Causes of Autoimmune Encephalitis
Autoimmune encephalitis is caused by pathogenic autoantibodies directed against neuronal surface antigens, synaptic proteins, or intracellular neuronal antigens, and can be triggered by malignancies (paraneoplastic), infections (particularly herpes simplex virus), immune checkpoint inhibitors, or arise idiopathically without an identifiable trigger 1.
Primary Etiological Categories
The causes of autoimmune encephalitis fall into four main categories 1:
1. Paraneoplastic (Tumor-Associated)
- Underlying malignancy triggers immune response against tumor antigens that cross-react with neuronal tissue
- More common in patients with constitutional symptoms (fever, night sweats, unintentional weight loss)
- Classical paraneoplastic syndromes typically involve antibodies against intracellular antigens (Hu, Yo, Ri, CV2, Ma2) 2
- Some surface antibody syndromes (NMDAR, AMPAR) can also be paraneoplastic
2. Post-Infectious
- Herpes simplex virus (HSV) encephalitis is a recognized trigger, particularly for anti-NMDA receptor encephalitis 3
- Preceding viral infection, fever, or viral-like prodrome is common 1
- The infection may trigger autoimmune response weeks after the initial viral illness
3. Iatrogenic (Drug-Induced)
- Immune checkpoint inhibitors (ICIs) can cause accelerated paraneoplastic encephalitis in cancer patients 1
- TNF-α inhibitors have been implicated 1
- ICI-associated AE represents a steroid-responsive condition requiring early recognition
4. Idiopathic (Cryptogenic)
- No identifiable trigger found despite thorough evaluation 4
- More common in patients with personal or family history of other autoimmune disorders 1
- Represents a significant proportion of cases
Immunological Mechanisms
The pathophysiology differs based on antibody target 2:
Antibodies to Surface/Synaptic Antigens (Directly Pathogenic)
- NMDAR, AMPAR, LGI1, CASPR2, GABA-A/B receptors, DPPX, glycine receptor
- These antibodies bind extracellular epitopes and are directly pathogenic
- Generally more responsive to immunotherapy
- Can occur with or without underlying malignancy
Antibodies to Intracellular Antigens (T-Cell Mediated)
- Classical onconeural antibodies (Hu, Yo, Ri, CV2, Ma2)
- Likely represent T-cell mediated cytotoxicity with antibodies serving as biomarkers
- Strongly associated with underlying malignancy
- Generally less responsive to immunotherapy
- GAD65 antibodies (in high titers) can mediate AE despite targeting intracellular antigen 1
Critical Clinical Pitfalls
Important caveat: The diffuse immune reaction in AE typically results in multifocal brain inflammation, leading to a polysyndromic presentation that is the clinical hallmark 1. While certain antibodies associate with stereotypical symptoms (e.g., faciobrachial dystonic seizures in LGI1-antibody encephalitis), significant symptom overlap exists between all antibody types.
Cancer screening is mandatory in relevant cases: CT chest/abdomen/pelvis with contrast, and if negative, consider mammogram/breast MRI, pelvic ultrasound, and/or whole body FDG-PET guided by clinical presentation and cancer risk factors 1.
The estimated prevalence is 14 per 100,000 5, making AE now more common than any single infectious cause of encephalitis in Western populations 6, though infectious causes remain more common in Asia.