Bilateral centromedian nucleus of thalamus responsive neurostimulation for pediatric-onset drug-resistant epilepsy.

Neuromodulation therapies offer an efficacious treatment alternative for patients with drug-resistant epilepsy (DRE), particularly those unlikely to benefit from surgical resection. Here we present our retrospective single-center case series of patients with pediatric-onset DRE who underwent responsive neurostimulation (RNS) depth electrode implantation targeting the bilateral centromedian nucleus (CM) of the thalamus between October 2020 and October 2022. Sixteen patients were identified; seizure outcomes, programming parameters, and complications at follow-up were reviewed. The median age at implantation was 13 years (range 3.6-22). Six patients (38%) were younger than 12 years of age at the time of implantation. Ictal electroencephalography (EEG) patterns during patients' most disabling seizures were reliably detected. Ten patients (62%) achieved 50% or greater reduction in seizure frequency at a median 1.3 years (range 0.6-2.6) of follow-up. Eight patients (50%) experienced sensorimotor side effects, and three patients (19%) had superficial pocket infection, prompting the removal of the RNS device. Side effects of stimulation were experienced mostly in monopolar-cathodal configuration and alleviated with programming change to bipolar configuration or low-frequency stimulation. Closed-loop neurostimulation using RNS targeting bilateral CM is a feasible and useful therapy for patients with pediatric-onset DRE.

Clustered variants in the 5' coding region of TRA2B cause a distinctive neurodevelopmental syndrome.

PURPOSE: Transformer2 proteins (Tra2α and Tra2ß) control splicing patterns in human cells, and no human phenotypes have been associated with germline variants in these genes. The aim of this work was to associate germline variants in the TRA2B gene to a novel neurodevelopmental disorder. METHODS: A total of 12 individuals from 11 unrelated families who harbored predicted loss-of-function monoallelic variants, mostly de novo, were recruited. RNA sequencing and western blot analyses of Tra2ß-1 and Tra2ß-3 isoforms from patient-derived cells were performed. Tra2ß1-GFP, Tra2ß3-GFP and CHEK1 exon 3 plasmids were transfected into HEK-293 cells. RESULTS: All variants clustered in the 5' part of TRA2B, upstream of an alternative translation start site responsible for the expression of the noncanonical Tra2ß-3 isoform. All affected individuals presented intellectual disability and/or developmental delay, frequently associated with infantile spasms, microcephaly, brain anomalies, autism spectrum disorder, feeding difficulties, and short stature. Experimental studies showed that these variants decreased the expression of the canonical Tra2ß-1 isoform, whereas they increased the expression of the Tra2ß-3 isoform, which is shorter and lacks the N-terminal RS1 domain. Increased expression of Tra2ß-3-GFP were shown to interfere with the incorporation of CHEK1 exon 3 into its mature transcript, normally incorporated by Tra2ß-1. CONCLUSION: Predicted loss-of-function variants clustered in the 5' portion of TRA2B cause a new neurodevelopmental syndrome through an apparently dominant negative disease mechanism involving the use of an alternative translation start site and the overexpression of a shorter, repressive Tra2ß protein.

Inequities in Therapy for Infantile Spasms: A Call to Action.

OBJECTIVE: The aim of this study was to determine whether selection of treatment for children with infantile spasms (IS) varies by race/ethnicity. METHODS: The prospective US National Infantile Spasms Consortium database includes children with IS treated from 2012 to 2018. We examined the relationship between race/ethnicity and receipt of standard IS therapy (prednisolone, adrenocorticotropic hormone, vigabatrin), adjusting for demographic and clinical variables using logistic regression. Our primary outcome was treatment course, which considered therapy prescribed for the first and, when needed, the second IS treatment together. RESULTS: Of 555 children, 324 (58%) were non-Hispanic white, 55 (10%) non-Hispanic Black, 24 (4%) non-Hispanic Asian, 80 (14%) Hispanic, and 72 (13%) other/unknown. Most (398, 72%) received a standard treatment course. Insurance type, geographic location, history of prematurity, prior seizures, developmental delay or regression, abnormal head circumference, hypsarrhythmia, and IS etiologies were associated with standard therapy. In adjusted models, non-Hispanic Black children had lower odds of receiving a standard treatment course compared with non-Hispanic white children (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.20-0.89; p = 0.02). Adjusted models also showed that children with public (vs. private) insurance had lower odds of receiving standard therapy for treatment 1 (OR, 0.42; CI, 0.21-0.84; p = 0.01). INTERPRETATION: Non-Hispanic Black children were more often treated with non-standard IS therapies than non-Hispanic white children. Likewise, children with public (vs. private) insurance were less likely to receive standard therapies. Investigating drivers of inequities, and understanding the impact of racism on treatment decisions, are critical next steps to improve care for patients with IS. ANN NEUROL 2022;92:32-44.

