Case 1: 58-year-old man presented with episodes of recurrent encephalitis. Patient presented with new-onset headaches, subacute mental status change with inability to perform ADLs, rapidly declining memory, progressive imbalance causing wheelchair dependence, polychondritis, hearing loss, elevated inflammatory markers and weight loss. Infectious/metabolic workup was unremarkable. CSF showed mildly elevated cell count, protein of 60, and 6 oligoclonal bands (OCBs). Serum/CSF encephalopathy panel was unrevealing. Patient was started on IV steroids and methotrexate resulting in some improvement. While on methotrexate, patient had another relapse with 4 OCBs in CSF. MRI brain showed subtle FLAIR hyperintensity along the lateral margin of the body and tail of hippocampus and amygdala with hippocampal volume loss. Patient was then switched to rituximab with significant improvement.

Case 2: 67-year-old man with new-onset seizures and cognitive decline. MRI showed abnormal FLAIR hyperintensity in the left frontal lobe and cingulate gyrus. CSF antibody testing was unremarkable. Patient had low positive calcium-channel antibodies, ANA 1:80, positive cardiolipin and inflammatory CSF. Patient did not respond to two anti-epileptics and was started on steroids with significant improvement. Patient was weaned off steroids and started on azathioprine with resolution of seizures, sustained clinical improvement, complete reversal of abnormal MRI and negative calcium-channel antibodies.

Antibody-negative autoimmune encephalitis is difficult to diagnose but prompt treatment with immunosuppressants is necessary to prevent irreversible damage. Due to lack of availability of antibody testing in some centers and probability of autoimmune encephalitis related to antibodies not yet discovered, thoughtful approach to clinical presentation, CSF, EEG, and MRI findings is essential to formulate accurate diagnosis and treatment plan to prevent devastating consequences.