Paraneoplastic Encephalomyelitis

Paraneoplastic encephalomyelitis is a multifocal inflammatory syndrome of the brain, brainstem, cerebellum, spinal cord and dorsal root ganglia caused by an immune response to a cancer. It is usually associated with anti-Hu (ANNA-1) antibodies and small cell lung cancer.

It is rare. Anti-Hu syndromes affect about 1 in 100,000 people each year, and neurological symptoms arise in about 1% of patients with small cell lung cancer. The mean age is 60 years, and men and women are about equally affected.

Antibodies and tumours. Anti-Hu with small cell lung cancer (70 to 80%), anti-CV2/CRMP5 with small cell lung cancer and thymoma, anti-Ma2 with testicular cancer, and anti-amphiphysin with breast and lung cancers.

Course. Subacute progression over weeks to months, ending in severe disability or death; the median survival of anti-Hu disease is about 1 to 2 years and is usually determined by the cancer and neurological decline.

Pathophysiology.

Cytotoxic T cell responses to onconeural antigens (Hu proteins) expressed in tumour and neurons cause neuronal loss and inflammation in the limbic system, brainstem, spinal cord and dorsal root ganglia.

Antibodies are markers of the response rather than the cause of injury in intracellular antigen syndromes.

• Limbic encephalitis: subacute memory loss, confusion, seizures, psychiatric change.
• Brainstem encephalitis: vertigo, ophthalmoplegia, dysarthria, dysphagia, central hypoventilation.
• Cerebellar degeneration, myelitis and motor neuron disease like syndromes.
• Sensory neuronopathy: painful asymmetric sensory loss and ataxia; autonomic failure and gastrointestinal pseudo obstruction.
• Multifocal combinations in most patients.

Red flags.

• Respiratory failure, bulbar failure or status epilepticus.
• Rapid cognitive decline or coma.
• Weight loss, cough, haemoptysis or smoking history.

• Clinical syndrome plus a well characterised onconeural antibody (anti-Hu, CV2/CRMP5, Ma2, amphiphysin) in serum or cerebrospinal fluid, or a cancer found within 5 years.
• MRI of the brain and spine (T2 or FLAIR changes in the medial temporal lobes, brainstem or cord; normal in some), EEG for seizures.
• Cerebrospinal fluid: lymphocytic pleocytosis, raised protein, oligoclonal bands, and exclusion of infection and cytology.
• CT chest, abdomen and pelvis, then FDG-PET, bronchoscopy and testicular ultrasound; repeat imaging every 3 to 6 months for 2 to 4 years if negative.
• Nerve conduction studies for neuropathy and neuronopathy; exclude herpes encephalitis, autoimmune encephalitis with surface antibodies and metabolic causes.

Differential diagnosis. Herpes simplex encephalitis, autoimmune encephalitis (anti-LGI1, anti-NMDA receptor), Creutzfeldt-Jakob disease, metastases, leptomeningeal disease, neurosarcoidosis, Wernicke encephalopathy, and non-paraneoplastic myelitis.

• Treat the cancer as soon as possible (chemotherapy, radiotherapy, surgery); this is the only treatment that can stop the autoimmune injury.
• Immunotherapy for rapidly progressive disease, started early: methylprednisolone 1000 mg intravenously once daily for 3 to 5 days. Maximum 5 g in a course. Monitor blood pressure, glucose, mood and infection. Avoid with active untreated infection; use caution in diabetes and peptic ulcer.
• Intravenous immunoglobulin 2 g/kg in total over 2 to 5 days, or plasma exchange (5 exchanges over 10 days). Maximum 2 g/kg in any 4 week period. Monitor renal function, thrombosis, hypersensitivity and aseptic meningitis; check IgA before the first dose. Avoid in IgA deficiency with anti-IgA antibodies; use caution in renal impairment and heart failure.
• Cyclophosphamide 750 mg/m2 intravenously every 4 weeks for up to 6 cycles, or rituximab 1000 mg intravenously on days 1 and 15, for patients who do not respond, in discussion with oncology. Maximum 1000 mg/m2 for cyclophosphamide and 1000 mg for each rituximab dose. Give cyclophosphamide with mesna and fluids; monitor full blood count, urine and infection; screen for hepatitis B before rituximab; avoid both in pregnancy and active infection; reduce cyclophosphamide in renal impairment.
• Seizures: levetiracetam 500 mg orally or intravenously twice daily, increased by 500 mg twice daily every 2 weeks as needed to a maximum of 1500 mg twice daily. Monitor mood and renal function. Reduce dose when creatinine clearance is 50 to 80 mL/min (500 to 1000 mg twice daily), 30 to 50 mL/min (250 to 750 mg twice daily) and under 30 mL/min (250 to 500 mg twice daily).
• Supportive care: respiratory support, nutrition, swallowing, rehabilitation, psychological support and early palliative care.

Monitoring. Review at 2 to 4 weeks, then every 3 months; repeat cancer screening every 3 to 6 months for 4 years; track neurological scores.

Referral and escalation. Neurology and oncology urgently; intensive care for respiratory or bulbar failure; palliative care early.

Special groups. Older adults: higher risk of infection and falls on immunotherapy. Pregnancy: urgent oncology and obstetric input.