Efficacy of cannabidiol in convulsive and nonconvulsive seizure types associated with treatment-resistant epilepsies in the Expanded Access Program.

The cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure = 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic), nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic absence), and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction = 47%-100%), and nonconvulsive seizure types and epileptic spasms (median percentage reduction = 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE, who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.

Potential induction of epileptic spasms by nonselective voltage-gated sodium channel blockade: Interaction with etiology.

PURPOSE: Epileptic spasms are often preceded by focal (or multifocal) seizures. Based on a series of case reports suggesting that carbamazepine and oxcarbazepine may induce epileptic spasms, we set out to rigorously evaluate the potential association between exposure to voltage-gated sodium channel blockade and latency to epileptic spasms. METHODS: We identified 50 cases (children with focal seizures and evolution to epileptic spasms) and 50 controls (children with focal seizures without evolution to epileptic spasms). For each patient, we reviewed all sequential neurology encounters between onset of epilepsy and emergence of epileptic spasms. For each encounter we recorded seizure-frequency and all anti-seizure therapy exposures. Using multivariable Cox proportional hazards regression, we evaluated the association between voltage-gated sodium channel exposure (carbamazepine, oxcarbazepine, lacosamide, or phenytoin) and latency to epileptic spasms onset, with adjustment for etiology and seizure-frequency. RESULTS: Latency to epileptic spasms onset was independently associated with exposure to sodium channel blockade (hazard ratio = 2.4; 95% CI 1.1-5.2; P = 0.03) and high-risk etiology (hazard ratio = 2.8; 95% CI 1.5-5.1; P = 0.001). With assessment for interaction between sodium channel blockade and etiology, we identified an estimated 7-fold increased risk of epileptic spasms with the combination of sodium channel blockade and high-risk etiology (hazard ratio = 7.0, 95% CI 2.5-19.8; P < 0.001). CONCLUSION: This study suggests that voltage-gated sodium channel blockade may induce epileptic spasms among children at risk on the basis of etiology. Further study is warranted to replicate these findings, ascertain possible drug- and dose-specific risks, and identify potential mechanisms of harm.

Overcoming presynaptic effects of VAMP2 mutations with 4-aminopyridine treatment.

Clinical and genetic features of five unrelated patients with de novo pathogenic variants in the synaptic vesicle-associated membrane protein 2 (VAMP2) reveal common features of global developmental delay, autistic tendencies, behavioral disturbances, and a higher propensity to develop epilepsy. For one patient, a cognitively impaired adolescent with a de novo stop-gain VAMP2 mutation, we tested a potential treatment strategy, enhancing neurotransmission by prolonging action potentials with the aminopyridine family of potassium channel blockers, 4-aminopyridine and 3,4-diaminopyridine, in vitro and in vivo. Synaptic vesicle recycling and neurotransmission were assayed in neurons expressing three VAMP2 variants by live-cell imaging and electrophysiology. In cellular models, two variants decrease both the rate of exocytosis and the number of synaptic vesicles released from the recycling pool, compared with wild-type. Aminopyridine treatment increases the rate and extent of exocytosis and total synaptic charge transfer and desynchronizes GABA release. The clinical response of the patient to 2 years of off-label aminopyridine treatment includes improved emotional and behavioral regulation by parental report, and objective improvement in standardized cognitive measures. Aminopyridine treatment may extend to patients with pathogenic variants in VAMP2 and other genes influencing presynaptic function or GABAergic tone, and tested in vitro before treatment.

The economic burden of caregiving in epilepsy: An estimate based on a survey of US caregivers.

