Characterization of seizures and EEG findings in creatine transporter deficiency due to SLC6A8 mutation.

Seizures occur in up to 59% of boys with creatine transporter deficiency (CTD). While seizure phenotypes have been previously described, electroencephalogram (EEG) findings have only been reported in several case reports. In this prospective observational study, we report seizure characteristics and EEG findings in combination with neurobehavioral and SLC6A8 pathogenic variants in twenty males with CTD. Eighteen study participants (SP) underwent video-EEG, and seven had follow-up EEG recordings. Seizures typically occurred by age of 2 years. Thirteen (65%) had non-febrile seizures, requiring anti-seizure medications in nine. Four had febrile seizures. Seizures were bilateral tonic-clonic in 7 SP and focal impaired awareness in 5 SP; often responding to 1 to 2 antiseizure medications. EEG showed slowing in 5 SP, beta activity in 6 SP, and focal/multifocal, and/or generalized epileptiform activity in 9 SP. Follow-up EEGs in 7 SP showed emergence of epileptiform activity in 1 SP, and increased activity in 2 SP. In conclusion, seizures were frequent in our cohort but tended to respond to antiseizure medications. Longitudinal follow up provided further insight into emergence of seizures and EEG abnormalities soliciting future studies with long term follow up. Biomarkers of epileptogenicity in CTD are needed to predict seizures in this population.

Work, Parenting, and Well-being: An International Survey of Neurologists During the COVID-19 Pandemic.

Background and Objectives: COVID-19 reframed the relationship between work and home and, in general, made both more difficult-especially for parents. We hypothesized that, among neurologists, the effects of the pandemic on productivity and on well-being would be greater on those with children than on those without children and that the effects would be greater on women with children than on men with children. Methods: We conducted an international electronic survey launched by the Practice Current section of the American Academy of Neurology. The survey included questions on demographics (self-identified gender, number of children and elderly dependents, childcare support, and country and state when applicable), workflow changes because of COVID-19, impacted domains, and productivity and well-being using the Likert scale. Counts are presented as descriptive statistics. Statistical analysis was performed using Mann-Whitney U and Kruskal-Wallis tests. Results: We collected 243 fully completed surveys from providers in all continents with high representation of the United States (76%), providers who identified as women (71.6%), and neurologists with children (91%) among respondents. A majority worked remotely (28% fully, 43% mix). Neurologists reported decreased academic productivity (72%), work benefits (65%), and time for writing (48%). These findings were more prominent in respondents with children and among women practicing outside of the United States. Increased pressure from productivity expectations and lack of time for family were reported by 47% and 41% of respondents, respectively. Discussion: The disruption from the COVID-19 pandemic affected academic productivity and decreased the well-being of neurologists in general and of neurologists with children more drastically. This could potentially hinder the promotion and retention of junior neurologists who were juggling life and work during the pandemic outbreak and its recurrent surges.

Seizure and anatomical outcomes of repeat laser amygdalohippocampotomy for temporal lobe epilepsy: A single-institution case series.

OBJECTIVE: In patients with treatment-refractory temporal lobe epilepsy (TLE), a single stereotactic laser interstitial thermotherapy (LITT) procedure is sometimes insufficient to ablate epileptogenic tissue, particularly the medial structures often implicated in TLE. In patients with seizure recurrence after initial ablation, the extent to which a second ablation may achieve improved seizure outcomes is uncertain. The objective of this study was to investigate the feasibility and potential efficacy of repeat LITT amygdalohippocampotomy as a worthwhile strategy for intractable temporal lobe epilepsy by quantifying changes to targeted mesial temporal lobe structures and seizure outcomes. METHODS: Patients who underwent two LITT procedures for drug-resistant mesial TLE at our institution were included in the study. Lesion volumes for both procedures were calculated by comparing post-ablation intraoperative sequences to preoperative anatomy. Clinical outcomes after the initial procedure and repeat procedure were classified according to Engel scores. RESULTS: Five consecutive patients were included in this retrospective case series: 3 with right- and 2 with left-sided TLE. The median interval between LITT procedures was 294 days (range: 227-1918). After the first LITT, 3 patients experienced class III outcomes, 1 experienced a class IV, and 1 experienced a class IB outcome. All patients achieved increased seizure freedom after a second procedure, with class I outcomes (3 IA, 2 IB). CONCLUSIONS: Repeat LITT may be sufficient to achieve satisfactory seizure outcomes in some individuals who might otherwise be considered for more aggressive resection or palliative neuromodulation. A larger study to establish the potential value of repeat LITT amygdalohippocampotomy vs. other re-operation strategies for persistent, intractable temporal lobe epilepsy is worth pursuing.

