John R. Mytinger

Response To Treatment In A Prospective National Infantile Spasms Cohort.

Infantile spasms are seizures associated with a severe epileptic encephalopathy presenting in the first 2 years of life, and optimal treatment continues to be debated. This study evaluates early and sustained response to initial treatments and addresses both clinical remission and electrographic resolution of hypsarrhythmia. Secondarily, it assesses whether response to treatment differs by etiology or developmental status.

Early-life epilepsies and the emerging role of genetic testing

Importance Early-life epilepsies are often a consequence of numerous neurodevelopmental disorders, most of which are proving to have genetic origins. The role of genetic testing in the initial evaluation of these epilepsies is not established. Objective To provide a contemporary account of the patterns of use and diagnostic yield of genetic testing for early-life epilepsies. Design, Setting, and Participants In this prospective cohort, children with newly diagnosed epilepsy with an onset at less than 3 years of age were recruited from March 1, 2012, to April 30, 2015, from 17 US pediatric hospitals and followed up for 1 year. Of 795 families approached, 775 agreed to participate. Clinical diagnosis of the etiology of epilepsy were characterized based on information available before genetic testing was performed. Added contributions of cytogenetic and gene sequencing investigations were determined. Exposures Genetic diagnostic testing. Main Outcomes and Measures Laboratory-confirmed pathogenic variant. Results Of the 775 patients in the study (367 girls and 408 boys; median age of onset, 7.5 months [interquartile range, 4.2-16.5 months]), 95 (12.3%) had acquired brain injuries. Of the remaining 680 patients, 327 (48.1%) underwent various forms of genetic testing, which identified pathogenic variants in 132 of 327 children (40.4%; 95% CI, 37%-44%): 26 of 59 (44.1%) with karyotyping, 32 of 188 (17.0%) with microarrays, 31 of 114 (27.2%) with epilepsy panels, 11 of 33 (33.3%) with whole exomes, 4 of 20 (20.0%) with mitochondrial panels, and 28 of 94 (29.8%) with other tests. Forty-four variants were identified before initial epilepsy presentation. Apart from dysmorphic syndromes, pathogenic yields were highest for children with tuberous sclerosis complex (9 of 11 [81.8%]), metabolic diseases (11 of 14 [78.6%]), and brain malformations (20 of 61 [32.8%]). A total of 180 of 446 children (40.4%), whose etiology would have remained unknown without genetic testing, underwent some testing. Pathogenic variants were identified in 48 of 180 children (26.7%; 95% CI, 18%-34%). Diagnostic yields were greater than 15% regardless of delay, spasms, and young age. Yields were greater for epilepsy panels (28 of 96 [29.2%]; P < .001) and whole exomes (5 of 18 [27.8%]; P = .02) than for chromosomal microarray (8 of 101 [7.9%]). Conclusions and Relevance Genetic investigations, particularly broad sequencing methods, have high diagnostic yields in newly diagnosed early-life epilepsies regardless of key clinical features. Thorough genetic investigation emphasizing sequencing tests should be incorporated into the initial evaluation of newly presenting early-life epilepsies and not just reserved for those with severe presentations and poor outcomes.

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

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.

Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort

Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first‐line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome.

Optimizing Care with a Standardized Management Protocol for Patients with Infantile Spasms

The primary aim of this quality improvement initiative was to increase the number of patients receiving first-line therapy (adrenocorticotropic hormone, corticosteroids, vigabatrin) as the initial treatment for infantile spasms. We implemented a standardized management protocol for infantile spasms based on the best available data and expert consensus. To assess the impact of this intervention, we compared the 3-month remission rates between prestandardization (January 2009 to August 2012) and poststandardization (September 2012 to May 2014) cohorts. We found that the percentage of patients receiving first-line therapy as the initial treatment was 57% (31/54) in the prestandardization cohort and 100% (35/35) in the poststandardization cohort (P < .001). The rate of infantile spasms remission was higher poststandardization compared to prestandardization (78.8% vs 30.6%, P < .001). Management standardization led to all patients receiving first-line therapy as the initial treatment and was associated with a significantly improved rate of infantile spasms remission 3 months after diagnosis.

Synthetic ACTH Is Not Superior to Prednisolone for Infantile Spasms: Randomized Clinical Trials and Tribulations.

