Erfan Bashar
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Autoimmune Encephalitis — Pathophysiology

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Educational scope notice: This is a study note for medical students, not medical advice, diagnosis, or treatment guidance. Clinical management should follow local protocols and current guidelines.

Autoimmune encephalitis means inflammation of the brain caused by an immune attack on neuronal proteins. The attack takes two different forms. The form determines both the tumour risk and the response to treatment.

The paraneoplastic context

In paraneoplastic disease, a tumour outside the nervous system produces proteins that resemble neuronal proteins. The immune system attacks the tumour and cross-reacts with the brain. Neurological symptoms often appear before the tumour is found, which is why tumour screening continues even after a negative first pass.

Surface antibodies cause the injury directly

Antibodies against cell-surface targets, such as the NMDA receptor, LGI1, CASPR2, GABA-B receptor, or AMPA receptor, reach their target directly. They disrupt its function by internalising the receptor, blocking it, or interfering with its signalling. Because the antibody itself causes the injury, removing or blocking it with immunotherapy often helps. The outlook is generally better.

Intracellular antibodies mark a T-cell injury

Antibodies against intracellular targets, such as Hu (ANNA-1), Yo, Ri (ANNA-2), or Ma2, mainly mark the injury rather than causing it. The damage comes from cytotoxic T cells directed at the same proteins, with the antibodies arising secondarily to that T-cell damage. Immunotherapy therefore helps less. The tumour association is stronger, and the prognosis is generally worse. This is a pattern across syndromes, not a rule for any individual patient.

GAD antibodies break this grouping. Their target sits inside the cell, yet the syndromes can resemble surface-antibody disease. Treat GAD as its own case rather than forcing it into either class.

What each pattern means for tumour risk

Paraneoplastic disease usually involves intracellular antibodies. Surface-antibody syndromes carry variable, antibody-specific tumour risk, generally classed as low to moderate. The antibody result therefore changes the urgency and direction of the tumour search.

How antibodies reach the brain across the blood-brain barrier remains incompletely understood. That gap does not change management.

Evidence anchors

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