Claude Steriade

Seizures are a well-recognized and often prominent manifestation of autoimmune encephalitic syndromes. Progress in detection of pathogenic neural autoantibodies has led to increased awareness of autoimmune causes of seizures. Clinical studies of patients with these autoantibodies have improved our understanding of the seizure characteristics, treatments, and seizure prognosis in these disorders. The International League Against Epilepsy (ILAE) Autoimmunity and Inflammation Taskforce proposes conceptual definitions for two main diagnostic entities: (a) acute symptomatic seizures secondary to autoimmune encephalitis, and (b) autoimmune-associated epilepsy, the latter of which suggests an enduring predisposition to seizures. Such a distinction is relevant when discussing the pathophysiology, treatment, prognosis, and social consequences of these disorders. We discuss the role of biomarkers in the application of these conceptual definitions and illustrate their use in patients cared for by members of the task force.

BACKGROUND: A need exists to characterise the long-term cognitive outcomes in patients who recovered from autoimmune encephalitis and to identify the modifiable factors associated with improved outcomes. METHODS: We retrospectively analysed data from patients diagnosed with autoimmune encephalitis in our outpatient autoimmune encephalitis clinic over a 5-year period, where the Montreal Cognitive Assessment (MoCA) is routinely administered. RESULTS: In total, 21 patients met the inclusion criteria, of whom 52% had persistent cognitive impairment at their latest follow-up (median delay to testing=20 months, range 13-182). Visuospatial and executive abilities, language, attention, and delayed recall were predominantly affected. Patients with status epilepticus at presentation had lower total MoCA scores at their last follow-up (median total score 21, range 15-29) compared with patients without status epilepticus at presentation (median total score 27.5, range 21-30; r 2=0.366, p=0.004). Patients who experienced delays of more than 60 days from symptom onset to initiation of treatment (either immunosuppression or tumour removal) were more likely to have a MoCA score compatible with cognitive impairment at their last follow-up (r 2=0.253, p=0.0239; z-score=-2.01, p=0.044). CONCLUSIONS: Our study suggests that the MoCA may be used to evaluate cognition in recovering patients with autoimmune encephalitis. Delays to treatment shorter than 60 days and absence of status epilepticus at onset were associated with better performance on the MoCA obtained more than 1 year after symptom onset, and may predict better long-term cognitive outcomes.

<h3>Objective</h3> To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals. <h3>Methods</h3> Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or <i>LGI1</i>/<i>CASPR2</i> (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients. <h3>Results</h3> Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, &gt;0.99). Younger age (ρ = −0.56; <i>p</i> = 0.01), lower VILIP-1 (ρ = −0.60; <i>p</i> &lt; 0.01) and SNAP-25 (ρ = −0.54; <i>p</i> = 0.01), and higher log₁₀(YKL-40/SNAP-25) (ρ = 0.48; <i>p</i> = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; <i>p</i> = 0.02) and neurogranin (ρ = 0.55; <i>p</i> = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge. <h3>Conclusions</h3> CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.