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Felbamate in the treatment of refractory epileptic spasms
Epilepsy Research 161 (2020) 106284
Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Felbamate in the treatment of refractory epileptic spasms a,
a
a
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T a
Shaun A. Hussain *, Brenda Asilnejad , Jaeden Heesch , Mario Navarro , Matthew Ji , Daniel W. Shreyb, Rajsekar R. Rajaramana, Raman Sankara,c a b c
David Geffen School of Medicine and UCLA Mattel Children's Hospital, Los Angeles, CA, United States Division of Neurology, Children’s Hospital of Orange Country and Department of Pediatrics, University of California, Irvine, CA, United States Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: West syndrome Epileptic spasms Hypsarrhythmia
Several small case series provide conflicting impressions of the efficacy of felbamate for treatment of epileptic spasms. Using a large single-center cohort of children with epileptic spasms, we retrospectively evaluated the efficacy and safety of felbamate. We identified all patients with video-EEG confirmed epileptic spasms who were treated with felbamate at our center. We quantified felbamate exposure by calculating peak and weightedaverage weight-based dose. Clinical response was defined as resolution of epileptic spasms for at least 28 days, beginning not more than 3 months after felbamate initiation. Electroclinical response was defined as clinical response accompanied by overnight video-EEG demonstrating freedom from epileptic spasms and hypsarrhythmia. Among a cohort of 476 infants, we identified 62 children who were treated with felbamate, of whom 58 had previously failed treatment with hormonal therapy or vigabatrin. Median peak and weighted-average felbamate dosages were 47 and 40 mg/kg/day, respectively. Five (8%) children were classified as clinical responders and two (3%) children were classified as electroclinical responders. Among 17 patients with latency from epileptic spasms onset to felbamate initiation of less than 12 months, we observed 4 (24%) clinical responders. This study suggests that felbamate may be efficacious for treatment of epileptic spasms and that further rigorous study is warranted.
1. Introduction Epileptic spasms are most often encountered in the setting of West syndrome, in which they are accompanied by hypsarrhythmia (including variations thereof), and neurodevelopmental impairment (Shields, 2006). In this context, diagnostic delay and unsuccessful treatment are associated with poor long-term developmental outcomes (O’Callaghan et al., 2011; Riikonen, 2004). There is broad agreement that the most effective first-line therapies for epileptic spasms include hormonal therapy — chiefly adrenocorticotropic hormone (Baram et al., 1996) and prednisolone (Eliyan et al., 2019)) — vigabatrin (Go et al., 2012; Pellock et al., 2010; Vigevano and Cilio, 1997), administered individually (Knupp et al., 2016a), simultaneously (O’Callaghan et al., 2017), or sequentially (Knupp et al., 2016b; Ko et al., 2018). With a cumulative short-term response rate to hormonal therapy and vigabatrin of approximately 66%, and cumulative long-term relapse rate approaching 50% (Hayashi et al., 2016; Rajaraman et al., 2016), approximately 33% of patients achieve long-term remission with first-line therapy. As such, there is a significant unmet need for effective
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treatments to combat refractory epileptic spasms. At present, practitioners must choose from an array of therapies supported only by limited and often conflicting data, including felbamate, zonisamide, topiramate, valproic acid, several benzodiazepines, cannabidiol, the ketogenic diet, and corpus callosotomy (Hussain, 2018; Song et al., 2017). At our center we have frequently employed felbamate after failure of hormonal therapy and vigabatrin, on the basis of encouraging but conflicting reports of efficacy (Dozières-Puyravel et al., 2019; EspeLillo et al., 1993; Hosain et al., 1997; Hurst and Rolan, 1995; Stafstrom, 1996). In this study, we retrospectively explored the efficacy, safety, and tolerability of felbamate in a large cohort of children with epileptic spasms. 2. Methods 2.1. Standard protocol approvals The participation of human subjects and the analyses presented here were approved by the institutional review board of the University of
Corresponding author at: UCLA Pediatric Neurology, 10833 Le Conte Ave, Room 22-474, Los Angeles, CA, 90095-1752, USA. E-mail address: [email protected] (S.A. Hussain).
https://doi.org/10.1016/j.eplepsyres.2020.106284 Received 14 November 2019; Received in revised form 29 January 2020; Accepted 1 February 2020 Available online 03 February 2020 0920-1211/ © 2020 Elsevier B.V. All rights reserved.
Epilepsy Research 161 (2020) 106284
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California, Los Angeles.
Table 1 Baseline characteristics of the study cohort. Total patients, n Female, n (%) Age of onset of IS, months, median (IQR) Latency from IS onset to felbamate initiation, months, median (IQR) Number of treatments prior to FBM, median (IQR) Prior treatment with hormonal therapy and/or vigabatrin, n (%) Ongoing hypsarrhythmia at the time of FBM initiation, n (%) Development Normal development prior to onset of IS, n (%) Etiology Unknown, n (%) Knowna, n (%) Structural, n (%) Genetic, n (%) Metabolic, n (%) Total duration of follow-up, mo, median (IQR)
2.2. Study design This was a retrospective cohort study. Using a database which includes all patients who underwent video-EEG monitoring at the UCLA Mattel Children’s Hospital, we identified patients with video-EEG confirmed epileptic spasms who were treated with felbamate. There were no additional criteria for inclusion or exclusion.
