Autoimmune encephalitis (AE) is a serious condition where the immune system mistakenly attacks healthy brain cells, causing inflammation. This response is driven by antibodies that target specific proteins on nerve cells, disrupting normal brain function. Diagnosing AE is a complex, multi-step process combining clinical observation, laboratory tests, and specialized imaging. Since symptoms often mimic other neurological and psychiatric disorders, diagnosis involves ruling out other causes and confirming autoimmune markers. Prompt treatment with immunotherapy significantly improves patient outcomes.
Initial Clinical Suspicion and Differential Diagnosis
The diagnostic process begins with recognizing a specific pattern of acute or subacute symptom onset, typically developing over weeks to three months. Clinicians look for a rapid decline in cognitive function, such as short-term memory loss, along with altered mental status or new psychiatric symptoms like psychosis, agitation, or hallucinations. New-onset seizures, which may not be easily controlled, also raise suspicion for an underlying inflammatory process.
The first step is a rigorous differential diagnosis to exclude other life-threatening conditions that present similarly. Infectious causes, particularly viral infections like Herpes Simplex Virus (HSV), must be ruled out immediately because they require urgent treatment. Doctors also exclude structural issues such as brain tumors, stroke, or metabolic disorders, which produce neurological and behavioral changes.
Initial clinical assessments, including a detailed patient history and neurological exam, help narrow the focus before specialized testing. This initial triage ensures non-autoimmune causes are excluded before proceeding to specific tests for autoimmune biomarkers. A diagnosis of possible AE is only considered once alternative causes have been ruled out.
Key Laboratory Investigations for Biomarkers
Once clinical suspicion is established and alternative diagnoses are excluded, the next phase focuses on identifying specific autoimmune markers. This requires analyzing two primary fluids: blood serum and cerebrospinal fluid (CSF). A lumbar puncture collects CSF, the fluid bathing the brain and spinal cord, making it a superior medium for detecting central nervous system inflammation.
The CSF is analyzed for signs of inflammation, such as an elevated white blood cell count, known as pleocytosis. The presence of oligoclonal bands (OCBs) or an elevated IgG index also suggests an immune response within the central nervous system. However, the most definitive laboratory evidence comes from testing both the serum and CSF for specific neuronal surface antibodies.
These tests look for antibodies that target proteins on brain cell surfaces, which cause the illness. Examples include antibodies against the N-methyl-D-aspartate (NMDA) receptor, Leucine-rich glioma-inactivated 1 (LGI1), and Contactin-associated protein-like 2 (CASPR2). While blood testing is often performed first, detecting these antibodies in the CSF provides stronger evidence that the immune attack is occurring within the brain. Identifying a specific antibody confirms the autoimmune nature and often dictates the specific syndrome, such as anti-NMDA receptor encephalitis.
Structural and Functional Assessments
In addition to fluid analysis, non-fluid-based assessments visualize the brain and measure its electrical activity. Magnetic Resonance Imaging (MRI) is a standard tool used to rule out structural causes like tumors, but it can also reveal characteristic patterns of inflammation. While the MRI can sometimes appear normal early in the disease course, it may show swelling or abnormal signal intensity in specific areas, such as the medial temporal lobes, suggestive of limbic encephalitis.
Electroencephalography (EEG) measures the electrical activity of the brain and is a routine part of the evaluation. The EEG can detect abnormal patterns consistent with inflammation, general slowing of brain waves, or subtle seizure activity that may not be clinically obvious. In certain types of AE, such as anti-NMDA receptor encephalitis, a pattern called “extreme delta brush” can be observed, which strongly supports the diagnosis.
In more complex or seronegative cases—where no antibodies are found—a Positron Emission Tomography (PET) scan may be used to look for functional changes. A PET scan assesses the metabolic activity of different brain regions, showing areas of abnormally decreased or increased activity. These imaging and functional tests help establish the anatomical location and severity of the inflammation, even when antibody results are delayed or inconclusive.
Synthesizing Results and Confirmation
The final step involves bringing together all the clinical, laboratory, and imaging data to reach a definitive conclusion. Neurologists use standardized diagnostic criteria, such as the 2016 criteria developed by Graus and colleagues, to systematically assess diagnostic confidence. This framework allows doctors to categorize the diagnosis as “possible,” “probable,” or “definite” autoimmune encephalitis.
A definite diagnosis is typically achieved when the characteristic clinical presentation is combined with the presence of a known pathogenic neuronal surface antibody. However, even without an identified antibody, a diagnosis of “probable” or “definite” seronegative AE can be made if the clinical symptoms, CSF findings, and imaging results are highly consistent with the condition. This is important because antibody testing can take days or weeks, and treatment often needs to begin immediately to prevent permanent brain injury.
The process is one of exclusion followed by confirmation, where the clinical picture guides the initial suspicion, and specialized tests provide objective biological evidence. By correlating the patient’s rapidly progressing symptoms, inflammatory markers in the CSF, and abnormalities on the MRI or EEG, clinicians can confidently confirm the diagnosis. This comprehensive synthesis ensures the patient receives the appropriate and timely immunotherapy necessary to halt the immune attack on the brain.