OBJECTIVE: The burden of caregiving for persons with epilepsy (PWEs) has not been examined previously in the United States. We assessed the clinical impact and direct and indirect economic costs for caregivers of PWEs. METHODS: An internet survey of 500 caregivers of PWEs was conducted from May to July 2015 using a combination of validated instruments and questions designed specifically for this survey. Caregivers were stratified by PWE age (adult/child) and disease severity (low: 0 vs high: 1 + seizures in the prior month). Annual self-reported direct and indirect costs were reported per caregiver and extrapolated to all US caregivers. The economic burden of caregiving for PWEs was defined as the difference between costs for caregivers and the general population. RESULTS: Caregivers reported that PWEs averaged 11.4 seizures in the prior month. Eighty percent of respondents were female and the average age was 44.3. Since becoming a caregiver, many reported anxiety (52.8%), depression (41.0%), and insomnia (30.8%). Annual mean direct medical costs for caregivers of children with low vs high seizure frequency were $4344 and $10 162, respectively. Costs for caregivers of adult PWEs were $4936 and $8518. Mean indirect costs associated with caregiving for a child with low vs high seizure frequency were $20 529 and $40 137; those for caregivers of an adult were $13 981 and $28 410. The cost estimates are higher vs the general US population; annual per-person healthcare utilization costs were $2740 and productivity loss costs were $5015. When extrapolating to the US population of PWE caregivers, annual costs exceeded $62 billion vs $14 billion for the general population, resulting in a caregiver burden of nearly $48 billion. SIGNIFICANCE: The clinical and economic burden of caregivers for PWE were substantial, and greatest for those caring for children with frequent seizures. The impact on caregivers should be considered when estimating the value of interventions that control epilepsy.

Synthetic pharmaceutical grade cannabidiol for treatment of refractory infantile spasms: A multicenter phase-2 study.

PURPOSE: Limited data suggest that cannabidiol (CBD) may be effective for treatment of refractory infantile spasms (IS). This study was designed to more rigorously evaluate the efficacy and safety of synthetic CBD in the treatment of IS. METHODS: Children six to 36 months of age with IS that failed treatment with both adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) were eligible for enrollment. Children receiving clobazam were excluded. After baseline overnight video-electroencephalography (vEEG) to confirm diagnosis and ascertain hypsarrhythmia, patients were treated with synthetic CBD oral solution (20 mg/kg/day). Overnight video-EEG was repeated after 14 days, and both baseline and repeat video-EEGs were completely de-identified and reviewed in a pairwise fashion by an independent, blinded pediatric electroencephalographer. The primary efficacy endpoint was freedom from spasms and hypsarrhythmia on day 14. RESULTS: Nine patients were enrolled, comprising an older (median age = 23 months) cohort with long-standing IS (median duration = 13 months) and numerous prior treatment failures (median = 6). One patient responded to therapy and eight patients exhibited neither clinical nor electrographic response. CONCLUSIONS: The immediate but temporary response in a single patient suggests that CBD oral solution is not particularly effective in highly refractory cases, but may, nevertheless, be effective in younger patients with shorter durations of IS. Further study, examining both short- and long-term outcomes, is warranted to further evaluate the efficacy and safety of CBD oral solution in the treatment of IS.

Amantadine: A new treatment for refractory electrical status epilepticus in sleep.

PURPOSE: Electrical status epilepticus in sleep (ESES) is an electrographic abnormality linked to language abnormalities and cognitive dysfunction and specifically associated with Landau-Kleffner syndrome (LKS), the syndrome of continuous spike and wave in slow-wave sleep (CSWS), and autistic regression with epileptiform EEG (AREE). As first-line therapies for treatment of ESES display inadequate efficacy and confer substantial risk, we set out to describe our center's experience with amantadine in the treatment of ESES. METHODS: Patients with video-EEG-confirmed ESES who received amantadine were retrospectively identified in a clinical EEG database. Spike-wave index, before and after amantadine exposure, was compared in a pairwise fashion. In an exploratory analysis, we cataloged reported changes in language functioning, cognition, and autistic features, which accompanied treatment. RESULTS: We identified 20 patients with ESES-associated syndromes. Median cumulative weighted average amantadine dosage was 2.1 mg/kg/d (interquartile range (IQR): 1.1, 4.5), and median duration of therapy was 11.5 months (IQR: 7.8, 26.6). In comparison with median baseline spike-wave index (76%), post-amantadine spike-wave index (53%) was reduced, with P = 0.01. Six (30%) patients exhibited complete (or nearly complete) resolution of ESES. A majority of patients exhibited subjective cognitive, linguistic, or behavioral benefit. Amantadine was generally well-tolerated despite substantial dosage and duration of therapy. CONCLUSIONS: This study suggests that amantadine may be effective in the treatment of ESES-associated syndromes but warrants replication in a more rigorous study.

A comparison of levetiracetam and phenobarbital for the treatment of neonatal seizures associated with hypoxic-ischemic encephalopathy.

