Anti-CASPR2 Encephalitis

Anti-CASPR2 encephalitis is an autoimmune disorder caused by antibodies against contactin associated protein like 2. It causes limbic encephalitis, peripheral nerve hyperexcitability (neuromyotonia), neuropathic pain, insomnia and autonomic dysfunction, and in some patients the full Morvan syndrome.

It is rare, with an estimated incidence of under 1 in every million people each year. The median age is 60 years, and about 85% of patients are men.

Associations. HLA-DRB1*11:01. Thymoma is found in about 20% overall, and in over a third of those with Morvan syndrome.

Course. Subacute or chronic over weeks to months, with relapse in about 25%. Response to immunotherapy is good in most, but treatment is often delayed.

Pathophysiology.

IgG4 antibodies against CASPR2 interfere with its interaction with contactin-2 and the clustering of Kv1 potassium channels at juxtaparanodes and in the hippocampus.

The loss of Kv1 channel function leads to nerve hyperexcitability and limbic network dysfunction.

• Limbic encephalitis: memory loss, confusion, behavioural change and seizures.
• Neuromyotonia: cramps, muscle twitching (fasciculations, myokymia), stiffness and delayed relaxation.
• Neuropathic pain, burning feet, and hyperhidrosis; severe insomnia (agrypnia).
• Autonomic features: cardiac arrhythmia, hypertension, constipation and urinary dysfunction.
• Morvan syndrome: encephalopathy, neuromyotonia, dysautonomia and severe insomnia with hallucinations; cerebellar ataxia in some.

Red flags.

• Status epilepticus, cardiac arrhythmia or severe insomnia with hallucinations.
• Weight loss, cough or a mediastinal mass (thymoma or lung cancer).
• Rapid cognitive decline.

• Clinical syndrome with CASPR2 antibodies in serum and, ideally, cerebrospinal fluid.
• Electromyography showing neuromyotonic discharges, fibrillations or myokymia.
• MRI of the brain (medial temporal T2 or FLAIR hyperintensity in about 40%); EEG; polysomnography for sleep disturbance.
• CT of the chest, abdomen and pelvis and FDG-PET to find thymoma or other tumours; repeat screening if negative.
• Serum sodium, creatine kinase, ECG and ambulatory monitoring; test for LGI1 and other antibodies.

Differential diagnosis. Anti-LGI1 encephalitis, Isaacs syndrome from other causes, stiff person syndrome, motor neurone disease, small fibre neuropathy, herpes encephalitis, Creutzfeldt-Jakob disease and chronic insomnia.

• Treat any tumour, particularly thymoma resection.
• First line immunotherapy: methylprednisolone 1000 mg intravenously once daily for 3 to 5 days, with intravenous immunoglobulin 2 g/kg in total over 2 to 5 days or plasma exchange (5 exchanges over 10 days). Maximum 5 g of methylprednisolone in a course and 2 g/kg of immunoglobulin in any 4 week period. Monitor blood pressure, glucose, mood, infection, renal function, thrombosis and aseptic meningitis; check IgA before immunoglobulin. Avoid with active untreated infection and in IgA deficiency with anti-IgA antibodies; use caution in diabetes, renal impairment and heart failure.
• Continue with oral prednisolone 1 mg/kg daily (maximum 60 mg) tapered over 6 to 12 months with bone and gastric protection; monitor blood pressure, glucose and infection.
• Second line therapy for poor response or relapse: rituximab 1000 mg intravenously on days 1 and 15, repeated at 6 months if indicated. Maximum 1000 mg for each dose. Screen for hepatitis B before treatment; monitor infusion reactions, infection and immunoglobulins. Avoid in active infection and pregnancy.
• Neuromyotonia and cramps: carbamazepine 100 mg orally twice daily, increased by 100 mg every 2 days to a usual 400 to 800 mg daily in 2 to 3 divided doses. Maximum 1600 mg daily. Monitor sodium, full blood count and liver function; check HLA-B*1502 in at risk Asian ancestry; stop at the first rash. Avoid in atrioventricular block and porphyria; reduce dose in hepatic impairment and older adults.
• Neuropathic pain: pregabalin 75 mg orally twice daily, increased after 1 week to 150 mg twice daily, then to a maximum of 300 mg twice daily (600 mg daily). Monitor sedation, weight gain, oedema, mood and misuse. Adjust for renal function: creatinine clearance 30 to 59 mL/min, 75 to 300 mg daily; 15 to 29 mL/min, 25 to 150 mg daily; under 15 mL/min, 25 to 75 mg daily.
• Cardiac monitoring for arrhythmia; sleep hygiene and cognitive rehabilitation; treat anxiety and depression.

Monitoring. Review at 2 to 4 weeks, then every 3 months for 2 years; track cognition, sleep, pain, cramps and antibody titres; repeat tumour screening yearly for 4 years.

Referral and escalation. Neurology and neuroimmunology; cardiothoracic surgery and oncology for thymoma; sleep medicine and cardiology as needed.

Special groups. Older men: the usual group, so check sodium and cardiac risk. Pregnancy: specialist neuroimmunology and obstetric care.