Case Presentation: A 66-year-old male with hypertension, type 2 diabetes, hyperlipidemia, pulmonary emboli with +lupus anticoagulant, and intrathecal morphine pump presented for increasingly frequent episodic altered sensorium. Episodes were described as < 30 seconds of paresthesia, speech arrest, and déjà vu; no loss of consciousness or focal deficits. Onset was 2-3 months prior with associated fatigue, poor oral intake, and impaired memory. On arrival he was tachycardic, orthostatic, with elevated ESR: 48mm/hr and hs-CRP: 0.96mg/dL. EEG showed mild right hemispheric cerebral dysfunction, no epileptic discharges. On hospital day (HD) 4, brain MRI showed edema and heterogenous enhancement of right mesial temporal lobe suggesting acute encephalitis; acyclovir initiated. Fluoroscopic-guided lumbar puncture showed total protein: 85mg/dL, no abnormal cytology or microbial meningitis; acyclovir discontinued. CSF and serum were negative for encephalopathy autoantibodies. Contrast CT abdomen/pelvis was unremarkable. Continuous EEG showed right temporal dysfunction without epileptic discharges and push-button events suspected to be auras. Patient started oxcarbazepine for suspected temporal lobe epilepsy with subsequent improvement. Brain MRI on HD+11 showed resolved right temporal lobe enhancement and decreased edema. A month later, probable autoimmune antibody-negative limbic encephalitis was diagnosed. Patient received 5-days methylprednisolone then prednisone taper with resolution of episodes but residual memory and executive function deficits.
Discussion: Autoimmune encephalitis (AE) is acute to subacute brain inflammation thought to be mediated by autoantibodies against synaptic receptors, ion channels, cell-surface proteins, or intracellular antigens and can be a paraneoplastic or idiopathic process (1). Some autoantibodies produce well-defined syndromic phenotypes; others present nonspecifically with confusion, memory impairment, mood changes, and seizures (1). Diagnosis can be challenging and is an area of unmet need per the FDA (2). Presenting symptoms are vague, varied, or suggestive of other conditions. Imaging and studies can be normal or nonspecific (3, 4). Common CSF findings are mild-to-moderate lymphocytic pleocytosis, elevated IgG index, or oligoclonal bands (1). Bilateral enhancement of the medial temporal lobes on T2-weighted FLAIR MRI sequences is suggestive of limbic encephalitis (1). Antibody testing is not always available or can take weeks to return, sensitivity and specificity vary, and known antibodies are limited (5). Antibody negative AE is not uncommon due to insufficient sensitivity of assay, activity of not yet identified antibody, or non-antibody mediated inflammation (5, 6). Recommendations for diagnosis have shifted from antibody-based to a clinical diagnosis (1, 5, 7). With high clinical suspicion for AE, early initiation of immunosuppressive therapy prior to antibody results might improve outcomes with reduced cognitive impairment and relapse (1). First-line therapy is high dose steroids, IVIG, and/or PLEX; less commonly used agents include rituximab, cyclophosphamide, tocilizumab, and steroid sparing maintenance agents (1, 5, 8).
Conclusions: Autoimmune encephalitis (AE) can present with nonspecific neurocognitive symptoms. Understanding the diagnostic criteria for antibody-negative AE, a high degree of suspicion, prompt diagnosis, and early initiation of immunosuppressants are imperative for best outcome.