No abstract

Functional networks may have value as objective markers of treatment response in ES, with potential to facilitate rapid identification of personalized, effective treatments.

Summary 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.

SUMMARYObjective: 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 (j) were calculated for the assessment of hypsarrhythmia and each feature. Results: Although IRR was favorable in determining whether a study was normal or abnormal (j = 0.89), reliability was unfavorable for assessment of hypsarrhythmia (j = 0.40), modified hypsarrhythmia (j = 0.47), high voltage (j = 0.37), disorganization (j = 0.22), multifocal epileptiform discharges (j = 0.68), interictal voltage attenuations (j = 0.21), slowing (j = 0.20), asymmetry (j = 0.26), and asynchrony (j = 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.

SUMMARYObjective: 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. KEY WORDS: West syndrome, Epileptic spasms, Toxicity, Neuroimaging.Infantile spasms (also known as epileptic spasms in the most recently proposed International League Against Epilepsy (ILAE) classification scheme 1 ) is an often devastating form of epilepsy with onset in the first year of life; is frequently attributed to one of many structural, genetic, or metabolic disorders; and is usually accompanied by neurodevelopmental arrest or regression.2 Infantile spasms is characterized by clusters of brief seizures termed spasms and a spectrum of severe electroencephalographic abnormalities including hypsarrhythmia.3 A lack of prompt and successful treatment is associated with adverse long-term 8 Despite recognized efficacy, 9,10 the use of VGB has been limited foremost by reports of retinopathy resulting in permanent peripheral visual field defects termed VGB-associated visual field loss (VAVFL).11,12 Estimates of VAVFL risk vary substantially, though the risk appears to be lower among children, 13 and especially low among infants with treatment duration <12 months.14 Similarly, in a recent large-sca...

Summary Objective This study investigated the short-term response to a standardized hormonal therapy protocol for treatment of infantile spasms. Methods Twenty-seven children with video-EEG confirmed infantile spasms received very high dose (8 mg/kg/day, max 60 mg/day) oral prednisolone for 2 weeks. Response (absence of both hypsarrhythmia and spasms) to prednisolone was ascertained by repeat overnight video-EEG. Responders were tapered off over 2 weeks and non-responders were immediately transitioned to high dose (150 IU/m2/day) intramuscular ACTH for 2 additional weeks. Response was again determined by overnight video-EEG after ACTH therapy. Results Sixty-three percent (17/27) of patients responded completely to prednisolone. Subsequently, 40% (4/10) of prednisolone non-responders exhibited a complete response after an additional 2-week course with ACTH. Among 27 subjects with median follow-up of 13.5 months (interquartile range 4.8-25.9), 12% (2/17) of prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response. Significance Very high dose prednisolone demonstrated significantly higher efficacy than previously reported for lower doses in prior studies. High dose ACTH may be superior to very high dose prednisolone, and in lieu of a definitive clinical trial, the choice between prednisolone and ACTH for initial treatment of infantile spasms remains controversial.

Objective.Compare the effectiveness of initial treatment for infantile spasms.Methods.The National Infantile Spasms Consortium prospectively followed children with new onset infantile spasms that began at age 2-24 months at 23 US centers (2012-2018). Freedom from treatment failure at 60 days required no second treatment for infantile spasms and no clinical spasms after 30 days of treatment initiation. We managed treatment selection bias with propensity score weighting and within-center correlation with generalized estimating equations.Results.Freedom from treatment failure rates were: ACTH 88/190 (46%), oral steroids 42/95 (44%), vigabatrin 32/87 (37%), and non-standard therapy 4/51 (8%). Changing from oral steroids to ACTH was not estimated to affect response (observed 44% estimated to change to 44% [95% CI 34–54]). Changing from non-standard therapy to ACTH would improve response from 8% to 39 [17–67]%, and to oral steroids from 8% to 38 [15–68]%. There were large but not statistically significant estimated effects of changing from vigabatrin to ACTH (29% to 42 [15–75]%), vigabatrin to oral steroids (29% to 42 [28–57]%), and non-standard therapy to vigabatrin (8% to 20 [6-50]%). Among children treated with vigabatrin, those with tuberous sclerosis complex (TSC) responded more often than others (62% vs 29%; p<0.05)Conclusion.Compared to non-standard therapy, ACTH and oral steroids are superior for initial treatment of infantile spasms. The estimated effectiveness of vigabatrin is between ACTH / oral steroids and non-standard therapy, though the sample was underpowered for statistical confidence. When used, vigabatrin worked best for TSC.Classification of Evidence:This study provides Class III evidence that for children with new onset infantile spasms, ACTH or oral steroids were superior to non-standard therapies.

Interictal FR are detectable on scalp EEG and may potentially serve as a biomarker of epilepsy in children with TSC.