Faculty Bibliography

OBJECTIVE:Postencephalitic epilepsy is often resistant to antiseizure medications, leading to evaluation for epilepsy surgery. Characterizing its localization carries implications for optimal surgical approach. We aimed to determine whether a prior history of encephalitis is associated with specific epileptogenic networks among patients with drug resistant epilepsy undergoing stereotactic EEG (SEEG). METHODS:We conducted a retrospective cohort study of drug resistant epilepsy, with and without a prior history of encephalitis. We analyzed SEEG recordings to identify patterns of seizure onset and organization. Seventeen patients with a history of encephalitis (of infectious etiology in two subjects) were identified from a database of patients undergoing SEEG and were compared to seventeen drug-resistant epilepsy controls without a history of encephalitis matched for confounding variables including pre-implantation hypotheses, epilepsy duration, age, and sex. RESULTS:Independent bilateral seizures were noted in 65% of the postencephalitic epilepsy cohort. We identified four SEEG-ictal patterns in patients with a prior history of encephalitis: (1) anteromesial temporal onset (24%), (2) anteromesial temporal onset with early spread to the perisylvian region (29%), (3) perisylvian (59%) and (4) synchronized anteromesial temporal and perisylvian (29%) onsets. Patterns 3 and 4, with perisylvian involvement at onset, were unique to the encephalitis group (p = 0.0003 and 0.04 respectively) and exhibited a "patchwork" organization. None of the encephalitis patients vs 5/7 matched controls had Engel I outcome (p = 0.0048). CONCLUSIONS:Postencephalitic epilepsies involve anteromesial temporal and perisylvian networks, often in a bilateral independent manner. Unique ictal patterns involving the perisylvian regions was identified in the encephalitis group, but not in the matched control group. SIGNIFICANCE/CONCLUSIONS:These findings may reflect a selective vulnerability of the perisylvian regions to epilepsy resulting from encephalitis, significantly mitigating the chances of success with SEEG-guided temporal resections.

Introduction: Antiseizure medications are the mainstay of epilepsy treatment. Currently therapies are not specific to epilepsy etiology, and control seizures in two thirds of cases. Drugs in clinical development aim to bridge that gap by targeting novel receptors and epileptogenesis. While currently approved antiseizure medications target focal or generalized epilepsies regardless of etiology, newly approved and investigational epilepsy drugs also target rare or orphan epilepsy syndrome indications, such as Lennox-Gastaut or Dravet syndrome. We identified investigational drugs through the Epilepsy Foundation pipeline tracker and conference proceedings of recent novel epilepsy drug conferences (XV AEDD, XIV EILAT).Areas Covered: We review antiseizure medications in clinical development and their targets (GABA, T-type calcium channels, 5-HT, potassium channels). We also discuss drugs with unknown or multiple mechanisms of action (cannabinoids, carisbamate, cenobamate). Therapies with potential disease-modifying effects in preclinical and clinical development are then outlined, ranging from gene-targeted treatments (antisense oligonucleotide, gene therapy, antisense transcript regulators) targeting specific genetic epilepsies, mTOR inhibitors, to inflammation-targeted treatments.Expert Opinion: Drugs to treat novel targets to control seizures as well as prevent epileptogenesis offer great promise. To assess disease modifying agents, we may need new clinical trial designs. Precision medicine therapies for genetic epilepsies may control seizures and restore brain health.

BACKGROUND AND PURPOSE/OBJECTIVE:New-onset refractory status epilepticus is a clinical condition characterized by acute and prolonged pharmacoresistant seizures without a pre-existing relevant neurologic disorder, prior epilepsy, or clear structural, toxic, or metabolic cause. New-onset refractory status epilepticus is often associated with antineuronal antibodies and may respond to early immunosuppressive therapy, reflecting an inflammatory element of the condition. FDG-PET is a useful diagnostic tool in inflammatory and noninflammatory encephalitis. We report here FDG-PET findings in new-onset refractory status epilepticus and their correlation to disease activity, other imaging findings, and outcomes. MATERIALS AND METHODS/METHODS:Twelve patients who met the criteria for new-onset refractory status epilepticus and who had FDG-PET and MR imaging scans and electroencephalography at a single academic medical center between 2008 and 2017 were retrospectively identified. Images were independently reviewed by 2 radiologists specialized in nuclear imaging. Clinical characteristics and outcome measures were collected through chart review. RESULTS:= .028). CONCLUSIONS:Both FDG-PET hypometabolism and hypermetabolism are seen in the setting of new-onset refractory status epilepticus and may represent markers of disease activity.