PURPOSE: Seizures are common in term infants with hypoxic-ischemic encephalopathy (HIE) undergoing therapeutic hypothermia. Although phenobarbital (PHB) is generally considered first-line therapy, some centers have embraced third-generation antiepileptic drugs (AEDs) such as levetiracetam (LEV) given the impression of comparable efficacy and superior tolerability. We set out to compare the efficacy of PHB and LEV in a large single-center cohort. METHODS: We retrospectively identified consecutive newborns with HIE who were monitored with continuous video-electroencephalogram (VEEG) for the duration of therapeutic hypothermia. After identification of seizures, infants were treated with PHB or LEV at the discretion of treating physicians. We assessed time to seizure freedom as a function of AED choice, with adjustment for HIE severity and initial seizure frequency using the Kaplan-Meier procedure and multivariate Cox proportional hazards regression. RESULTS: We identified 78 infants with HIE. Among 44 (56%) patients who had VEEG-confirmed seizures, 34 became seizure-free during monitoring, and the remaining 10 died. Initial treatment with LEV, in comparison with PHB, predicted a shorter interval to seizure freedom in a univariate analysis (Hazard ratio (HR) = 2.58, P = 0.007), even after adjustment for initial seizure frequency and an unbiased ad hoc measure of HIE severity (adjusted HR = 2.57, P = 0.010). This effect was recapitulated in an analysis in which patients with treatment crossover were excluded. As expected, severity of HIE was an independent predictor of longer duration to seizure freedom (HR = 0.16, P < 0.001) and remained a significant predictor after adjustment for initial seizure burden and treatment agent. CONCLUSION: Despite a relatively small sample size and retrospective design, this study suggests that LEV is a viable alternative to PHB in the treatment of neonatal seizures associated with HIE. A large-scale randomized controlled trial is needed to confirm these findings.

Recognition of Infantile Spasms Is Often Delayed: The ASSIST Study.

OBJECTIVES: To characterize and quantify diagnostic and treatment delay among children with infantile spasms, and to estimate the developmental impact of this delay. STUDY DESIGN: In this cohort study, we surveyed the parents of 100 patients with infantile spasms about their experiences with diagnosis and treatment, and ascertained medical and sociodemographic factors potentially related to care of these infants. We specifically determined the latency to first visit an "effective provider," defined as a provider who identified infantile spasms, and prescribed an appropriate first-line treatment, namely adrenocorticotropic hormone, corticosteroids, or vigabatrin. Time to the first visit to an effective provider was evaluated using Cox proportional hazards regression. RESULTS: The median time from the onset of infantile spasms to first visit with an effective provider was 24.5 days. Only 29% of patients were evaluated by an effective provider within 1 week of infantile spasms onset. The time to first effective provider visit was associated with parental language preference, but with no other sociodemographic characteristics. Parents' suspicions that "something is wrong" were often discounted by healthcare providers, and survey respondents frequently reported that pediatricians and neurologists were unfamiliar with infantile spasms. CONCLUSION: This study demonstrates that substantial delay (ie, >1 week) in appropriate care is common, and suggests that the poor awareness of infantile spasms among healthcare providers is at least partly responsible for preventable and potentially significant delays in treatment.

Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent.

OBJECTIVE: Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible-and largely asymptomatic-signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena. METHODS: Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure. RESULTS: We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039). SIGNIFICANCE: We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy.

The impact of hypsarrhythmia on infantile spasms treatment response: Observational cohort study from the National Infantile Spasms Consortium.

OBJECTIVE: The multicenter National Infantile Spasms Consortium prospective cohort was used to compare outcomes and phenotypic features of patients with infantile spasms with and without hypsarrhythmia. METHODS: Patients aged 2 months to 2 years were enrolled prospectively with new-onset infantile spasms. Treatment choice and categorization of hypsarrhythmia were determined clinically at each site. Response to therapy was defined as resolution of clinical spasms (and hypsarrhythmia if present) without relapse 3 months after initiation. RESULTS: Eighty-two percent of patients had hypsarrhythmia, but this was not associated with gender, mean age, preexisting developmental delay or epilepsy, etiology, or response to first-line therapy. Infants with hypsarrhythmia were more likely to receive standard treatment (adrenocorticotropic hormone, prednisolone, or vigabatrin [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-4.7] and preexisting epilepsy reduced the likelihood of standard treatment (OR 3.2, 95% CI 1.9-5.4). Hypsarrhythmia was not a determinant of response to treatment. A logistic regression model demonstrated that later age of onset (OR 1.09 per month, 95% CI 1.03-1.15) and absence of preexisting epilepsy (OR 1.7, 95% CI 1.06-2.81) had a small impact on the likelihood of responding to the first-line treatment. However, receiving standard first-line treatment increased the likelihood of responding dramatically: vigabatrin (OR 5.2 ,95% CI 2-13.7), prednisolone (OR 8, 95% CI 3.1-20.6), and adrenocorticotropic hormone (ACTH; OR 10.2, 95% CI 4.1-25.8) . SIGNIFICANCE: First-line treatment with standard therapy was by far the most important variable in determining likelihood of response to treatment of infantile spasms with or without hypsarrhythmia.

