Paraneoplastic Limbic Encephalitis

Paraneoplastic limbic encephalitis is an immune mediated inflammation of the limbic system (hippocampi, amygdala, insular and cingulate cortex) caused by an immune response to a tumour, characterised by subacute short term memory loss, confusion, behavioural change and seizures. Early recognition and tumour directed treatment limit the damage, and immunotherapy can improve outcome in antibody types directed at surface antigens.

It is rare, with an incidence of about 1 case in 100,000 people each year for autoimmune encephalitis overall, of which the paraneoplastic form is a minority. Median age at onset is 60 for onconeuronal antibody types (anti-Hu, anti-CRMP5) and about 30 to 40 for anti-Ma2 (testicular tumours in young men).

Associated tumours: small cell lung cancer (anti-Hu, CRMP5, amphiphysin, AMPAR, GABA-B), testicular germ cell tumours (anti-Ma2), thymoma, breast (anti-Ri, amphiphysin), and ovarian teratoma and lymphoma (anti-NMDAR in other presentations).

Pathophysiology. Antibodies against intracellular onconeuronal antigens (Hu, Ma2, CRMP5) are markers of cytotoxic T-cell mediated neuronal death, which responds poorly to therapy. Antibodies against surface antigens (AMPA receptor, GABA-B receptor, LGI1, CASPR2) directly alter receptor function and respond better to immunotherapy.

Prognosis. Outcomes with intracellular antigen antibodies are poor (neurological deficits remain in most), whereas surface antibody types often improve with immunotherapy and tumour treatment. Overall survival is determined largely by the tumour.

• Subacute (days to weeks, usually under 12 weeks) short term memory loss, disorientation, confusion.
• Temporal lobe seizures (focal impaired awareness, often refractory), mood change, anxiety, depression, hallucinations or personality change.
• Sleep disturbance, hyponatraemia (LGI1), and faciobrachial dystonic seizures (LGI1).
• Extra-limbic signs in some (brainstem or cerebellar features, neuropathy).

Red flags.

• Status epilepticus.
• Rapidly progressive cognitive decline or reduced consciousness.
• Severe psychiatric symptoms with risk to self.

• MRI of the brain: T2/FLAIR hyperintensity of one or both medial temporal lobes (normal in a minority).
• EEG (temporal slowing and epileptiform discharges), CSF (lymphocytic pleocytosis, raised protein, oligoclonal bands), exclusion of infection (herpes simplex PCR, other viral and bacterial causes).
• Antibodies in serum and CSF: anti-Hu (ANNA-1), Ma2, CRMP5 (CV2), amphiphysin, GAD65, AMPAR, GABA-B, LGI1, CASPR2, NMDAR.
• Tumour search: CT of the chest, abdomen and pelvis, whole body FDG-PET-CT, testicular ultrasound, mammography or breast MRI and pelvic imaging. Repeat every 3 to 6 months for up to 4 years if the search is negative and a high risk antibody is found.

Differential diagnosis.

• Herpes simplex encephalitis and other infectious encephalitis
• Non-paraneoplastic autoimmune limbic encephalitis (LGI1, GAD65)
• Hashimoto encephalopathy, metabolic encephalopathy and nonconvulsive status epilepticus
• Primary CNS lymphoma, glioma, Creutzfeldt-Jakob disease and neurosyphilis

Treat the tumour first, with early immunotherapy in parallel. Delay worsens outcome.

Tumour treatment. Surgery, chemotherapy or radiotherapy for the tumour as early as possible (for example orchidectomy for a testicular germ cell tumour, chemotherapy for small cell lung cancer, thymectomy for thymoma).

First line immunotherapy.

• 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 on alternate days) is an alternative, or is used after steroids and immunoglobulin when the response is poor.

Second line immunotherapy (no response at 2 to 4 weeks, or for relapse).

• 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, and repeat at 6 months if relapse occurs and B cells have returned.
• Cyclophosphamide: 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.

Seizure control. Levetiracetam 500 mg orally twice daily, increased by 500 mg twice daily every 1 to 2 weeks to a usual 1000 to 1500 mg twice daily after a seizure; maximum 3000 mg daily.

It is not continued as prophylaxis in seizure free patients after the early postoperative period.

• Monitoring: mood, irritability, somnolence, renal function.
• Adjustment: creatinine clearance 50 to 79 mL/min 500 to 1000 mg twice daily, 30 to 49 mL/min 250 to 750 mg twice daily, under 30 mL/min 250 to 500 mg twice daily.
• Avoid enzyme inducing antiseizure drugs because they lower temozolomide and lomustine exposure.

Psychiatric symptoms. Short courses of antipsychotic or benzodiazepine therapy at the lowest effective dose and monitored closely, with a psychiatrist if needed.

Monitoring. Neurological and cognitive testing (including neuropsychology), MRI at 3 to 6 months, and repeat tumour screening. Hyponatraemia and sodium monitoring.

Referral and escalation.

• Urgent neurology referral on suspicion; start immunotherapy after infection is excluded.
• Emergency admission for status epilepticus or reduced consciousness.

Special groups.

• Young men with anti-Ma2: testicular ultrasound and microlithiasis assessment, and orchidectomy if a tumour is found.
• Older adults: caution with steroids and immunoglobulin (thrombotic and renal risk).
• Pregnancy: immunoglobulin and plasma exchange preferred, with teratoma assessment.