Faculty Bibliography

Idiopathic and acquired pedophilia are two different disorders with two different etiologies. However, the differential diagnosis is still very difficult, as the behavioral indicators used to discriminate the two forms of pedophilia are underexplored, and clinicians are still devoid of clear guidelines describing the clinical and neuroscientific investigations suggested to help them with this difficult task. Furthermore, the consequences of misdiagnosis are not known, and a consensus regarding the legal consequences for the two kinds of offenders is still lacking. The present study used the Delphi method to reach a global consensus on the following six topics: behavioral indicators/red flags helpful for differential diagnosis; neurological conditions potentially leading to acquired pedophilia; neuroscientific investigations important for a correct understanding of the case; consequences of misdiagnosis; legal consequences; and issues and future perspectives. An international and multidisciplinary board of scientists and clinicians took part in the consensus statements as Delphi members. The Delphi panel comprised 52 raters with interdisciplinary competencies, including neurologists, psychiatrists, neuropsychologists, forensic psychologists, expert in ethics, etc. The final recommendations consisted of 63 statements covering the six different topics. The current study is the first expert consensus on a delicate topic such as pedophilia. Important exploitable consensual recommendations that can ultimately be of immediate use by clinicians to help with differential diagnosis and plan and guide therapeutic interventions are described, as well as future perspectives for researchers.

Epilepsy has a high prevalence and can severely impair quality of life and increase the risk of premature death. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in drug-resistant epilepsy and most often results from respiratory and cardiac impairments due to brainstem dysfunction. Epileptic activity can spread widely, influencing neuronal activity in regions outside the epileptic network. The brainstem controls cardiorespiratory activity and arousal and reciprocally connects to cortical, diencephalic, and spinal cord areas. Epileptic activity can propagate trans-synaptically or via spreading depression (SD) to alter brainstem functions and cause cardiorespiratory dysfunction. The mechanisms by which seizures propagate to or otherwise impair brainstem function and trigger the cascading effects that cause SUDEP are poorly understood. We review insights from mouse models combined with new techniques to understand the pathophysiology of epilepsy and SUDEP. These techniques include in vivo, ex vivo, invasive and non-invasive methods in anesthetized and awake mice. Optogenetics combined with electrophysiological and optical manipulation and recording methods offer unique opportunities to study neuronal mechanisms under normal conditions, during and after non-fatal seizures, and in SUDEP. These combined approaches can advance our understanding of brainstem pathophysiology associated with seizures and SUDEP and may suggest strategies to prevent SUDEP.

Introduction: Previous case-control studies of sudden unexpected death in epilepsy (SUDEP) patients failed to identify ECG features (peri-ictal heart rate, heart rate variability, corrected QT interval, postictal heart rate recovery, and cardiac rhythm) predictive of SUDEP risk. This implied a need to derive novel metrics to assess SUDEP risk from ECG. Methods: We applied Single Spectrum Analysis and Independent Component Analysis (SSA-ICA) to remove artifact from ECG recordings. Then cross-frequency phase-phase coupling (PPC) was applied to a 20-s mid-seizure window and a contour of −3 dB coupling strength was determined. The contour centroid polar coordinates, amplitude (alpha) and angle (theta), were calculated. Association of alpha and theta with SUDEP was assessed and a logistic classifier for alpha was constructed. Results: Alpha was higher in SUDEP patients, compared to non-SUDEP patients (p < 0.001). Theta showed no significant difference between patient populations. The receiver operating characteristic (ROC) of a logistic classifier for alpha resulted in an area under the ROC curve (AUC) of 94% and correctly classified two test SUDEP patients. Discussion: This study develops a novel metric alpha, which highlights non-linear interactions between two rhythms in the ECG, and is predictive of SUDEP risk.

OBJECTIVE:Identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. METHODS:Frozen brain tissue (ages 2-19 years) was obtained from control autopsy (n=14), surgical PWE (n=10), and surgical RE cases (n=27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p<0.05) and label-free quantitative mass spectrometry (false discovery rate<5%) in the three groups. RESULTS:, z=5.61). Proteomics detected fewer altered targets. SIGNIFICANCE/CONCLUSIONS:In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.