OBJECTIVE:We aimed to determine the rates and predictors of resection and seizure freedom after bilateral stereo-electroencephalography (SEEG) implantation. METHODS:We reviewed 184 patients who underwent bilateral SEEG implantation (2009-2015). Noninvasive and invasive evaluation findings were collected. Outcomes of interest included subsequent resection and seizure freedom. Statistical analyses employed multivariable logistic regression and proportional hazard modeling. Preoperative and postoperative seizure frequency, severity, and quality of life scales were also compared. RESULTS:Following bilateral SEEG implantation, 106 of 184 patients (58%) underwent resection. Single seizure type (P = 0.007), a family history of epilepsy (P = 0.003), 10 or more seizures per month (P = 0.004), lower number of electrodes (P = 0.02), or sentinel electrode placement (P = 0.04) was predictive of undergoing a resection, as were lack of nonlocalized (P < 0.0001) or bilateral (P < 0.0001) ictal-onset zones on SEEG. Twenty-six of 81 patients (32% with follow-up greater than 1 year) remained seizure-free. Predictors of seizure freedom were single seizure type (P = 0.01), short epilepsy duration (P = 0.008), use of 2 or fewer antiepileptic drugs (AEDs) at the time of surgery (P = 0.0006), primary localization hypothesis involving the frontal lobe (P = 0.002), sentinel electrode placement only (P = 0.02), and lack of overlap between ictal-onset zone and eloquent cortex (P = 0.04), along with epilepsy substrate histopathology (P = 0.007). Complete resection of a suspected focal cortical dysplasia showed a trend to increased likelihood of seizure freedom (P = 0.09). The 44 of 55 patients (80%) who underwent resection and experienced seizure recurrence had >50% seizure reduction, as opposed to 26 of 45 patients (58%) who continued medical therapy alone (P = 0.003). Seventy-two percent of patients had a clinically meaningful quality of life improvement (>10% decrease in the Quality of Life in Epilepsy [QOLIE-10] score) at 1 year. SIGNIFICANCE/CONCLUSIONS:A strong preimplantation hypothesis of a suspected unifocal epilepsy increases the odds of resection and seizure freedom. We discuss a tailored approach, taking into account localization hypothesis and suspected epilepsy etiology in guiding implantation and subsequent surgical strategy.

OBJECTIVE:Anti-NMDA receptor encephalitis (NMDARE) may not respond to first line immunotherapy. Biomarkers to track disease course and guide escalation of immunotherapy are needed. We describe the evolution of EEG in four patients with NMDARE requiring prolonged intensive care. METHODS:Within a database of 121 patients with immune-mediated neurological disorders, ten with NMDARE were retrospectively identified. Four patients did not respond to first line immunotherapy. Continuous EEG was reviewed and correlated with clinical status and treatment. RESULTS:Intermittent polymorphic delta slowing was present in all patients. Generalized rhythmic delta occupied increasing proportion of the EEG as disease progressed, at times with superimposed beta. The institution of second line immunotherapy was followed by progressive decrease in rhythmic delta, predating clinical improvement. In one patient who did not respond to second line immunotherapy, rhythmic delta continued to occupy a majority of the recording. The extreme delta pattern was not seen in a comparison cohort of patients with autoimmune encephalitis without anti-NMDA-R antibodies. CONCLUSIONS:Extreme delta, with or without brushes, increases with progression of NMDARE, responds to escalation of immunotherapy, predating clinical improvement, and is likely specific to NMDA-R antibodies. SIGNIFICANCE/CONCLUSIONS:Extreme delta may be a surrogate marker of disease activity in NMDARE refractory to first line immunotherapy.

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.

PURPOSE/OBJECTIVE:We sought to characterize the electroclinical features of seizures associated with autoimmune encephalitis and their relevance to outcome. METHODS:19 patients with seizures and autoimmune encephalitis were identified from a database of 100 patients (2008-2017) with autoimmune neurological disorders. Clinical and electroclinical characteristics were collected. Persistent seizures at last follow-up were then correlated with electroclinical features. RESULTS:Status epilepticus (53%) and early intractability to AEDs (median time to second AED 9.5 days) marked the onset of refractory seizures (median number of AEDs 3). Seizure semiology (abdominal (16%), psychic (42%), olfactory (6%) auras), interictal temporal epileptiform discharges (42%), and ictal onset in the temporal region (63%) mirrored radiologic involvement of the medial temporal regions (on MRI in 74% and/or FDG-PET in 75%). In addition, multimodal auras, with somatosensory (26%), autonomic (26%), gustatory (11%), and visual (16%), features were seen in 82% of patients with focal aware seizures, invoking broader involvement of the perisylvian regions. A change in seizure semiology and EEG findings was often seen. Electroclinical features were similar regardless of antibody type, with the exception of the association of faciobrachial dystonic seizures with LGI1 antibodies. Eight patients had medically intractable seizures at last follow-up and were more likely than patients with seizure remission to have generalized tonic-clonic seizures and temporal lobe involvement on the basis of semiological features, interictal EEG and MRI changes. CONCLUSIONS:Seizures associated with autoimmune encephalitis exhibit common electroclinical features which show dynamic evolution over time. We propose a role for the temporo-perisylvian regions in their generation.