Long-Range Temporal Correlations Reflect Treatment Response in the Electroencephalogram of Patients with Infantile Spasms.

Infantile spasms syndrome is an epileptic encephalopathy in which prompt diagnosis and treatment initiation are critical to therapeutic response. Diagnosis of the disease heavily depends on the identification of characteristic electroencephalographic (EEG) patterns, including hypsarrhythmia. However, visual assessment of the presence and characteristics of hypsarrhythmia is challenging because multiple variants of the pattern exist, leading to poor inter-rater reliability. We investigated whether a quantitative measurement of the control of neural synchrony in the EEGs of infantile spasms patients could be used to reliably distinguish the presence of hypsarrhythmia and indicate successful treatment outcomes. We used autocorrelation and Detrended Fluctuation Analysis (DFA) to measure the strength of long-range temporal correlations in 21 infantile spasms patients before and after treatment and 21 control subjects. The strength of long-range temporal correlations was significantly lower in patients with hypsarrhythmia than control patients, indicating decreased control of neural synchrony. There was no difference between patients without hypsarrhythmia and control patients. Further, the presence of hypsarrhythmia could be classified based on the DFA exponent and intercept with 92% accuracy using a support vector machine. Successful treatment was marked by a larger increase in the DFA exponent compared to those in which spasms persisted. These results suggest that the strength of long-range temporal correlations is a marker of pathological cortical activity that correlates with treatment response. Combined with current clinical measures, this quantitative tool has the potential to aid objective identification of hypsarrhythmia and assessment of treatment efficacy to inform clinical decision-making.

Prevention of infantile spasms relapse: Zonisamide and topiramate provide no benefit.

OBJECTIVE: There is scant evidence to guide the management of infantile spasms after successful response to initial therapies. There is significant risk of relapse, largely because effective pharmacologic treatments cannot be continued long term because of concern for significant adverse events. Zonisamide (ZNS) and topiramate (TPM) are commonly used to prevent relapse, and the purpose of this study was to specifically evaluate the efficacy of ZNS and TPM as agents for secondary prevention of infantile spasms. METHODS: Patients with video-electroencephalography (EEG) confirmed resolution of infantile spasms were retrospectively identified. Relevant clinical data were systematically collected, including lead time from onset of spasms to successful treatment response, etiology of infantile spasms, number of treatment failures prior to response, timing of relapse, and detailed exposure data for ZNS and TPM. RESULTS: We identified 106 patients with response to hormonal therapy (n = 58), vigabatrin (n = 25), or surgery (n = 23). To prevent relapse of infantile spasms, 37 patients received ZNS, 34 received TPM, 3 received both ZNS and TPM, and 38 patients received neither ZNS nor TPM. There were 44 relapses, occurring a median of 6.9 (3.2-10.8) months after initial response. Time to relapse was not affected by treatment with ZNS or TPM. Relapse was less likely among patients who were older (hazard ratio 0.97 [per month], p = 0.036) and those who responded to surgical resection (hazard ratio = 0.28, p = 0.017). Of note, we identified a relatively refractory cohort with multiple treatment failures and long lead time to initial response. SIGNIFICANCE: In this refractory cohort, neither ZNS nor TPM was successful in preventing relapse of infantile spasms, despite relatively high dosages. At this time, aside from surgical resection in eligible candidates, there is no known treatment that is efficacious in the prevention of relapse of infantile spasms.

A lack of clinically apparent vision loss among patients treated with vigabatrin with infantile spasms: The UCLA experience.

