The challenges in making animal models of complex human epilepsy phenotypes with varied aetiology highlights the need to develop alternative disease models that can address the limitations of animal models by effectively recapitulating human pathophysiology. The advances in stem cell technology provide an opportunity to use human iPSCs to make disease-in-a-dish models. The focus of this review is to report the current information and progress in the generation of epileptic patient-specific iPSCs lines, isogenic control cell lines, and neuronal models. These in vitro models can be used to study the underlying pathological mechanisms of epilepsies, anti-seizure medication resistance, and can also be used for drug testing and drug screening with their isogenic control cell lines.

Few studies have evaluated acute immunotherapy and relapse prevention strategies in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody (Ab)-mediated encephalitis. The objective of this study was to analyze the outcomes of acute and long-term immunotherapy strategies in this population. We undertook a multicenter cohort study of 55 patients with anti-LGI1 Ab-mediated encephalitis, either recruited prospectively or identified retrospectively from 10 Australian hospitals as part of the Australian Autoimmune Encephalitis Consortium. Clinical data were collected, including treatment durations of all relevant immunotherapies. Clinical outcomes that we examined included (1) time to first clinical relapse, (2) improvement on modified Rankin Scale (mRS), and (3) favorable binary composite clinical-functional outcome at 12 months. A favorable outcome was defined as fulfilling all three of mRS less than 3, a score of 1 or less in the memory dysfunction component of the Clinical Assessment Scale in Autoimmune Encephalitis, and absence of drug-resistant epilepsy. Rituximab, adjusted for concomitant use of other immunotherapies, was associated with increased time to first relapse (hazard ratio 0.10; 95% CI 0.001-0.85; p = 0.03). Intravenous pulsed methylprednisolone was associated with an improvement in mRS (OR 4.48; 95% CI 1.03-21.3; p = 0.048) and a favorable composite clinical-functional outcome (OR 4.96; 95% CI 1.07-27.2; p = 0.049) at 12 months. Rituximab may be effective at preventing relapses in patients with anti-LGI1 Ab-mediated encephalitis. Acute methylprednisolone treatment may be associated with favorable outcomes at 12 months. This study provides Class IV evidence that for patients with anti-LGI1 Ab-mediated encephalitis, rituximab prevents relapses and acute methylprednisolone is associated with favorable outcomes at 12 months.

Objective: Differentiating status epilepticus (SE) from prolonged psychogenic nonepileptic seizures (pPNES) can be difficult clinically. We aimed to define the utility of peripheral cell counts, cell ratios, and lactate levels in distinguishing SE from pPNES.Methods: Retrospective two‐center study investigating the sensitivity and specificity of acute (≤12 h of event offset) peripheral cell counts, cell ratios (neutrophil–lymphocyte ratio, neutrophil–monocyte ratio, monocyte–lymphocyte ratio, platelet–lymphocyte ratio, systemic immune‐inflammatory index [SII], systemic inflammatory response index [SIRI]), and lactate levels in differentiating SE from pPNES. Patients were identified from two tertiary hospitals, with one forming the development cohort and the other the validation cohort. Using generalized additive models to generate biomarker vs time curves, optimal blood collection times were defined for set parameters. Three diagnostic scores combining neutrophil count, SII, or SIRI with lactate levels were developed and validated in separate cohorts.Results: For the development cohort, 1262 seizure‐like events were reviewed and 79 SE and 44 pPNES events were included. For the validation cohort, 241 events were reviewed and 20 SE and 11 pPNES events were included. Individually, the biomarkers generally had low sensitivity and reasonable specificity for differentiating SE from pPNES, with the neutrophil count, SIRI, and SII performing best with sensitivities of 0.65–0.84, specificities of 0.64–0.89, and ROC AUCs of 0.78–0.79. Lactate levels peaked at 60 min, while cell counts and ratios peaked after 240 min. Combining early peaking lactate levels and later peaking neutrophil count, SIRI or SII resulted in three scores that improved predictive potential with sensitivities of between 0.75 and 0.79, specificities between 0.93 and 1.00, and ROC AUCs of 0.89–0.91.Significance: Lactate levels peak early post‐SE, whereas cell counts and ratios do so later. The differing post‐event time profiles of lactate levels vs neutrophil count, SIRI, and SII allow incorporation into three separate scores which can assist in differentiating SE from pPNES.

Background Human prion diseases are a group of rare neurological diseases with a minority due to genetic mutations in the prion protein (PRNP) gene. The D178N mutation is associated with both Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotype modified by a polymorphism at codon 129 with the methionine/valine (MV) polymorphism associated with atypical presentations leading to diagnostic difficulty. Case We present a case of fatal familial insomnia secondary to a PRNP D178N mutation with 129MV disease modifying polymorphism who had no family history, normal MRI, electroencephalography (EEG), cerebrospinal fluid (CSF) and positron emission tomography findings and a negative real-time quaking-induced conversion result. Conclusion Patients with genetic prion disease may have no known family history and normal EEG, MRI brain and CSF findings. PRNP gene testing should be considered for patients with subacute progressive neurological and autonomic dysfunction.

Objective: Drug‐resistant epilepsy (DRE) affects >25 million people worldwide and is often associated with neuroinflammation. Increasing evidence links deficiency or malfunctioning of the enzyme phosphoglycerate dehydrogenase (PHGDH), which converts 3‐phosphoglycerate to generate serine and the neurotransmitter glycine, with (drug‐resistant) epilepsy. Moreover, PHGDH, which is primarily expressed in astrocytes within the brain, has been identified as a critical enzyme in driving macrophage polarization toward an anti‐inflammatory state. Hence, PHGDH activators may be beneficial for treating DRE by exhibiting both antiseizure and anti‐inflammatory activity. The objective of this study was to identify such PHGDH activators. Methods: We screened a drug repurposing library for PHGDH activators and assessed their antiseizure and anti‐inflammatory properties using various zebrafish and mouse epilepsy models and explored the mechanistic consequences of activating PHGDH in a cell line, in astrocytes, and in zebrafish heads. Finally, we assessed the efficacy of clioquinol as add‐on treatment in three severe DRE patients in a clinical open pilot proof‐of‐concept study. Results: We identified haloquinolines from a drug repurposing library as potent activators of PHGDH. The most promising haloquinoline clioquinol can increase the catalytic activity of PHGDH up to 2.5‐fold, thereby increasing de novo glycine biosynthesis and resulting in reduced glutamate levels. Moreover, we show that clioquinol has PHGDH‐dependent antiseizure activity as well as anti‐inflammatory properties in vivo using various zebrafish and mouse epilepsy models. Finally, we demonstrate the efficacy of clioquinol as add‐on treatment in severe DRE patients; two patients showed a 37%–47% reduction in seizure frequency, and all three patients noted a positive impact on quality of life and seizure severity. Significance: Increasing activity of PHGDH is a promising new approach to treat DRE.