Immunotherapy and Tumor Screening Guidelines for NMDA‑Receptor Antibody‑Positive Autoimmune Encephalitis

First‑Line Immunotherapy

High‑dose intravenous corticosteroids (e.g., methylprednisolone) are the preferred initial agent and should be started immediately once infection is excluded on CSF analysis. 1
If the presentation is severe (new‑onset refractory status epilepticus, severe dysautonomia, or ICU admission), combine corticosteroids with IVIG or plasma exchange from the outset rather than waiting for treatment failure. [2][3]
IVIG is favored over plasma exchange in patients who are agitated or have bleeding disorders. [1][2]
Plasma exchange (5–10 sessions every other day) is preferred for patients with severe hyponatremia, high thromboembolic risk (including cancer), or concomitant demyelination. [1][2]
Retrospective data show that plasma exchange added to corticosteroids yields greater improvement in Modified Rankin Scale scores than corticosteroids alone. 1
If no clinical, radiological, or electrophysiological improvement is seen by the end of the initial treatment cycle, add IVIG or plasma exchange to the corticosteroid regimen. [1][2]
Expert consensus: 62 % of clinicians add a different first‑line therapy when the initial agent fails, whereas only 26 % proceed directly to second‑line agents. 3

All patients should undergo contrast‑enhanced CT of the chest, abdomen, and pelvis as the initial cancer‑screening study. [1][4]
Young and middle‑aged adults require pelvic ultrasound (transvaginal or transabdominal in females; testicular ultrasound in males) to detect teratoma. 4
For female patients not up‑to‑date with breast screening or with strong family history, obtain a mammogram (add breast MRI if suspicion remains high). 4
When the initial CT is negative but suspicion for malignancy persists (e.g., based on smoking history, advanced age, or contraindication to contrast), perform a whole‑body FDG‑PET scan. [1][4]
If pelvic ultrasound is equivocal for teratoma, follow with pelvic MRI for definitive assessment. 4

Initiate second‑line agents 2–4 weeks after completing combined first‑line therapy if there is no meaningful clinical or radiological improvement. [5][6]
In severe or refractory cases, some clinicians start second‑line therapy earlier (≈2 weeks after first‑line initiation). 6
Rituximab is the preferred second‑line agent (chosen by ~80 % of experts); it is less toxic than cyclophosphamide and specifically targets antibody‑mediated autoimmunity. [5][6]7
- Typical dosing: 375 mg/m² weekly for 4 weeks or two 1000 mg infusions given 2 weeks apart. 6
Cyclophosphamide (600–1000 mg/m²) is reserved for cell‑mediated autoimmunity such as classical paraneoplastic syndromes with intracellular antibodies. [5][6]
For refractory disease not responding to rituximab or cyclophosphamide, consider tocilizumab (IL‑6 inhibitor) or bortezomib (proteasome inhibitor); evidence is limited. [5][2]

After acute treatment, start bridging therapy with a gradual oral prednisone taper, monthly IVIG, or monthly IV methylprednisolone. [1][2]

Do not delay immunotherapy while awaiting antibody confirmation; clinical suspicion alone justifies immediate treatment. 1

High‑dose intravenous corticosteroid is the preferred first‑line agent and should be initiated promptly after infectious causes are excluded by cerebrospinal fluid analysis. 8
In patients with severe disease (refractory new‑onset status epilepticus, marked dysautonomia, or requiring intensive‑care support), corticosteroid should be combined from the outset with either intravenous immunoglobulin (IVIG) or plasma exchange. 8

IVIG is favored for patients who are agitated or have bleeding tendencies. 8
Plasma exchange (typically 5–10 sessions on alternate days) is preferred for those with severe hyponatremia, high thrombo‑embolic risk (including underlying malignancy), or concurrent demyelinating disorders. 8
Retrospective analyses indicate that adding plasma exchange to corticosteroid therapy produces a greater improvement in Modified Rankin Scale scores than corticosteroid alone. 8

If no clinical, radiologic, or electrophysiologic improvement is observed at the end of the initial treatment cycle, IVIG or plasma exchange should be added to the ongoing corticosteroid regimen. 8

When initial contrast CT of chest, abdomen, and pelvis is negative but suspicion for malignancy remains high (e.g., history of smoking or advanced age), whole‑body FDG‑PET imaging is recommended. 8

Second‑line agents should be introduced 2–4 weeks after completion of the first‑line combination if meaningful clinical or radiologic improvement has not occurred. 8
Rituximab is the preferred second‑line therapy (selected by ~80 % of experts) because it is less toxic than cyclophosphamide and specifically targets antibody‑mediated autoimmunity. 8
Cyclophosphamide (600–1000 mg/m²) is reserved for cell‑mediated autoimmune processes such as classic paraneoplastic syndromes associated with intracellular antibodies. 8

For cases unresponsive to rituximab or cyclophosphamide, consider IL‑6 inhibition with tocilizumab or proteasome inhibition with bortezomib; current evidence is limited. 8

After acute immunotherapy, initiate a bridging regimen consisting of a gradual oral prednisone taper, monthly IVIG, or monthly intravenous methylprednisolone. 8
Long‑term maintenance therapy is generally unnecessary except in patients with a particularly severe or prolonged disease course. (no citation needed)

Relapse occurs in 10–30 % of patients, most commonly within the first two years after onset; the 2‑year relapse risk is approximately 12 %, and about two‑thirds of relapses are milder than the initial episode. 8