2.3. Data ascertainment All data were derived from the electronic medical record. For each patient, we recorded the date of (1) birth, (2) onset of epileptic spasms, (3) initiation of felbamate, (4) response (if any), (5) relapse (if any), and (6) most recent follow-up. To quantify felbamate exposure, we sequentially reviewed each neurology progress note and recorded patient weight (kg) and total daily dosage (mg/day) to enable calculation of the peak weight-based dose (mg/kg/day) and weighted-average weightbased dose (mg/kg/day). As we were chiefly interested in prompt response to felbamate, we only evaluated the first three months of felbamate exposure, with the assumption that response after 90 days is more likely attributed to other therapies or spontaneous resolution.
62 29 (47%) 5.2 (2.9, 12.4) 26.7 (11.7, 61.9) 5 (4, 8) 58 (94%) 20 (32%) 35 (56%) 20 (32%) 42 (68%) 28 (45%) 26 (42%) 5 (8%) 61.9 (27.6, 102.3)
a
As some patients exhibited dual-classification, the sum of specific etiologic classifications (i.e. structural, genetic, metabolic) exceeded the sum of patients with known etiology. Abbreviations: IS: infantile spasms; IQR: interquartile range.
3. Results 3.1. Subjects Baseline clinical and demographic characteristics of the study cohort are summarized in Table 1. Among a cohort of 474 patients with video-EEG confirmed epileptic spasms who were evaluated at UCLA between April 2007 and April 2019, we identified 62 children who were treated with felbamate. Although the median age of epileptic spasms onset was 5.2 months (IQR 2.9, 12.4), median age at felbamate initiation was 39.0 months (21.7, 76.9) and median latency from epileptic spasms onset to felbamate treatment was 26.7 months (11.7, 61.9). Twenty (32%) patients exhibited continued hypsarrhythmia immediately prior to felbamate initiation. Prior failure of a first-line therapy (ACTH, corticosteroids, or vigabatrin) was observed among 58 (94%) patients, and the median number of treatment failures prior to felbamate exposure was 5 (4, 8). Among the four patients in which felbamate was used before hormonal therapy and vigabatrin, the precise rationale for non-standard therapy was not clearly articulated in the medical record. We speculate that decision-making was guided by impressions of medical frailty (perhaps vulnerability to hormonal therapy side-effects) and patient age; three patients were > 24 months of age at the time of epileptic spasms diagnosis, and thus beyond the upper age limit for US Food and Drug Administration approved use of ACTH and vigabatrin.
2.4. Efficacy measures Clinical response was defined as parent-reported resolution of epileptic spasms for a duration of at least 28 days, beginning within 3 months of initiating felbamate. Electroclinical response was defined as clinical response (as above) with overnight video-EEG confirmation of freedom from epileptic spasms and hypsarrhythmia. With recognition that (1) approximately 20% of children do not exhibit hypsarrhythmia at baseline (Demarest et al., 2017), (2) hypsarrhythmia often resolves or attenuates with incomplete response to first-line therapy, and (3) the identification of hypsarrhythmia (and resolution thereof) is undermined to some extent by poor inter-rater reliability (Hussain et al., 2015), the purpose of our electoclincial outcome assessment was not to demonstrate prompt eradication of hypsarrhythmia. Rather, we sought to simply verify that clinical response was not contradicted by a followup video-EEG demonstrating either ongoing (clinically unrecognized) epileptic spasms or enduring hypsarrhythmia.
2.5. Adverse events With regard to treatment-emergent adverse events during felbamate exposure, we focused on appetite reduction and/or weight loss, insomnia, sedation, transaminitis (defined as alanine aminotransferase greater than two times the upper limit of normal), and leucopenia (defined as total white blood cell count less than half the lower limit of normal) noted in the medical record.
3.2. Felbamate efficacy and exposure Five (8%) children were classified as clinical responders. Of these five, only two patients underwent video-EEG to confirm response, and both were classified as electroclinical responders. The first electoclinical responder originally presented to another hospital at age 5 months with epileptic spasms and hypsarrhythmia, and failed sequential trials of prednisolone, ACTH, vigabatrin, topiramate, levetiracetam, valproic acid, oxcarbazepine, clobazam, and the ketogenic diet. Just prior to felbamate initiation at age 3 years, the patient exhibited continued daily clusters of epileptic spasms, but not hypsarrhythmia. EEG showed diffuse slowing, disorganization, abundant and almost exclusively right hemispheric epileptiform discharges, and normal voltage. Felbamate treatment led to “immediate” improvement and ultimate cessation of epileptic spasms on day 19 of treatment, at a dose of 27 mg/kg/day. Follow-up overnight video-EEG confirmed absence of epileptic spasms, and demonstrated a reduction in
2.6. Statistical methods Summary statistics for continuous variables were presented as median and interquartile range (IQR) given nonparametric distributions. Comparisons of continuous and dichotomous variables were accomplished with the Wilcoxon rank-sum test and the Fisher exact test, respectively. All comparisons were two-sided and P values less than 0.05 were considered statistically significant. Statistical calculations were facilitated with STATA software (Statacorp, version 14, College Station, Texas, USA). 2
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the burden of epileptiform discharges and improvement in organization, but with continued diffuse slowing. At that time, the parent reported that the patient was considerably more alert and interactive. However, follow-up MRI led to discovery of right-hemispheric polymicrogyria and cortical dysplasia. Upon epileptic spasms relapse and electrographic deterioration—after 7 months of felbamate treatment—the patient underwent hemispherectomy, after which the patient has maintained seizure-freedom for two years. The second electroclinical responder first presented to UCLA at 6 weeks of age with super-refractory status epilepticus in the setting of acute traumatic brain injury with resultant hypoxic-ischemic injury (with widespread cortical laminar necrosis but relative sparing of subcortical structures). Over the span of one week, multifocal seizures resolved following the administration of multiple anti-seizure drugs, including continuous pentobarbital infusion, as well as initiation