Clinical features and drug-resistance in pediatric epilepsy with co-occurring autism: A retrospective comparative cohort study.

OBJECTIVE: We conducted a retrospective comparative cohort study to determine the phenotypic and real-world management differences in children with epilepsy and co-occurring autism as compared to those without autism. METHODS: Clinical variables, EEG, brain MRI, genetic results, medical and non-medical treatment were compared between 156 children with both epilepsy and autism, 156 randomly selected and 156 demographically matched children with epilepsy only. Logistic regression analyses were conducted to determine predictors of drug-resistant epilepsy (DRE). RESULTS: As compared to the'matched' cohort, more patients with autism had generalized motor seizures although not statistically significant after Benjamini-Hochberg correction (54.5%, vs 42.3%, p = .0314); they had a lower rate of electroclinical syndromes (12.8%, vs 30.1%, p = .0002). There were more incidental MRI findings but less positive MRI findings to explain their epilepsy in children with autism (26.3%, vs 13.8% and 14.3%, vs 34.2%, respectively; p = .0003). In addition, LEV, LTG, and VPA were the most common ASMs prescribed to children with autism, as opposed to LEV, OXC, and LTG in children without autism. No difference in the major EEG abnormalities was observed. Although the rates of DRE were similar (24.8%, vs 26.6%, p = .7203), we identified two clinical and five electrographic correlates with DRE in children with both epilepsy and autism and a final prediction modeling of DRE that included EEG ictal findings, focal onset seizures, generalized motor seizures, abnormal EEG background, age of epilepsy onset, and history of SE, which were distinct from those in children without autism. SIGNIFICANCE: Our study indicates that detailed seizure history and EEG findings are the most important evaluation and prediction tools for the development of DRE in children with epilepsy and co-occurring autism. Further studies of epilepsy in specific autism subgroups based on their etiology and clinical severity are warranted.

Clinical and Instrumental Follow-Up of Childhood Absence Epilepsy (CAE): Exploration of Prognostic Factors.

Background: Idiopathic generalized epilepsies (IGEs) represent 15−20% of all cases of epilepsy in children. This study explores predictors of long-term outcome in a sample of children with childhood absence epilepsy (CAE). Methods: The medical records of patients with CAE treated at a university paediatric hospital between 1995 and 2022 were systematically reviewed. Demographics and relevant clinical data, including electroencephalogram, brain imaging, and treatment outcome were extracted. Outcomes of interest included success in seizure control and seizure freedom after anti-seizure medication (ASM) discontinuation. An analysis of covariance using the diagnostic group as a confounder was performed on putative predictors. Results: We included 106 children (age 16.5 ± 6.63 years) with CAE with a mean follow-up of 5 years. Seizure control was achieved in 98.1% (in 56.6% with one ASM). Headache and generalized tonic-clonic seizures (GTCS) were more frequent in children requiring more than one ASM (p < 0.001 and p < 0.002, respectively). Of 65 who discontinued ASM, 54 (83%) remained seizure-free, while 11 (17%) relapsed (mean relapse time 9 months, range 0−18 months). Relapse was associated with GTCS (p < 0.001) and number of ASM (p < 0.002). Conclusions: A history of headache or of GTCS, along with the cumulative number of ASMs utilized, predicted seizure recurrence upon ASM discontinuation. Withdrawing ASM in patients with these characteristics requires special attention.

Seizure freedom after laser amygdalohippocampotomy guided by bilateral responsive neurostimulation in pediatric epilepsy: illustrative case.

