falls, dependence; adjustment: reduce by 0.5 mg every 1 to 2 weeks when stopping, use lower doses in older adults and in hepatic or respiratory impairment, avoid alcohol and other sedatives
• Sleep disturbance and irritability are treated with behavioural measures and short courses of melatonin or other sedatives under specialist supervision.

Paediatric immunotherapy. Combination treatment (corticosteroids or corticotropin, intravenous immunoglobulin, rituximab and sometimes cyclophosphamide) is started early and escalated in line with severity, with doses set by the paediatric neurology and oncology team on weight and body surface area. Maintenance treatment continues for 1 to 2 years or longer to reduce relapse.

Rehabilitation. Physiotherapy, occupational therapy, speech and language therapy, and developmental, educational and psychological support.

Monitoring. Validated scoring of opsoclonus, myoclonus and ataxia at each visit, repeated tumour screening, and long term developmental assessment. Relapses with infection or tapering are common (about 50% in children).

Referral and escalation.

• Urgent referral to paediatric or adult neurology and oncology on suspicion.
• Emergency admission for severe dysphagia, aspiration or reduced consciousness.

Special groups.

• Children: avoid live vaccines during immunosuppression, and coordinate with a paediatric neuro oncology team.
• Adults with anti-Ri: breast and gynaecological screening and treatment as soon as the tumour is found.
• Pregnancy: immunoglobulin and plasma exchange preferred, with avoidance of cyclophosphamide.