of the ketogenic diet. The patient was discharged home on phenobarbital, levetiracetam, lacosamide and the ketogenic diet, and over several months, he was successfully transitioned to levetiracetam monotherapy. During this span the patient remained seizure-free, but exhibited global developmental stagnation. The patient re-presented at age 12 months with epileptic spasms, without hypsarrhythmia. VideoEEG confirmed epileptic spasms, and the interictal tracing showed diffuse slowing, disorganization, frequent multifocal epileptiform discharges. Although voltage was within the normal range at the time of epileptic spasms onset, it contrasted with marked voltage attenuation observed on prior EEGs obtained at 3 and 5 months of age. The patient was then treated unsuccessfully with sequential trials of zonisamide, cannabidiol (parental administration of a community-sourced cannabidiol extract), and vigabatrin. After 8 months of ongoing epileptic spasms (multiple clusters per day), the patient began felbamate with rapid titration over 3 weeks to a dose of 118 mg/kg/day. The exact time of epileptic spasms resolution is unclear from the medical record, but spasms cessation began not more than 28 days after felbamate initiation, at which point an overnight video-EEG confirmed absence of epileptic spasms, and improvement on interictal EEG such that organization changed from “poor” to “fair”, and epileptiform discharges were less frequent. Of note, voltage decreased from the “normal” range to the low-voltage pre-spasms baseline (20–50 μV). Importantly, this patient’s cognitive outcome is poor and there has been no identifiable impact on development as a function of epileptic spasms or treatment thereof. The remaining three patients classified as clinical responders presented with epileptic spasms in the setting of prior focal (or likely multifocal) seizures, with etiology of (1) glycyine encephalopathy, (2) compound heterozygous TBC1D24 pathogenic variants, and (3) unknown etiology, respectively. Although none of these three patients exhibited classic hypsarrhythmia immediately prior to felbamate initiation, all three exhibited a highly epileptiform interictal pattern (albeit lacking high-voltage). Clinical resolution of epileptic spasms occurred within one month in each case, but all three exhibited a relatively prompt (within 1 year) transition to Lennox-Gastaut syndrome, with emergence of tonic seizures, as well as interictal slow spike-wave on EEG. In all three cases, a follow-up overnight video-EEG was performed more than 3 months after felbamate initiation (thus beyond our 3 month window for response), and after emergence of tonic seizures. As such, although the delayed follow-up video-EEG examinations exhibit lack of epileptic spasms and hypsarrhythmia, they do not provide meaningful data to support the impression of electroclinical remission. Among 54 patients with detailed felbamate exposure data available, the median peak and weighted-average weight-based felbamate dosage was 47.4 mg/kg/day (IQR 37.7, 64.1) and 40.4 mg/ kg/day (IQR 27.4, 56.2), respectively. Having observed very long intervals from epileptic spasms onset to felbamate initiation in general, we then evaluated clinical response (resolution of epileptic spasms) as a function of the duration of epileptic spasms prior to felbamate exposure. In contrast to just one (2%) responder among the 45 patients
Fig. 1. Clinical response as a function of epileptic spasms duration before felbamate treatment. Abbreviation: ES: epileptic spasms.
with a duration of epileptic spasms greater than 12 months, there were 4 (24%) responders among the 17 patients with duration of epileptic spasms less than 12 months (P = 0.02; Fig. 1). 3.3. Tolerability and safety Treatment-emergent adverse events were common in this series. With our targeted evaluation of side effects noted in the medical record, we observed diminished appetite and/or weight loss in 16 (23%), insomnia in 9 (15%), and sedation in 8 (13%) children. There was a single case each of transaminitis and leucopenia—both of which were asymptomatic and resolved with reduction in felbamate dosage—and specifically no instances of hepatic failure, aplastic anemia, or death. In exploratory analyses, none of the identified side effects were associated with peak or weighted-average felbamate dosage (all P > 0.1, without correction for multiple comparisons). 4. Discussion To our knowledge, this is the largest study to evaluate felbamate for treatment of epileptic spasms, and it is distinguished by reliance on relatively strict criteria for response and careful quantification of felbamate exposure. Although our observed response rate was low, and indistinguishable from the rate of spontaneous remission of epileptic spasms observed in two natural history studies (Hrachovy et al., 1991; Jeavons and Bower, 1961), there is reason to believe felbamate may nevertheless be effective. Firstly, we believe to some extent that our low response rates reflect the highly refractory character of the study population. Indeed, the vast majority of children in our series had failed a first-line therapy prior to felbamate exposure and latency from epileptic spasms onset to felbamate initiation was typically years in duration. Conversely, it is noteworthy that 4 of 5 clinical responders received felbamate within 12 months of epileptic spasms onset. Secondly, we speculate that response rates might have been higher if we had utilized higher dosage or more rapid titration. Although the dosage used in our series was largely guided by the recommended dosage for treatment of children with Lennox-Gastaut syndrome (45 mg/kg/day) (The Felbamate study group, 1993), several investigators have observed higher efficacy with dosage approaching 100 mg/kg/day (Zupanc et al., 2010). Similarly, peak felbamate dosage in prior studies of epileptic spasms has ranged from 15 to 120 mg/kg/day (Dozières-Puyravel et al., 2019; Espe-Lillo et al., 1993; Hosain et al., 1997; Hurst and Rolan, 1995; Stafstrom, 1996). 3
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Table 2 Summary of prior studies. Study
Sample size (n)
Peak dosage (mg/kg/day)
Resolution of epileptic spasms (%)
50% responder rate (%)a
Espe-Lillo et al., 1993 Hurst and Rolan, 1995 Stafstrom, 1996 Hosain et al., 1997 Dozières-Puyravel et al., 2019 Present study
3 4 3 11 29 62
45 15-30 90-120 15-75 37 (25–45)b 47 (38–64)c
0 75 0 9 28 8
100 75 No data 91 No data No data
a b c
The percentage of patients with at least 50% reduction in seizure-frequency. Mean (range). Median (interquartile range).