BACKGROUND: For patients with difficult-to-lateralize temporal lobe epilepsy, the use of chronic recordings as a diagnostic tool to inform subsequent surgical therapy is an emerging paradigm that has been reported in adults but not in children. OBSERVATIONS: The authors reported the case of a 15-year-old girl with pharmacoresistant temporal lobe epilepsy who was found to have bitemporal epilepsy during a stereoelectroencephalography (sEEG) admission. She underwent placement of a responsive neurostimulator system with bilateral hippocampal depth electrodes. However, over many months, her responsive neurostimulation (RNS) recordings revealed that her typical, chronic seizures were right-sided only. This finding led to a subsequent right-sided laser amygdalohippocampotomy, resulting in seizure freedom. LESSONS: In this case, RNS chronic recording provided real-world data that enabled more precise seizure localization than inpatient sEEG data, informing surgical decision-making that led to seizure freedom. The use of RNS chronic recordings as a diagnostic adjunct to seizure localization procedures and laser ablation therapies in children is an area with potential for future study.

Vitamin B6 decreases the risk of levetiracetam discontinuation in children with epilepsy: A retrospective study.

OBJECTIVES: Levetiracetam (LEV) is an anti-seizure medication (ASM) known to have significant behavioral side effects in children with epilepsy. These side effects may be improved by supplemental vitamin B6 (pyridoxine) use. Our research aimed to study risk factors for LEV side effects and the role of vitamin B6 in altering this risk. METHODS: We retrospectively analyzed the demographic and clinical profile of all pediatric patients on LEV treatment between July 2019 and December 2020. T-tests, Chi-square and Fisher exact tests were used to assess predictors of LEV discontinuation. A p-value of <0.05 was considered statistically significant. RESULTS: 150/240 (62%) children were on additional medications besides LEV for epilepsy management. Thirty-five percent children reported side effects, especially behavioral and mood concerns. Of the patients who reported side effects on LEV, 71% were taking vitamin B6 (n = 59). The rate of LEV discontinuation was significantly lower for children on vitamin B6 than children not taking B6, regardless of monotherapy or polypharmacy (49% v 88% respectively, p = 0.001). Over half of the patients who were able to remain on LEV reported improved behavior with B6 supplementation as compared to those who were unable to continue LEV (17/30, 57% versus 0/26, 0%; p < 0.001). CONCLUSIONS: Levetiracetam side effects significantly impact the tolerability of this ASM in children with epilepsy. Our results suggest that vitamin B6 supplementation can significantly reduce the odds of discontinuing LEV due to its behavioral side effects.

Paroxysmal Hypothermia With Prominent Parkinsonian Features After Suprachiasmatic Tumor Resection.

Paroxysmal hypothermia (PH) is a rare syndrome of stereotyped episodes of hypothermia, bradycardia, and altered mental status occurring in patients with hypothalamic lesions. Prior cases have mentioned bradykinesia, ataxia, and dysarthria, but parkinsonism has not been described as a specific feature of PH. We report two patients, an adult and a child, who developed PH after suprachiasmatic tumor resection, both with clinical presentations notable for prominent parkinsonian features despite no evidence of parkinsonism during the intervening months and years. We propose a diagnostic algorithm and scoring tool to aid in the clinical diagnosis of PH presenting as parkinsonism.

Physicians' Perspectives on Presurgical Discussion and Shared Decision-Making in Pediatric Epilepsy Surgery.

Objective: To qualitatively explore the approach of pediatric epilepsy providers when counseling regarding surgical options for epilepsy, presenting risks and benefits of surgery, overcoming resistance to surgery, and fostering shared decision making with patients and families. Methods: We conducted in-depth interviews with 11 academic clinicians (5- neurologists, 5- epileptologists, 1- neurosurgeon) from a Level 4 pediatric epilepsy center to explore how physicians communicate and pursue surgical decision-making. Results: A blended inductive-deductive analysis revealed three key themes (with subthemes) of presurgical discussions: (1) Candidate selection and initial discussion about epilepsy surgery (neurologists compared to epileptologists, the timing of the discussion, reluctant families) (2) Detailed individualized counseling about epilepsy surgery (shared decision-making [enablers and barriers] and risk-benefit analysis [balancing risks and benefits, statistical benefit estimation, discussion about SUDEP, prognostication about cognitive and behavioral outcomes, risks of surgery]) (3) Tools to improve decision-making (educational interventions for patients and families and provider- and organization-specific interventions). Significance: Presurgical discussions lack uniformity among physicians who treat epilepsy. Despite general interest in collaborative decision-making, experts raised concern about lack of exposure to communication training and clinical tools for optimizing decision-making, a high number of families who do not feel equipped to share the decision making leaving the decision-making entirely to the physician, and paucity of practical resources for individualized risk-benefit counseling. Clinical practice guidelines should be developed to reduce existing practice variations in presurgical counseling. Further consensus is needed about when and how to initiate the conversation about epilepsy surgery, essential components of the discussion, and the utility of various tools to improve the utilization of epilepsy surgery.