Rationale: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is characterized by global developmental impairment and early-onset, refractory seizures. In a recent placebo-controlled study, ganaxolone reduced major motor seizure frequency (MMSF) in patients with CDD. Here we report further data at a minimum of 1-year in the open-label extension (OLE).
Method(s): Patients with CDD (aged 2-19 years) who completed the double-blind phase were eligible to receive ganaxolone in the OLE. Assessments included changes in MMSF from pre-randomization baseline to 3-month intervals in the OLE, responder rates (>=50% and >=75% MMSF reductions), Clinical Global Impression of Improvement (CGI-I), safety, and tolerability.
Result(s): Eighty-eight patients (87.1%; median age of 5; 79.5% female) continued into the OLE (101 were randomized to the double-blind study). Median baseline 28-day MMSF was 50.6. The 1-year retention rate was 70.5% with 26 discontinuations. At the time of analysis, 34 participants had discontinued due to lack of efficacy (n = 12), adverse event (n = 10), or withdrawal by caregiver (n = 10) as the most common reasons. During months 1-3, 4-6, 7-9, and 10-12, patients experienced a median reduction in MMSF of 24.7%, 32.1%, 30.0%, and 42.2%, respectively. During months 13-24, MMSF reductions ranged from 44.2% to 56.1%. At 1 year, 46.3% and 23.9% of patients experienced a >=50% and >=75% reduction in MMSF, respectively. In the OLE, clinicians and caregivers rated 60.6% and 72.5% of the patients, respectively, as improved at 1 year. The most commonly reported adverse events were seizure (22.7%), somnolence (20.5%), vomiting (18.2%), and pyrexia (17.0%). There was one death reported due to sepsis, but it was deemed unrelated to study treatment.
Conclusion(s): Reductions in MMSF at 1 year and beyond provide supportive evidence for the maintenance of effect of ganaxolone in seizures associated with CDD. Ganaxolone was generally well-tolerated in the OLE with safety findings consistent with the double-blind phase

INTRODUCTION/UNASSIGNED:Alzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10-22% and subclinical epileptiform abnormalities occur in 22-54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy. METHODS/UNASSIGNED:= 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level. RESULTS/UNASSIGNED: DISCUSSION/UNASSIGNED:We found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.

OBJECTIVE:Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS:We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS:Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION/CONCLUSIONS:Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.

OBJECTIVE:Prolonged postictal generalized electroencephalographic suppression (PGES) is a potential biomarker for sudden unexpected death in epilepsy (SUDEP), which may be associated with dysfunctional autonomic responses and serotonin signaling. To better understand molecular mechanisms, PGES duration was correlated to 5HT1A and 5HT2A receptor protein expression and RNAseq from resected hippocampus and temporal cortex of temporal lobe epilepsy patients with seizures recorded in preoperative evaluation. METHODS:Analyses included 36 cases (age = 14-64 years, age at epilepsy onset = 0-51 years, epilepsy duration = 2-53 years, PGES duration = 0-93 s), with 13 cases in all hippocampal analyses. 5HT1A and 5HT2A protein was evaluated by Western blot and histologically in hippocampus (n = 16) and temporal cortex (n = 9). We correlated PGES duration to our previous RNAseq dataset for serotonin receptor expression and signaling pathways, as well as weighted gene correlation network analysis (WGCNA) to identify correlated gene clusters. RESULTS: = .25). WGCNA identified four modules correlated with PGES duration, including positive correlation with synaptic transcripts (p = .040, Pearson correlation r = .52), particularly potassium channels (KCNA4, KCNC4, KCNH1, KCNIP4, KCNJ3, KCNJ6, KCNK1). No modules were associated with serotonin receptor signaling. SIGNIFICANCE/CONCLUSIONS:Higher hippocampal 5HT2A receptor protein and potassium channel transcripts may reflect underlying mechanisms contributing to or resulting from prolonged PGES. Future studies with larger cohorts should assess functional analyses and additional brain regions to elucidate mechanisms underlying PGES and SUDEP risk.

PURPOSE/OBJECTIVE:Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. METHODS:We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. RESULTS:We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. CONCLUSION/CONCLUSIONS:Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.