that felbamate is generally safe and well-tolerated, especially relative to hormonal therapy and vigabatrin. Still, we acknowledge that our method to quantify adverse events was limited. It is likely that some side effects were poorly documented in the medical record, and that we have underestimated adverse event rates as a consequence. Nonetheless, successful management of side effects is critical in the use of felbamate, especially when practitioners employ high dose regimens. In two recent studies, discontinuation rates ranged from 6 to 25%, and seemed to vary as a function of specific side effect mitigation strategies (Heyman et al., 2014; Shah et al., 2016). Given consensus that hormonal therapy and vigabatrin should be used first-line for treatment of infantile spasms (Go et al., 2012; Knupp et al., 2016a; Pellock et al., 2010), this study provides limited support for consideration of felbamate after failure of first-line therapies. However, there are no adequate studies that directly compare felbamate with other candidate treatment options, such as the ketogenic diet, topiramate, zonisamide, various benzodiazepines, and cannabidiol. To this end, further study is needed to better evaluate and prioritize all candidate therapies for treatment of patients with refractory epileptic spasms. As part of this effort, we believe a methodologicallysuperior prospective study of felbamate is warranted, ideally with implementation of (1) a higher target dosage and/or more rapid dose titration schedule, (2) a cohort with shorter duration of epileptic spasms, (3) an appropriate control group, and (4) more robust outcome measures such as blinded review of pre- and post-treatment video-EEG.
Prior studies of felbamate for treatment of epileptic spasms provide only a limited guide for practitioners. In Table 2, we have summarized the diverse response rates and dosage regimens utilized in these reports and placed the current study in this context. Importantly, we must acknowledge that it is challenging to compare and contrast these studies given the relatively small size of each study, and the implementation of highly varied criteria for patient inclusion and response. With this perspective in mind, our prior suggestion that higher dosage may be more efficacious is contradicted by the observation that the studies with highest dosage seem to exhibit the lowest response rates. However, it should be acknowledged that a lack of identification of a dose-response relationship may be misleading when evaluating studies in which dosage is flexible or incompletely dictated by protocol. We suspect that the inverse dose-response relationship across studies may be explained by practitioners preferentially titrating to high dose in patients with initial non-response. Indeed, none of these reports permit a rigorous within-study comparison of “low” versus “high” dose. It is also notable that although the rate of complete resolution of epileptic spasms was low in the studies of Espe-Lillo et al. (Espe-Lillo et al., 1993) and Hosain et al. (Hosain et al., 1997), both studies reported high proportions of patients with at least 50% reduction in seizure frequency (50% responder rate). In addition to our data and prior reports, there is a potential mechanistic basis for efficacy of felbamate—namely N-methyl-D-aspartate (NMDA) signaling. In particular, gain of function mutations of GRIN1 and GRIN2B (encoding the NR1 and NR2B NMDA receptor subunits, respectively) have been linked to infantile spasms (Epi4K Consortium et al., 2013; Lemke et al., 2014), and NMDA acutely provokes seizures in a contemporary model of infantile spasms (Chachua et al., 2011; Velísek et al., 2007). As such, given that felbamate blocks glutamatemediated calcium currents via the NMDA receptor (Rho et al., 1994), it is at least a logical treatment for infantile spasms. The same rationale supports the phase II clinical trial (ClinicalTrials.gov NCT02829827) of radiprodil—a negative allosteric modulator of NR2B subunit-containing NMDA receptors—for treatment of refractory infantile spasms (Mullier et al., 2017). Importantly, we must note the methodologic limitations of this study. It should be emphasized that neither this study nor any of the previous studies are randomized, double-blind, placebo-controlled studies. All of these uncontrolled, retrospective studies are vulnerable to potential biases in the parent-report of epileptic spasms resolution, as well as biases that impact the identification of hypsarrhythmia (and resolution thereof) (Hussain et al., 2015), or the decision to report results at all (publication bias). Furthermore, given the highly-refractory character of our epileptic spasms cohort, as well as our implementation of a generous time-limit (3 months) for clinical and electroclinical response, it is difficult to compare our reported response rates with other studies. In particular, there was a very limited opportunity to observe prompt resolution of hypsarrhythmia, as only one-third of children in this series exhibited ongoing hypsarrhythmia at the time of felbamate initiation. With regard to tolerability and safety, this study supports the view
Declaration of Competing Interest Dr. Hussain has received research support from the Epilepsy Therapy Project, the Milken Family Foundation, the Hughes Family Foundation, the Elsie and Isaac Fogelman Endowment, Eisai, Lundbeck, Insys, GW Pharma, UCB Biopharma, Zogenix, and the NIH (R34MH089299). He has received honoraria for service on the scientific advisory boards of Mallinckrodt, Upsher-Smith Laboratories, Insys, UCB Biopharma, and Zogenix; as a consultant to UCB, Mallinckrodt, Insys, GW Pharma, West Therapeutic Development, Aquestive Therapeutics, Shennox, and Amzell; and on the speaker’s bureau for Mallinckrodt and GW Pharmaceuticals. Dr. Rajaraman has received research support from Marinus and the International CDKL5 Research Foundation. Dr. Shrey has received research support from the Lennox-Gastaut Syndrome Foundation, UCB Biopharma, and Mallinckrodt, as well as the CHOC Children’s Physician Subspecialty Faculty Tithe Fund and the CHOC Children’s Physician Scientist Scholars Program. Dr. Sankar serves on scientific advisory boards or serves on the speaker’s bureau for and has received honoraria and funding for travel from Eisai, UCB Pharma, Sunovion, Supernus, Greenwich Biosciences, LivaNova, and on the advisory boards for Aquestive Therapeutics, West Therapeutic Development, Insys Development Company, and Zogenix; receives royalties from the publication of Pellock’s Pediatric Epilepsy, 4th ed. (Demos Publishing, 2016) and Epilepsy: Mechanisms, Models, and Translational Perspectives (CRC Press, 2011); serves on speakers’ bureaus 4
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for and has received speaker honoraria from Eisai, UCB, GlaxoSmithKline, LivaNova, Supernus, and BioMarin. He has received research support from SK Life Sciences and Insys Development Company, Inc. The remaining authors report no conflicts of interest.