A journey into the unknown: An ethnographic examination of drug-resistant epilepsy treatment and management in the United States.

Patients often recognize unmet needs that can improve patient-provider experiences in disease treatment management. These needs are rarely captured and may be hard to quantify in difficult-to-treat disease states such as drug-resistant epilepsy (DRE). To further understand challenges living with and managing DRE, a team of medical anthropologists conducted ethnographic field assessments with patients to qualitatively understand their experience with DRE across the United States. In addition, healthcare provider assessments were conducted in community clinics and Comprehensive Epilepsy Centers to further uncover patient-provider treatment gaps. We identified four distinct stages of the treatment and management journey defined by patients' perceived control over their epilepsy: Gripped in the Panic Zone, Diligently Tracking to Plan, Riding a Rollercoaster in the Dark, and Reframing Priorities to Redefine Treatment Success. We found that patients sought resources to streamline communication with their care team, enhanced education on treatment options beyond medications, and long-term resources to protect against a decline in control over managing their epilepsy once drug-resistant. Likewise, treatment management optimization strategies are provided to improve current DRE standard of care with respect to identified patient-provider gaps. These include the use of digital disease management tools, standardizing neuropsychiatrists into patients' initial care team, and introducing surgical and non-pharmacological treatment options upon epilepsy and DRE diagnoses, respectively. This ethnographic study uncovers numerous patient-provider gaps, thereby presenting a conceptual framework to advance DRE treatment. Further Incentivization from professional societies and healthcare systems to support standardization of the treatment optimization strategies provided herein into clinical practice is needed.

Differential activation of neuroinflammatory pathways in children with seizures: A cross-sectional study.

PURPOSE: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection. METHODS: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation. RESULTS: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1ß (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1ß (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels. CONCLUSIONS: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.

Equipoise in Management of Patients With Acute Symptomatic Carotid Stenosis (Hot Carotid).

OBJECTIVE: To explore differences in antithrombotic management of patients with acutely symptomatic carotid stenosis ("hot carotid") awaiting revascularization with endarterectomy or stenting (CEA/CAS). METHODS: We used a worldwide electronic survey with practice-related questions and clinical questions about 3 representative scenarios. Respondents chose their preferred antithrombotic regimen (1) in general, (2) if the patient was already on aspirin, or (3) had associated intraluminal thrombus (ILT) and identified clinical/imaging factors that increased or decreased their enthusiasm for additional antithrombotic agents. Responses among different groups were compared using multivariable logistic regression. RESULTS: We received 668 responses from 71 countries. The majority favored CT angiography (70.2%) to evaluate carotid stenosis, CEA (69.1%) over CAS, an aspirin-containing regimen (88.5%), and a clopidogrel-containing regimen (64.4%) if already on aspirin. Whereas diverse antithrombotic regimens were chosen, monotherapy was favored by 54.4%-70.6% of respondents across 3 scenarios. The preferred dual therapy was low-dose aspirin (75-100 mg) plus clopidogrel (22.2%) or high-dose aspirin (160-325 mg) plus clopidogrel if already on aspirin (12.2%). Respondents favoring CAS more often chose ≥2 agents (adjusted odds ratio [aOR] vs CEA: 2.00, 95% confidence interval 1.36-2.95, p = 0.001) or clopidogrel-containing regimens (aOR: 1.77, 1.16-2.70, p = 0.008). Regional differences included respondents from Europe less commonly choosing multiple agents if already on aspirin (aOR vs United States/Canada: 0.57, 0.35-0.93, p = 0.023), those from Asia more often favoring multiple agents (aOR: 1.95, 1.11-3.43, p = 0.020), vs those from the United States/Canada preferentially choosing heparin-containing regimens with ILT (aOR vs rest: 3.35, 2.23-5.03, p < 0.001). Factors increasing enthusiasm for ≥2 antithrombotics included multiple TIAs (57.2%), ILT (58.5%), and ulcerated plaque (57.4%); 56.3% identified MRI microbleeds as decreasing enthusiasm. CONCLUSIONS: Our results highlight the heterogeneous management and community equipoise surrounding optimal antithrombotic regimens for hot carotids.

