Residency · Residency · Neurology
Autoimmune Encephalitis: Antibody-Mediated Syndromes
Introduction
Autoimmune encephalitis (AE) encompasses a group of inflammatory brain diseases mediated by antibodies against neuronal cell-surface or intracellular antigens. Once considered rare, AE is now recognized as a common cause of new-onset seizures, psychiatric symptoms, and rapidly progressive cognitive decline. Early immunotherapy can be life-saving, making prompt recognition essential.
Classification of Antibody-Mediated Syndromes
Antibodies Against Cell-Surface Antigens
| Antibody | Syndrome | Demographics | Tumor Association | Key Feature |
|---|---|---|---|---|
| Anti-NMDAR | Encephalitis (psychiatric → seizures → movement disorder → autonomic) | Young women (median 21) | Ovarian teratoma (40%) | Orofacial dyskinesias, extreme delta brush |
| Anti-LGI1 | Limbic encephalitis | Older men (median 60) | Rare (<10%) | Faciobrachial dystonic seizures, hyponatremia |
| Anti-CASPR2 | Morvan syndrome, neuromyotonia | Older men | Thymoma | Peripheral nerve hyperexcitability, insomnia |
| Anti-GABA-B | Limbic encephalitis + seizures | Older adults | SCLC (50%) | Prominent seizures |
| Anti-AMPAR | Limbic encephalitis | Women | Breast, lung, thymoma | Relapses common |
| Anti-DPPX | Hyperekplexia, GI dysmotility | Middle-aged | Rare | Prodromal diarrhea/weight loss |
Anti-NMDA receptor encephalitis is the most common autoimmune encephalitis. Anti-LGI1 encephalitis presents as limbic encephalitis with faciobrachial dystonic seizures. Anti-CASPR2 encephalitis produces Morvan syndrome, limbic encephalitis, and neuromyotonia. Anti-AMPA receptor encephalitis causes limbic encephalitis often with tumor association. Anti-GABA-B receptor encephalitis presents with seizures and limbic encephalitis and is associated with small cell lung cancer. Anti-DPPX encephalitis causes hyperekplexia, GI dysmotility, and cognitive changes.
Antibodies Against Intracellular Antigens (Paraneoplastic)
Anti-Hu (ANNA-1) is associated with encephalomyelitis and sensory neuropathy in the setting of small cell lung cancer. Anti-Yo (PCA-1) causes cerebellar degeneration with ovarian or breast cancer. Anti-Ri (ANNA-2) produces opsoclonus-myoclonus with breast cancer. Anti-CV2/CRMP5 is associated with chorea, neuropathy, and optic neuritis in small cell lung cancer and thymoma. These antibodies are markers of an immune response rather than directly pathogenic; prognosis depends on tumor treatment.
Anti-NMDA Receptor Encephalitis
Clinical Stages
Anti-NMDA receptor encephalitis progresses through a characteristic sequence. The prodromal phase (1-2 weeks) involves fever, headache, and upper respiratory symptoms. This is followed by a psychiatric phase with anxiety, agitation, psychosis, bizarre behavior, and paranoia. The seizure phase produces generalized or focal seizures. The movement disorder phase manifests as orofacial dyskinesias, choreoathetosis, and dystonia. Finally, the autonomic and decreased consciousness phase brings central hypoventilation, autonomic instability, and catatonia. The median age is 21 years, with 80% of patients being female. Ovarian teratoma is present in approximately 40% of affected women.
Diagnosis
MRI may be normal in 50% of cases or show T2/FLAIR signal in the medial temporal lobes. CSF demonstrates lymphocytic pleocytosis, and CSF anti-NMDAR antibodies are more sensitive than serum testing. EEG shows diffuse slowing with the extreme delta brush pattern being pathognomonic (though present in fewer than 30% of cases). Pelvic MRI or ultrasound should be performed to screen for ovarian teratoma.
Anti-LGI1 Encephalitis
Anti-LGI1 encephalitis has a median age of onset of 60 years with a slight male predominance. The hallmark feature is faciobrachial dystonic seizures (FBDS): brief (less than 3 seconds), frequent (up to 100 per day), stereotyped arm and ipsilateral face contractions that often precede the development of frank encephalitis. Limbic encephalitis manifests as memory loss, confusion, and seizures. Hyponatremia due to SIADH occurs in approximately 60% of patients. MRI shows T2/FLAIR hyperintensity in the medial temporal lobes, often bilateral. Tumor association is rare (less than 10%). FBDS are often refractory to antiseizure medications but respond to immunotherapy.
Diagnostic Approach
Graus 2016 Clinical Criteria for Possible AE
The criteria require subacute onset (rapid progression over less than 3 months) of working memory deficits, altered mental status, or psychiatric symptoms, plus at least one of: new focal CNS findings, seizures not explained by prior epilepsy, CSF pleocytosis, or MRI features of encephalitis. Reasonable exclusion of alternative causes is required.
Recommended Workup
The evaluation should include serum and CSF antibody panels (cell-based assays preferred; CSF must always be sent), brain MRI with gadolinium, CSF analysis (cell count, protein, glucose, cytology, oligoclonal bands), EEG with continuous monitoring recommended, CT chest/abdomen/pelvis or whole-body PET-CT for occult malignancy, pelvic ultrasound or MRI in women with anti-NMDAR antibodies, and testicular ultrasound in men when appropriate.
Treatment
First-Line Immunotherapy
First-line treatment consists of IV methylprednisolone 1 g daily for 5 days, intravenous immunoglobulin (IVIG) 0.4 g/kg/day for 5 days, and plasma exchange (PLEX) with 5-7 exchanges. These are often used in combination, and early initiation improves outcomes.
Second-Line Immunotherapy
Rituximab (anti-CD20 B-cell depletion) is increasingly used as early second-line therapy. Cyclophosphamide is reserved for severe, refractory cases. Second-line therapy should be initiated if no improvement occurs within 2 weeks of first-line treatment.
Tumor Removal
Oncological treatment is essential when a tumor is identified. Ovarian teratoma removal in anti-NMDAR encephalitis dramatically improves outcomes. Repeat tumor screening at intervals should be performed if the initial screen is negative.
Long-Term Management
Maintenance immunosuppression with rituximab, mycophenolate, or azathioprine is used to prevent relapses. The relapse rate for anti-NMDAR encephalitis is approximately 12%, higher without maintenance therapy. Neuropsychological rehabilitation addresses cognitive sequelae.
Clinical Pearls
New-onset psychiatric symptoms with seizures or movement disorder in a young woman should prompt evaluation for anti-NMDA receptor encephalitis. Faciobrachial dystonic seizures are pathognomonic for anti-LGI1 encephalitis and respond to immunotherapy, not antiseizure medications alone. CSF should always be sent for antibody testing because serum alone is insufficient and may be falsely negative. Early immunotherapy and tumor removal (when applicable) are the strongest predictors of favorable outcome.
References
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
- Dalmau J, Armangue T, Planaguma J, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists. Lancet Neurol. 2019;18(11):1045-1057.
- Irani SR, Michell AW, Lang B, et al. Faciobrachial dystonic seizures precede LGI1 antibody limbic encephalitis. Ann Neurol. 2011;69(5):892-900.
- Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis. Lancet Neurol. 2013;12(2):157-165.