remission and long-term outcome in patients with infantile spasms. Epilepsia 32, 212–214. Hurst, D.L., Rolan, T.D., 1995. The use of felbamate to treat infantile spasms. J. Child Neurol. 10, 134–136. Hussain, S.A., 2018. Treatment of infantile spasms. Epilepsia Open 3 (Suppl. 2), 143–154. Hussain, S.A., Kwong, G., Millichap, J.J., et al., 2015. Hypsarrhythmia assessment exhibits poor interrater reliability: a threat to clinical trial validity. Epilepsia 56, 77–81. Jeavons, P.M., Bower, B.D., 1961. The natural history of infantile spasms. Arch. Dis. Child. 36, 17–22. Knupp, K.G., Coryell, J., Nickels, K.C., et al., 2016a. Response to treatment in a prospective national infantile spasms cohort. Ann. Neurol. 79, 475–484. Knupp, K.G., Leister, E., Coryell, J., et al., 2016b. Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort. Epilepsia 57, 1834–1842. Ko, A., Youn, S.E., Chung, H.J., et al., 2018. Vigabatrin and high-dose prednisolone therapy for patients with West syndrome. Epilepsy Res. 145, 127–133. Lemke, J.R., Hendrickx, R., Geider, K., et al., 2014. GRIN2B mutations in West syndrome and intellectual disability with focal epilepsy. Ann. Neurol. 75, 147–154. Mullier, B., Wolff, C., Sands, Z.A., et al., 2017. GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors. Neuropharmacology 123, 322–331. O’Callaghan, F.J.K., Lux, A.L., Darke, K., et al., 2011. The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study. Epilepsia 52, 1359–1364. O’Callaghan, F.J.K., Edwards, S.W., Alber, F.D., et al., 2017. Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. Lancet Neurol. 16, 33–42. Pellock, J.M., Hrachovy, R., Shinnar, S., et al., 2010. Infantile spasms: a U.S. Consensus report. Epilepsia 51, 2175–2189. Rajaraman, R.R., Lay, J., Alayari, A., Anderson, K., et al., 2016. Prevention of infantile spasms relapse: zonisamide and topiramate provide no benefit. Epilepsia 57, 1280–1287. Rho, J.M., Donevan, S.D., Rogawski, M.A., 1994. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-D-aspartate and gamma-aminobutyric acidA receptors. Ann. Neurol. 35, 229–234. Riikonen, R., 2004. Topical review: infantile spasms: therapy and outcome. J. Child Neurol. 19, 401–404. Shah, Y.D., Singh, K., Friedman, D., et al., 2016. Evaluating the safety and efficacy of felbamate in the context of a black box warning: a single center experience. Epilepsy Behav. 56, 50–53. Shields, W.D., 2006. Infantile spasms: little seizures, BIG consequences. Epilepsy Curr. 6, 63–69. Song, J.M., Hahn, J., Kim, S.H., et al., 2017. Efficacy of treatments for infantile spasms: a systematic review. Clin. Neuropharmacol. 40, 63–84. Stafstrom, C.E., 1996. The use of felbamate to treat infantile spasms. J. Child Neurol. 11, 170–171. Velísek, L., Jehle, K., Asche, S., et al., 2007. Model of infantile spasms induced by Nmethyl-D-aspartic acid in prenatally impaired brain. Ann. Neurol. 61, 109–119. Vigevano, F., Cilio, M.R., 1997. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia 38, 1270–1274. Zupanc, M.L., Roell Werner, R., Schwabe, M.S., et al., 2010. Efficacy of felbamate in the treatment of intractable pediatric epilepsy. Pediatr. Neurol. 42, 396–403.