Spatiotemporal distribution and age of seizure onset in a pediatric epilepsy surgery cohort with cortical dysplasia.

OBJECTIVE: Focal Cortical Dysplasias (CD) are a common etiology of refractory pediatric epilepsy and are amenable to epilepsy surgery. We investigated the association of lesion volume and location to age of seizure onset among children with CD who underwent epilepsy surgery. METHODS: A retrospective study of epilepsy surgery patients with pathologically-confirmed CD. Regions of interest (ROI) determined preoperative lesion volumes on 1.5 T and 3 T T2 and SPGR MRIs, and location in 7 distributed neural networks. Descriptive and inferential statistics were used. RESULTS: Fifty-five patients were identified: 35 girls (56.5 %). Median age of seizure onset: 19.0 months (range 0.02 months - 16.0 years). Median age of surgery: 7.8 years (range 2.89 months - 24.45 years). CD were frontal (n = 21, 38 %); temporal (n = 15, 27 %); parietal (n = 10, 18 %); occipital (n = 3, 5%); multilobar (n = 6, 11 %). Frontal FCD had seizure onset < 1-year-old (P = 0.10); temporal lobe CD seizure onset was more likely > 5-years-old (P= 0.06). Median lesion volume for CD was 23.23 cm3 (range: 1.87-591.73 cm3). Larger CD lesions were associated with earlier epilepsy (P = 0.01, r = -0.16). We did not find that lesions proximal to early maturing cortical regions were associated with earlier seizure onset. We found an association with CD location in the default mode network (DMN) and age onset < 5years old (P = 0.03). Age of seizure onset was negatively correlated with percent of CD overlapping motor cortex (P = 0.001, r =-0.794) but not with CD overlap of the visual cortex (P = 0.35). There was no effect of CD type on age of epilepsy onset. SIGNIFICANCE: Larger CD lesions are associated with earlier onset epilepsy. CD most commonly occurs within the DMN and Limbic network, and DMN is associated with seizure onset before 5-years-old. Percent of CD overlapping motor cortex correlates with earlier seizure onset. These observations may reflect patterns of brain maturation or regional differences in clinical expression of seizures.

Seizure phenotype in CLN3 disease and its relation to other neurologic outcome measures.

CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease-causing variant is an ~1-kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior, MR spectroscopy and CSF biochemical markers in a CLN3 cohort. We performed seizure phenotyping using clinical history, EEG, and the Unified Batten Disease Rating Scale (UBDRS) seizure score. We assessed correlations of seizure severity with disease severity (UBDRS capability), adaptive behavior composite score (ABC; Vineland-3), glutamate+glutamine+GABA and N-acetylaspartate+N-acetylaspartyl glutamate (MR spectroscopy), and CSF neurofilament light chain (NEFL) levels. In 20 participants, median age was 10.7 years (IQR = 7.8). Eighteen completed baseline EEG; 12 had a 1-year follow-up. Seizures were reported in 14 (8 1-kb deletion homozygotes), with median age at onset of 10.0 (IQR = 6.8). Epileptiform discharges were noted in 15 (9 homozygotes). Bilateral tonic clonic (n = 11) and nonmotor seizures (n = 7) were most common. UBDRS seizure score correlated with age (rp = 0.50; [0.08,0.77]; P = .02), UBDRS capability (rp = -0.57; [-0.81,-0.17]; P = .009) and ABC (rp = -0.66; [-0.85,-0.31]; P = .001) scores, glutamate+glutamine+GABA (rp = -0.54; [-0.80,-0.11]; P = .02) and N-acetylaspartate+N-acetylaspartyl glutamate (rp = -0.54; [-0.80,-0.11]; P = .02), and CSF NEFL (rp = 0.65; [0.29,0.85]; P = .002) levels. After controlling for age, correlations with ABC and CSF NEFL remained significant. In our CLN3 cohort, seizures and epileptiform discharges were frequent and often started by age 10 years without significant difference between genotypes. ABC and CSF NEFL correlate with UBDRS seizure score, reflecting the role of seizures in the neurodegenerative process. Longitudinal evaluations in a larger cohort are needed to confirm these findings.