DPPX Antibody Encephalitis

Dipeptidyl-peptidase-like protein 6 (DPPX) antibody encephalitis is a rare autoimmune disorder with antibodies against DPPX, a subunit of the Kv4.2 potassium channel complex. It affects mostly men in middle age (median about 50 years), and is often preceded by weight loss and diarrhoea. B-cell neoplasm is found in a minority.

Pathophysiology. Antibodies reduce Kv4.2 channel function and cause neuronal hyperexcitability in the central nervous system and the enteric system.

The core triad is prodromal gastrointestinal symptoms (diarrhoea, weight loss, 10 to 20 kg), cognitive impairment (confusion, memory loss, psychosis) and central hyperexcitability (tremor, myoclonus, startle, hyperekplexia, stiffness, seizures). Others are ataxia, brainstem signs, sleep disorder (insomnia, parasomnia), dysautonomia (including gastroparesis) and progressive encephalomyelitis with rigidity and myoclonus.

Red flags.

• Unexplained weight loss and diarrhoea with new confusion and tremor.
• Brainstem or respiratory involvement.

Serum and CSF DPPX antibodies by cell based assay. CSF shows mild pleocytosis, raised protein and sometimes oligoclonal bands. MRI is often normal, or shows non-specific change. EEG may be abnormal. Evaluate the gut (exclude infection and malabsorption), check for lymphoproliferative disease with CT, bone marrow or FDG-PET, and lymph node biopsy if warranted.

Differential diagnosis.

• Stiff person spectrum disorders (anti-GAD65, glycine receptor), Creutzfeldt-Jakob disease.
• Progressive encephalomyelitis with rigidity and myoclonus, other autoimmune encephalitis.
• Coeliac disease, Whipple disease and inflammatory bowel disease.

Immunotherapy. Early treatment gives a good chance of response, but relapse is frequent.

• Methylprednisolone 1 g IV daily for 3 to 5 days, then prednisolone 1 mg/kg daily (maximum 60 mg) tapered over months.
• Intravenous immunoglobulin 0.4 g/kg daily for 5 days, or plasma exchange.
• Second line: rituximab 1 g IV twice, 2 weeks apart. Cyclophosphamide, mycophenolate mofetil or azathioprine as maintenance.

Symptoms. Levetiracetam or valproate for seizures, clonazepam 0.5 mg at night, increased to 4 mg daily in divided doses, for startle, myoclonus and tremor. Support nutrition, with dietitian input.

Tumour. Treat any lymphoma.

Monitoring. Weight, gut symptoms, cognition and antibody levels where used, with relapse surveillance.

Referral and escalation. Refer to neurology, gastroenterology and haematology.