Paraneoplastic and Autoimmune Neurological Antibodies

Paraneoplastic and autoimmune neurological antibodies are autoantibodies in serum and cerebrospinal fluid that identify immune mediated disorders of the brain, spinal cord, nerves and neuromuscular junction. Two groups exist.

Onconeural antibodies (anti-Hu, anti-Yo, anti-Ri, anti-CV2/CRMP5, anti-amphiphysin, anti-Ma2, anti-SOX1) target intracellular antigens, act through T cells, respond poorly to treatment and strongly suggest an underlying cancer.

Neuronal surface antibodies (anti-NMDA receptor, anti-LGI1, anti-CASPR2, anti-AMPA receptor, anti-GABA-B receptor, anti-GABA-A receptor, anti-DPPX, anti-IgLON5, anti-glycine receptor) target extracellular antigens, are directly pathogenic and respond to immunotherapy.

Testing is done by tissue based immunofluorescence and cell based assays, confirmed by line immunoblot or immunoprecipitation, in both serum and CSF.

Autoimmune encephalitis has an incidence of about 1 in 100 000 each year, comparable with infectious encephalitis. Anti-NMDA receptor encephalitis is the commonest (young women, with ovarian teratoma in 20 to 50% of women over 12 years old), followed by anti-LGI1 (older men).

Paraneoplastic neurological syndromes occur in under 1% of cancer patients, most often with small cell lung cancer, breast, ovarian, testicular and thymic tumours, and the neurological syndrome often precedes the cancer diagnosis by months to years.

Indications. Subacute onset (under 3 months) of memory loss, confusion, psychiatric disturbance, seizures, movement disorder or decreased consciousness (limbic or autoimmune encephalitis). Faciobrachial dystonic seizures and hyponatraemia (anti-LGI1). Neuropsychiatric illness with orofacial dyskinesia, catatonia and autonomic instability in a young woman (anti-NMDA receptor).

Subacute cerebellar ataxia (anti-Yo, anti-Tr, anti-Hu). Sensory neuronopathy (anti-Hu). Stiff person spectrum (anti-GAD, anti-amphiphysin, anti-glycine receptor). Opsoclonus myoclonus (anti-Ri). Peripheral nerve hyperexcitability (anti-CASPR2). Rapidly progressive dementia. Unexplained refractory seizures. Known cancer with new neurological syndrome.

Specimen. Serum 2 mL and CSF 1 to 2 mL collected at the same time, both stored at 2 to 8 °C or frozen. Both are tested for neuronal surface antibodies, since CSF can be positive when serum is negative (anti-NMDA receptor), and serum can be positive with negative CSF (anti-LGI1, anti-CASPR2). Samples are taken before immunotherapy or plasma exchange.

Onconeural (intracellular) antibodies.

Neuronal surface antibodies.

Reference values. All are negative in healthy people. Results are reported as negative or positive with titre (immunofluorescence) or intensity (immunoblot). Cell based assay positives in serum only, with a negative CSF, need caution because of false positives (particularly anti-NMDA receptor IgA and IgM).

Critical values and findings needing immediate action.

• Anti-NMDA receptor or other neuronal surface antibody with seizures, decreased consciousness, hypoventilation or catatonia: urgent immunotherapy (high dose methylprednisolone, intravenous immunoglobulin or plasma exchange) without waiting for confirmation once infection is excluded, plus a tumour search (pelvic ultrasound or MRI for teratoma) and removal of any tumour.
• Positive onconeural antibody: urgent whole body search for cancer (CT chest, abdomen and pelvis, then PET-CT, mammography, testicular ultrasound), repeated at 3 to 6 months if negative, for up to 4 years.
• Rapidly progressive cerebellar syndrome or opsoclonus: prompt immunotherapy and tumour search, since delay leads to irreversible neuronal loss.
• Anti-LGI1 with hyponatraemia and seizures: treat seizures, correct sodium and start immunotherapy (excellent response).
• Anti-GABA-B with refractory seizures: urgent lung cancer search.

Interferences and pitfalls.

• A negative panel does not exclude autoimmune encephalitis (seronegative cases are 10 to 30%), and the diagnosis can be made on clinical and MRI, EEG and CSF criteria, with treatment started on probable disease.
• Antibody positivity in serum alone without a compatible syndrome is often non-specific, and low titre anti-Hu, anti-Ri or anti-GAD occasionally appear in healthy people and in cancer patients without neurological disease.
• Antibody tests are performed in specialist laboratories with a turnaround of 1 to 4 weeks, so treatment decisions cannot wait.
• Both serum and CSF are tested, and for anti-NMDA receptor, CSF is the most sensitive sample.
• Prior immunotherapy, plasma exchange and intravenous immunoglobulin can alter titres or cause false positive results.
• CSF often shows mild lymphocytic pleocytosis, raised protein and oligoclonal bands, but may be normal. MRI shows medial temporal hyperintensity in limbic encephalitis, but is normal in over 50% of anti-NMDA receptor cases.
• Infectious encephalitis (herpes simplex, varicella zoster, enterovirus, HIV, syphilis, tuberculosis), metabolic encephalopathy, drug toxicity, prion disease, CNS lymphoma and primary psychiatric illness must be excluded.
• Anti-GAD high titres (over 2000 U/mL) have clinical meaning in neurological disease, while low titres occur in type 1 diabetes.
• Anti-MOG and anti-aquaporin-4 antibodies define separate demyelinating disorders.

Special groups.

• Children: anti-NMDA receptor encephalitis occurs in children, with behavioural change, speech regression and seizures. Tumour is less common. Opsoclonus myoclonus is linked to neuroblastoma.
• Pregnancy: anti-NMDA receptor encephalitis can occur, and transplacental transfer may affect the newborn.
• Older adults: anti-LGI1 and anti-CASPR2 encephalitis, and onconeural syndromes with lung cancer, are more frequent. Smoking history raises suspicion for small cell lung cancer.
• Regions: infectious encephalitis (cerebral malaria, tuberculosis, HIV, neurocysticercosis, rabies) is the main differential, and antibody testing is rarely available.

Follow up tests. CSF cell count, protein, glucose, oligoclonal bands, IgG index and virology PCR, MRI brain with contrast, EEG, CT chest, abdomen and pelvis, PET-CT, pelvic MRI, testicular ultrasound, mammography, serum sodium, thyroid antibodies, ANA, GAD65 antibody, aquaporin-4 and MOG antibodies, voltage gated potassium channel complex antibodies, acetylcholine receptor and calcium channel antibodies, repeat tumour surveillance, and neuropsychological testing.