Acknowledgements This study was accomplished with support from the Mohammed F. Alibrahim Endowment, Elsie and Isaac Fogelman Endowment, the Epilepsy Therapy Project, the Milken Family Foundation, the Hughes Family Foundation, and the UCLA Children’s Discovery and Innovation Institute. References Baram, T.Z., Mitchell, W.G., Tournay, A., et al., 1996. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics 97, 375–379. Chachua, T., Yum, M.-S., Velíšková, J., et al., 2011. Validation of the rat model of cryptogenic infantile spasms. Epilepsia 52, 1666–1677. Consortium, E., Allen, A.S., Berkovic, S.F., et al., 2013. De novo mutations in epileptic encephalopathies. Nature 501, 217–221. Demarest, S.T., Shellhaas, R.A., Gaillard, W.D., et al., 2017. The impact of hypsarrhythmia on infantile spasms treatment response: observational cohort study from the National Infantile Spasms Consortium. Epilepsia 58, 2098–2103. Dozières-Puyravel, B., Nasser, H., Bellavoine, V., et al., 2019. Felbamate for infantile spasms syndrome resistant to first-line treatments. Dev. Med. Child Neurol (in press). The Felbamate study group, 1993. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). The felbamate study group in lennoxgastaut syndrome. N. Engl. J. Med. 328, 29–33. Eliyan, Y., Heesch, J., Alayari, A., et al., 2019. Very-high-Dose prednisolone before ACTH for treatment of infantile spasms: evaluation of a standardized protocol. Pediatr. Neurol. 99, 16–22. Espe-Lillo, J., Ritter, F., Frost, M., 1993. Safety and efficacy of felbamate in treatment of infantile spasms. Epilepsia 34 (Suppl. 6), 110. Go, C.Y., Mackay, M.T., Weiss, S.K., et al., 2012. Evidence-based guideline update: medical treatment of infantile spasms: report of the guideline development subcommittee of the american academy of neurology and the practice committee of the child neurology society. Neurology 78, 1974–1980. Hayashi, Y., Yoshinaga, H., Akiyama, et al., 2016. Predictive factors for relapse of epileptic spasms after adrenocorticotropic hormone therapy in West syndrome. Brain Dev. 38, 32–39. Heyman, E., Levin, N., Lahat, E., et al., 2014. Efficacy and safety of felbamate in children with refractory epilepsy. Eur. J. Paediatr. Neurol. 18, 658–662. Hosain, S., Nagarajan, L., Carson, D., et al., 1997. Felbamate for refractory infantile spasms. J. Child Neurol. 12, 466–468. Hrachovy, R.A., Glaze, D.G., Frost, J.D., 1991. A retrospective study of spontaneous
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Contents lists available at ScienceDirect
Epilepsy Research journal homepage: www.elsevier.com/locate/epilepsyres
Felbamate in the treatment of refractory epileptic spasms a,
a
a
a
T a
Shaun A. Hussain *, Brenda Asilnejad , Jaeden Heesch , Mario Navarro , Matthew Ji , Daniel W. Shreyb, Rajsekar R. Rajaramana, Raman Sankara,c a b c
David Geffen School of Medicine and UCLA Mattel Children's Hospital, Los Angeles, CA, United States Division of Neurology, Children’s Hospital of Orange Country and Department of Pediatrics, University of California, Irvine, CA, United States Department of Neurology, David Geffen School of Medicine, Los Angeles, CA, United States
A R T I C LE I N FO
A B S T R A C T
Keywords: West syndrome Epileptic spasms Hypsarrhythmia
Several small case series provide conflicting impressions of the efficacy of felbamate for treatment of epileptic spasms. Using a large single-center cohort of children with epileptic spasms, we retrospectively evaluated the efficacy and safety of felbamate. We identified all patients with video-EEG confirmed epileptic spasms who were treated with felbamate at our center. We quantified felbamate exposure by calculating peak and weightedaverage weight-based dose. Clinical response was defined as resolution of epileptic spasms for at least 28 days, beginning not more than 3 months after felbamate initiation. Electroclinical response was defined as clinical response accompanied by overnight video-EEG demonstrating freedom from epileptic spasms and hypsarrhythmia. Among a cohort of 476 infants, we identified 62 children who were treated with felbamate, of whom 58 had previously failed treatment with hormonal therapy or vigabatrin. Median peak and weighted-average felbamate dosages were 47 and 40 mg/kg/day, respectively. Five (8%) children were classified as clinical responders and two (3%) children were classified as electroclinical responders. Among 17 patients with latency from epileptic spasms onset to felbamate initiation of less than 12 months, we observed 4 (24%) clinical responders. This study suggests that felbamate may be efficacious for treatment of epileptic spasms and that further rigorous study is warranted.
1. Introduction Epileptic spasms are most often encountered in the setting of West syndrome, in which they are accompanied by hypsarrhythmia (including variations thereof), and neurodevelopmental impairment (Shields, 2006). In this context, diagnostic delay and unsuccessful treatment are associated with poor long-term developmental outcomes (O’Callaghan et al., 2011; Riikonen, 2004). There is broad agreement that the most effective first-line therapies for epileptic spasms include hormonal therapy — chiefly adrenocorticotropic hormone (Baram et al., 1996) and prednisolone (Eliyan et al., 2019)) — vigabatrin (Go et al., 2012; Pellock et al., 2010; Vigevano and Cilio, 1997), administered individually (Knupp et al., 2016a), simultaneously (O’Callaghan et al., 2017), or sequentially (Knupp et al., 2016b; Ko et al., 2018). With a cumulative short-term response rate to hormonal therapy and vigabatrin of approximately 66%, and cumulative long-term relapse rate approaching 50% (Hayashi et al., 2016; Rajaraman et al., 2016), approximately 33% of patients achieve long-term remission with first-line therapy. As such, there is a significant unmet need for effective
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treatments to combat refractory epileptic spasms. At present, practitioners must choose from an array of therapies supported only by limited and often conflicting data, including felbamate, zonisamide, topiramate, valproic acid, several benzodiazepines, cannabidiol, the ketogenic diet, and corpus callosotomy (Hussain, 2018; Song et al., 2017). At our center we have frequently employed felbamate after failure of hormonal therapy and vigabatrin, on the basis of encouraging but conflicting reports of efficacy (Dozières-Puyravel et al., 2019; EspeLillo et al., 1993; Hosain et al., 1997; Hurst and Rolan, 1995; Stafstrom, 1996). In this study, we retrospectively explored the efficacy, safety, and tolerability of felbamate in a large cohort of children with epileptic spasms. 2. Methods 2.1. Standard protocol approvals The participation of human subjects and the analyses presented here were approved by the institutional review board of the University of
Corresponding author at: UCLA Pediatric Neurology, 10833 Le Conte Ave, Room 22-474, Los Angeles, CA, 90095-1752, USA. E-mail address: [email protected] (S.A. Hussain).
https://doi.org/10.1016/j.eplepsyres.2020.106284 Received 14 November 2019; Received in revised form 29 January 2020; Accepted 1 February 2020 Available online 03 February 2020 0920-1211/ © 2020 Elsevier B.V. All rights reserved.