There are only three therapies with greater than class IV evidence to support their use for the treatment of infantile spasmsdadrenocorticotropic hormone (ACTH), vigabatrin, and oral corticosteroids.1 In the United States, only natural ACTH and vigabatrin are approved by the Food and Drug Administration for infantile spasms. However, for decades, oral corticosteroids have been used “off label” for the treatment of infantile spasms. In contrast to the price of ACTH and vigabatrin, oral corticosteroids are far less expensive (less than

Adrenal Function Testing Following Hormone Therapy for Infantile Spasms: Case Series and Review of Literature

40 for a 1-month course), easy to administer, and readily available in most parts of the world. In the United States, the price of ACTH can exceed

Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms.

100,000 for a typical one-month course and the price of vigabatrin can approximate

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

50,000 for a typical six-month course. So, despite the lack of Food and Drug Administration approval, oral corticosteroids are a desirable treatment option for patients with infantile spasms. A small class II randomized controlled trial of low-dose (2 mg/day in two divided doses) oral prednisone versus high-dose (150 IU/m2/day in two divided doses) natural ACTH reported that 13/15 (86.6%) patients randomized to ACTH achieved electroclinical remission 2 weeks after starting treatment compared with only 4/14 (28.6%) patients randomized to prednisone (P 1⁄4 0.002).1,2 However, the response to oral corticosteroids appears to be dosedependent.3 Increasing the response rate to oral corticosteroids may be as simple as increasing the dose.3 Although the class III randomized controlled trial by Lux and colleagues (United Kingdom Infantile Spasms Study [UKISS]) was not powered to compare hormone subgroups, prednisolone at a dose of 40-60 mg/day (in three to four divided doses) yielded a 2-week clinical remission rate of 70% compared with 76% for synthetic ACTH at 40-60 IU every other day (P 1⁄4 0.61).4 The combination of UKISS (despite the study’s shortcomings5) and the high cost of ACTH have profoundly affected clinical practice, with clinicians using oral corticosteroids more commonly.6-8 In this issue of Pediatric Neurology, Wanigasinghe and colleagues provide the first appropriately powered randomized controlled trial comparing synthetic ACTH to highdose oral prednisolone.9 The study comes from a single center in Sri Lanka, one of the largest children’s hospitals in the world. In this single-blind study with intention-to-treat analysis, 48 patients were randomized to prednisolone at 40-60mg/day in three to four divided doses and 49 patients

Improving the inter-rater agreement of hypsarrhythmia using a simplified EEG grading scale for children with infantile spasms

Prednisolone and adrenocorticotropic hormone (ACTH) are “hormone” therapies for infantile spasms. There is limited data on the occurrence of decreased adrenal reserve or signs of clinical adrenal insufficiency after hormone therapy. This is a retrospective medical record review of patients referred to our Infantile Spasms Program. Our standardized infantile spasms management guideline began in September 2012 and initially included a post-hormone laboratory assessment of adrenal function. Medical records were assessed for hormone treatments, adrenal function testing, and signs of adrenal insufficiency. Forty-two patients who received one or both hormone therapies met inclusion criteria. A post-hormone laboratory assessment of adrenal function was done in 14 patients. Of these 14 patients, 2 had an abnormal laboratory assessment of adrenal function, both by adrenal stimulation testing – one after ACTH and one after prednisolone. One patient received hydrocortisone replacement and the other received stress dose hydrocortisone as needed; neither patient developed signs of adrenal insufficiency. Another patient treated with both types of hormone therapy in tandem, who did not have a post-hormone laboratory assessment, developed signs of mild adrenal insufficiency and required replacement hydrocortisone. Our study suggests that adrenal suppression can occur after modern hormone therapy regimens. We found two patients with abnormal adrenal function testing after hormone therapy and another patient with signs adrenal insufficiency. Given the seriousness of adrenal crisis, caregiver education on the signs of adrenal insufficiency is critical. Greater vigilance may be indicated in patients receiving both types of hormone therapy in tandem. Although a routine post-hormone laboratory assessment of adrenal function may not be feasible in all patients, replacement or stress dose hydrocortisone is necessary for all patients with suspected adrenal insufficiency.