Question:

How is Autoimmune Encephalitis diagnosed?

Answer:

To consider a diagnosis of AE, the doctor takes a history of how the illness first appeared and progressed. They look at the symptoms the patient has and how they are currently presenting. AE is a complex diagnosis to make as the symptoms are broad, fluctuate and mimic many other diseases.

MRI often shows an increased signal on T2-weighted FLAIR imaging in the medial aspect of the temporal lobes. Although limbic encephalitis can occur with MRI evidence of unilateral involvement (or be normal) they are not considered to definite limbic encephalitis unless specific antibodies are subsequently detected. Unilateral involvement should raise the suspicion for other etiologies including herpes simplex virus encephalitis, varicella-zoster virus, tuberculosis, and neurosyphilis. Non-infectious etiologies such as gliomas may also be mistaken for encephalitis on neuroimaging.

Electroencephalogram (EEG) usually shows slow-wave activity or epileptiform discharges from the temporal lobes, suggestive of underlying inflammation. Clinically, any EEG that shows slow-wave activity or epileptiform discharges from the temporal lobes in a patient who meets criteria for possible AE should raise suspicion of the AE (even if neuroimaging is normal). Occasionally there can be a normal EEG, which does not rule out the diagnosis. Extreme delta brush can be seen specifically in anti-NMDA receptor encephalitis.

Lumbar Puncture and Cerebrospinal fluid (CSF) is tested to rule out all infectious causes and possible diseases that mimic AE. CSF can show leukocyte pleocytosis and oligoclonal bands, which supports a diagnosis of AE in the appropriate clinical context. However, there is low sensitivity. CSF can be helpful to exclude herpes simplex virus encephalitis as a differential diagnosis.

Various bloodwork can be considered:

• Inflammatory markers: Erythrocyte sedimentation rate (ESR), C-Reative Protein (CRP), ferritin
• Thyroid-stimulating hormone, free thyroxine, and thyroid autoantibodies (e.g., antithyroid peroxidase, antithyroglobulin, and anti–thyroid-stimulating hormone receptor)
• Systemic auto-antibodies: antinuclear antibodies (ANAs), extractable nuclear antigen autoantibodies (ENAs), rheumatoid factors (RFs), and anti-neutrophil cytoplasmic antibodies (ANCAs)
• Consider antinuclear antibodies and specific antinuclear antibodies (e.g., anti-double-stranded DNA and anti-Smith) if indicated by clinical presentation
• Consider serum complement and immunoglobulin levels if personal or family history of autoimmunity or immune deficiency

Do I need to have antibody results to establish a definite diagnosis of autoimmune encephalitis?

Not always. For limbic encephalitis, acute disseminated encephalomyelitis (ADEM), and Bickerstaff brainstem encephalitis (BBE) the diagnosis can be made without antibody studies or even if antibody results are negative. In these disorders, it is mandatory that the corresponding clinical criteria are strictly fulfilled. In limbic encephalitis and BBE, if criteria are partially fulfilled then the support of a positive antibody test is necessary to confirm the diagnosis. For the remaining types of autoimmune encephalitis, the antibody positivity is needed to establish a definite diagnosis of the type of AE.

Antibody Testing

• The autoantibodies associated with autoimmune encephalitis are all IgG antibodies. IgA or IgM antibodies against any of these antigens have unclear clinical significance.
• Serum and cerebrospinal fluid testing (CSF) should be performed for the most common antibodies in autoimmune encephalitis (anti-LGI1, GABABR, AMPAR, CASPR2, Hu, Ma2, and GAD).
• Some antibodies (e.g. – anti-LGI1) are more sensitive in serum, while others (e.g. – anti-GABABR) may only be identified in CSF. 

• The absence of autoantibodies does not exclude the possibility of an AE. However, measuring autoantibodies remains clinically important in identifying the immunological subgroup of an autoimmune encephalitis. This can help identify comorbidities, associated tumors (i.e. – malignancy screening), and prognosis. Also, in patients who do not meet the diagnostic criteria, the detection of autoantibodies can help establish the diagnosis of autoimmune limbic encephalitis.

References