BACKGROUND: Vigabatrin (VGB) is one of two FDA-approved medications for treatment of infantile spasms. Despite demonstrated efficacy, its use has been curtailed by reports indicating a substantial risk of VGB-associated visual field loss (VAVFL). As these reports have conflicted with our clinical observations in routine practice, we systematically reviewed the experiences of patients treated with VGB at UCLA to estimate the prevalence of clinically apparent VAVFL. METHODS: Patients with video-EEG-confirmed infantile spasms evaluated at our center between February 2007 and February 2014 were retrospectively identified. Among patients with VGB exposure, we documented relevant clinical factors and determined the duration of therapy, peak dosage, and cumulative dosage. Based on a review of serial neurologic and ophthalmologic reports and aided by electroretinography (ERG) assessments when available, we ascertained whether each patient had evidence of clinically apparent vision impairment (i.e., recognized by a neurologist or ophthalmologist during any follow-up visit) and whether or not the vision loss was attributed to VGB exposure (i.e., evidence of bilateral, symmetric, and peripheral visual field loss), either by the treating physician or on retrospective review by the study team. RESULTS: During the study period, 257 patients with video-EEG-confirmed infantile spasms were identified. One hundred and forty-three (56%) patients received VGB. Although visual loss of any cause was common among patients with (31%) and without (32%) VGB exposure, there were no cases in which visual field defects were plausibly linked to VGB. We estimate that the risk of clinically significant VAVFL does not exceed 3.2% (95% CI upper bound). Vision loss was never characterized as exclusively peripheral and was always better explained by other causes (e.g., hemianopsia following hemispherectomy and cortical vision impairment after hypoxic ischemic encephalopathy). Precise quantitative exposure data were available for 104 (73%) patients treated with VGB, among whom the median duration of treatment was 8.6 (IQR: 3.7-16.2) months, the median peak dosage was 141.5 (IQR: 104.8-166.0) mg/kg/day, and the median cumulative dosage was 314 (IQR: 140.8-645.7) grams. CONCLUSIONS: We found that the risk of clinically apparent vision loss is quite low among young children treated for infantile spasms. Our estimate of risk contrasts with prior studies and likely reflects our ascertainment of vision loss without the aid of perimetry or serial ERG, the short treatment duration, and the relatively young age of our patients. In the treatment of infantile spasms, risk-benefit assessment should consider both the low prevalence of ERG-identified VAVFL among patients with brief (<6-9months) exposure and the very low prevalence of clinically apparent VAVFL in this population.

Hypsarrhythmia assessment exhibits poor interrater reliability: a threat to clinical trial validity.

OBJECTIVE: Hypsarrhythmia is the classic interictal electroencephalographic pattern associated with infantile spasms, and characterized by high voltage, disorganization, and multifocal independent epileptiform discharges. Given this seemingly simple definition, one might expect excellent interrater reliability (IRR) in the identification of this pattern. Alternatively, it may be argued that assessments of voltage and disorganization are fairly subjective, and thus quite challenging in borderline cases. We sought to test the IRR of hypsarrhythmia assessment in a systematic fashion. METHODS: Six blinded pediatric electroencephalographers from four centers reviewed 22 electroencephalography (EEG) samples from patients with infantile spasms. Each sample was 5 min in duration and included only wakefulness. Raters determined if each EEG was abnormal and if hypsarrhythmia was present/absent, and characterized relevant features: voltage, organization, epileptiform discharges, slowing, interictal attenuations, symmetry, and synchrony. In addition, raters indicated their level of confidence for each assessment. Multirater kappa statistics (κ) were calculated for the assessment of hypsarrhythmia and each feature. RESULTS: Although IRR was favorable in determining whether a study was normal or abnormal (κ=0.89), reliability was unfavorable for assessment of hypsarrhythmia (κ=0.40), modified hypsarrhythmia (κ=0.47), high voltage (κ=0.37), disorganization (κ=0.22), multifocal epileptiform discharges (κ=0.68), interictal voltage attenuations (κ=0.21), slowing (κ=0.20), asymmetry (κ=0.26), and asynchrony (κ=0.08). Despite generally unsatisfactory interrater agreement, raters consistently reported high confidence in assessments. SIGNIFICANCE: This study contradicts the view that hypsarrhythmia assessment is straightforward. Even small variability in the identification of hypsarrhythmia has potentially deleterious consequences for clinical care, as its presence or absence impacts decisions to pursue high-risk and high-cost therapies. These inconsistencies may similarly confound studies in which abolition of hypsarrhythmia is an outcome measure. There is a great need for practical, reliable, and unbiased measures of hypsarrhythmia.

Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.