Autoimmune encephalitis (AE) is a serious neurological condition where the immune system mistakenly attacks healthy brain cells, causing inflammation and dysfunction. This process targets specific proteins or receptors on nerve cells, disrupting normal brain signaling. Diagnosing AE is challenging because its initial presentation often mimics infectious diseases (like viral encephalitis) or primary psychiatric disorders (like psychosis). The diagnostic process is a careful, multi-step investigation combining clinical observation, imaging, fluid analysis, and sometimes, a therapeutic trial. This comprehensive approach is necessary to distinguish AE from other conditions and ensure timely treatment.
Recognizing Initial Symptoms and Excluding Other Causes
Diagnosis begins by recognizing a subacute onset of symptoms that progress over days or weeks, differentiating AE from the rapid onset of acute infections. Patients present with non-specific neurological and psychiatric changes, including significant short-term memory loss, new seizures, and prominent behavioral changes such as psychosis or aggression.
A detailed patient history is essential to track the trajectory of these symptoms, which may include fluctuations in consciousness or abnormal movements. Clinicians must immediately exclude more common and urgent causes of brain inflammation through differential diagnosis. This involves testing to rule out infectious encephalitis, particularly herpes simplex virus (HSV), which requires immediate antiviral treatment.
Excluding metabolic issues, such as severe electrolyte imbalances or organ failure, and drug toxicity is also a high priority. Only after infectious and metabolic mimics are reasonably excluded can the focus shift to specialized testing for autoimmune causes.
Imaging and Monitoring Brain Function
Once AE is suspected, structural and functional tests are used to characterize the brain dysfunction. Magnetic Resonance Imaging (MRI) is routinely performed to visualize brain tissue. While MRI can appear entirely normal in many AE cases, it often reveals characteristic signs of inflammation, particularly in the limbic system, which controls memory and emotion.
These findings typically appear as T2 or FLAIR hyperintensities—bright spots indicating swelling or fluid accumulation—in the medial temporal lobes. The presence of these specific lesions, combined with a negative viral workup, strongly suggests autoimmune limbic encephalitis. MRI also helps exclude other structural issues like tumors or stroke that could explain the patient’s symptoms.
Simultaneously, an Electroencephalogram (EEG) monitors the electrical activity of the brain. The EEG can detect seizures, which are common in AE, especially those that are non-convulsive. Certain patterns, such as generalized slowing or unique findings like “extreme delta brush,” can support the diagnosis, though they are not consistently present across all AE subtypes.
Identifying Specific Autoantibodies in CSF and Blood
Definitive confirmation of autoimmune encephalitis relies on identifying specific autoantibodies that target neuronal surface proteins. This is accomplished primarily through a lumbar puncture to obtain Cerebrospinal Fluid (CSF). CSF is the ideal sample because it is closest to the site of inflammation, allowing for the detection of antibodies produced within the brain’s compartment.
Initial CSF analysis often shows non-specific signs of inflammation, such as a mild elevation in white blood cell count (pleocytosis) or mildly elevated protein levels. The presence of oligoclonal bands, markers of immune activity, may also be noted. However, these general inflammatory markers are not always present, and their absence does not rule out AE, necessitating specific antibody testing.
Specific antibody testing targets the neuronal surface antigens that the immune system is attacking. The most common target is the N-methyl-D-aspartate receptor (NMDAR), confirming anti-NMDAR encephalitis upon detection. Other frequently tested antibodies include those against leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), which are often associated with limbic encephalitis.
Testing is usually performed on both CSF and blood serum, as detection sensitivity varies by antibody. For example, the NMDAR antibody is most sensitive in the CSF, while LGI1 antibodies are often more readily detected in the serum. A positive result for a neuronal surface antibody in the appropriate clinical context establishes a definite diagnosis of autoimmune encephalitis.
Confirmation Through Immunotherapy Response
For patients who present with all the clinical and paraclinical features of AE but have negative antibody tests—a condition referred to as seronegative AE—the diagnosis may be confirmed by observing the patient’s response to treatment. Since antibody results can take several days or weeks, doctors often initiate empirical immunotherapy if suspicion for AE is high, as delaying treatment can lead to worse outcomes.
The therapeutic trial involves administering high-dose immune-modulating treatments, such as intravenous corticosteroids, intravenous immunoglobulin (IVIg), or plasma exchange. A rapid and demonstrable clinical improvement following the initiation of these therapies provides substantial evidence supporting the diagnosis of AE. If the patient’s neurological and psychiatric symptoms significantly improve, it retroactively confirms the underlying cause was an immune-mediated process. This clinical response becomes the final piece of evidence when definitive antibody testing remains inconclusive.