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California, Los Angeles.
Table 1 Baseline characteristics of the study cohort. Total patients, n Female, n (%) Age of onset of IS, months, median (IQR) Latency from IS onset to felbamate initiation, months, median (IQR) Number of treatments prior to FBM, median (IQR) Prior treatment with hormonal therapy and/or vigabatrin, n (%) Ongoing hypsarrhythmia at the time of FBM initiation, n (%) Development Normal development prior to onset of IS, n (%) Etiology Unknown, n (%) Knowna, n (%) Structural, n (%) Genetic, n (%) Metabolic, n (%) Total duration of follow-up, mo, median (IQR)
2.2. Study design This was a retrospective cohort study. Using a database which includes all patients who underwent video-EEG monitoring at the UCLA Mattel Children’s Hospital, we identified patients with video-EEG confirmed epileptic spasms who were treated with felbamate. There were no additional criteria for inclusion or exclusion.
2.3. Data ascertainment All data were derived from the electronic medical record. For each patient, we recorded the date of (1) birth, (2) onset of epileptic spasms, (3) initiation of felbamate, (4) response (if any), (5) relapse (if any), and (6) most recent follow-up. To quantify felbamate exposure, we sequentially reviewed each neurology progress note and recorded patient weight (kg) and total daily dosage (mg/day) to enable calculation of the peak weight-based dose (mg/kg/day) and weighted-average weightbased dose (mg/kg/day). As we were chiefly interested in prompt response to felbamate, we only evaluated the first three months of felbamate exposure, with the assumption that response after 90 days is more likely attributed to other therapies or spontaneous resolution.
62 29 (47%) 5.2 (2.9, 12.4) 26.7 (11.7, 61.9) 5 (4, 8) 58 (94%) 20 (32%) 35 (56%) 20 (32%) 42 (68%) 28 (45%) 26 (42%) 5 (8%) 61.9 (27.6, 102.3)
a
As some patients exhibited dual-classification, the sum of specific etiologic classifications (i.e. structural, genetic, metabolic) exceeded the sum of patients with known etiology. Abbreviations: IS: infantile spasms; IQR: interquartile range.
3. Results 3.1. Subjects Baseline clinical and demographic characteristics of the study cohort are summarized in Table 1. Among a cohort of 474 patients with video-EEG confirmed epileptic spasms who were evaluated at UCLA between April 2007 and April 2019, we identified 62 children who were treated with felbamate. Although the median age of epileptic spasms onset was 5.2 months (IQR 2.9, 12.4), median age at felbamate initiation was 39.0 months (21.7, 76.9) and median latency from epileptic spasms onset to felbamate treatment was 26.7 months (11.7, 61.9). Twenty (32%) patients exhibited continued hypsarrhythmia immediately prior to felbamate initiation. Prior failure of a first-line therapy (ACTH, corticosteroids, or vigabatrin) was observed among 58 (94%) patients, and the median number of treatment failures prior to felbamate exposure was 5 (4, 8). Among the four patients in which felbamate was used before hormonal therapy and vigabatrin, the precise rationale for non-standard therapy was not clearly articulated in the medical record. We speculate that decision-making was guided by impressions of medical frailty (perhaps vulnerability to hormonal therapy side-effects) and patient age; three patients were > 24 months of age at the time of epileptic spasms diagnosis, and thus beyond the upper age limit for US Food and Drug Administration approved use of ACTH and vigabatrin.
2.4. Efficacy measures Clinical response was defined as parent-reported resolution of epileptic spasms for a duration of at least 28 days, beginning within 3 months of initiating felbamate. Electroclinical response was defined as clinical response (as above) with overnight video-EEG confirmation of freedom from epileptic spasms and hypsarrhythmia. With recognition that (1) approximately 20% of children do not exhibit hypsarrhythmia at baseline (Demarest et al., 2017), (2) hypsarrhythmia often resolves or attenuates with incomplete response to first-line therapy, and (3) the identification of hypsarrhythmia (and resolution thereof) is undermined to some extent by poor inter-rater reliability (Hussain et al., 2015), the purpose of our electoclincial outcome assessment was not to demonstrate prompt eradication of hypsarrhythmia. Rather, we sought to simply verify that clinical response was not contradicted by a followup video-EEG demonstrating either ongoing (clinically unrecognized) epileptic spasms or enduring hypsarrhythmia.
2.5. Adverse events With regard to treatment-emergent adverse events during felbamate exposure, we focused on appetite reduction and/or weight loss, insomnia, sedation, transaminitis (defined as alanine aminotransferase greater than two times the upper limit of normal), and leucopenia (defined as total white blood cell count less than half the lower limit of normal) noted in the medical record.
3.2. Felbamate efficacy and exposure Five (8%) children were classified as clinical responders. Of these five, only two patients underwent video-EEG to confirm response, and both were classified as electroclinical responders. The first electoclinical responder originally presented to another hospital at age 5 months with epileptic spasms and hypsarrhythmia, and failed sequential trials of prednisolone, ACTH, vigabatrin, topiramate, levetiracetam, valproic acid, oxcarbazepine, clobazam, and the ketogenic diet. Just prior to felbamate initiation at age 3 years, the patient exhibited continued daily clusters of epileptic spasms, but not hypsarrhythmia. EEG showed diffuse slowing, disorganization, abundant and almost exclusively right hemispheric epileptiform discharges, and normal voltage. Felbamate treatment led to “immediate” improvement and ultimate cessation of epileptic spasms on day 19 of treatment, at a dose of 27 mg/kg/day. Follow-up overnight video-EEG confirmed absence of epileptic spasms, and demonstrated a reduction in
2.6. Statistical methods Summary statistics for continuous variables were presented as median and interquartile range (IQR) given nonparametric distributions. Comparisons of continuous and dichotomous variables were accomplished with the Wilcoxon rank-sum test and the Fisher exact test, respectively. All comparisons were two-sided and P values less than 0.05 were considered statistically significant. Statistical calculations were facilitated with STATA software (Statacorp, version 14, College Station, Texas, USA). 2
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the burden of epileptiform discharges and improvement in organization, but with continued diffuse slowing. At that time, the parent reported that the patient was considerably more alert and interactive. However, follow-up MRI led to discovery of right-hemispheric polymicrogyria and cortical dysplasia. Upon epileptic spasms relapse and electrographic deterioration—after 7 months of felbamate treatment—the patient underwent hemispherectomy, after which the patient has maintained seizure-freedom for two years. The second electroclinical responder first presented to UCLA at 6 weeks of age with super-refractory status epilepticus in the setting of acute traumatic brain injury with resultant hypoxic-ischemic injury (with widespread cortical laminar necrosis but relative sparing of subcortical structures). Over the span of one week, multifocal seizures resolved following the administration of multiple anti-seizure drugs, including continuous pentobarbital infusion, as well as initiation of the ketogenic diet. The patient was discharged home on phenobarbital, levetiracetam, lacosamide and the ketogenic diet, and over several months, he was successfully transitioned to levetiracetam monotherapy. During this span the patient remained seizure-free, but exhibited global developmental stagnation. The patient re-presented at age 12 months with epileptic spasms, without hypsarrhythmia. VideoEEG confirmed epileptic spasms, and the interictal tracing showed diffuse slowing, disorganization, frequent multifocal epileptiform discharges. Although voltage was within the normal range at the time of epileptic spasms onset, it contrasted with marked voltage attenuation observed on prior EEGs obtained at 3 and 5 months of age. The patient was then treated unsuccessfully with sequential trials of zonisamide, cannabidiol (parental administration of a community-sourced cannabidiol extract), and vigabatrin. After 8 months of ongoing epileptic spasms (multiple clusters per day), the patient began felbamate with rapid titration over 3 weeks to a dose of 118 mg/kg/day. The exact time of epileptic spasms resolution is unclear from the medical record, but spasms cessation began not more than 28 days after felbamate initiation, at which point an overnight video-EEG confirmed absence of epileptic spasms, and improvement on interictal EEG such that organization changed from “poor” to “fair”, and epileptiform discharges were less frequent. Of note, voltage decreased from the “normal” range to the low-voltage pre-spasms baseline (20–50 μV). Importantly, this patient’s cognitive outcome is poor and there has been no identifiable impact on development as a function of epileptic spasms or treatment thereof. The remaining three patients classified as clinical responders presented with epileptic spasms in the setting of prior focal (or likely multifocal) seizures, with etiology of (1) glycyine encephalopathy, (2) compound heterozygous TBC1D24 pathogenic variants, and (3) unknown etiology, respectively. Although none of these three patients exhibited classic hypsarrhythmia immediately prior to felbamate initiation, all three exhibited a highly epileptiform interictal pattern (albeit lacking high-voltage). Clinical resolution of epileptic spasms occurred within one month in each case, but all three exhibited a relatively prompt (within 1 year) transition to Lennox-Gastaut syndrome, with emergence of tonic seizures, as well as interictal slow spike-wave on EEG. In all three cases, a follow-up overnight video-EEG was performed more than 3 months after felbamate initiation (thus beyond our 3 month window for response), and after emergence of tonic seizures. As such, although the delayed follow-up video-EEG examinations exhibit lack of epileptic spasms and hypsarrhythmia, they do not provide meaningful data to support the impression of electroclinical remission. Among 54 patients with detailed felbamate exposure data available, the median peak and weighted-average weight-based felbamate dosage was 47.4 mg/kg/day (IQR 37.7, 64.1) and 40.4 mg/ kg/day (IQR 27.4, 56.2), respectively. Having observed very long intervals from epileptic spasms onset to felbamate initiation in general, we then evaluated clinical response (resolution of epileptic spasms) as a function of the duration of epileptic spasms prior to felbamate exposure. In contrast to just one (2%) responder among the 45 patients
Fig. 1. Clinical response as a function of epileptic spasms duration before felbamate treatment. Abbreviation: ES: epileptic spasms.
with a duration of epileptic spasms greater than 12 months, there were 4 (24%) responders among the 17 patients with duration of epileptic spasms less than 12 months (P = 0.02; Fig. 1). 3.3. Tolerability and safety Treatment-emergent adverse events were common in this series. With our targeted evaluation of side effects noted in the medical record, we observed diminished appetite and/or weight loss in 16 (23%), insomnia in 9 (15%), and sedation in 8 (13%) children. There was a single case each of transaminitis and leucopenia—both of which were asymptomatic and resolved with reduction in felbamate dosage—and specifically no instances of hepatic failure, aplastic anemia, or death. In exploratory analyses, none of the identified side effects were associated with peak or weighted-average felbamate dosage (all P > 0.1, without correction for multiple comparisons). 4. Discussion To our knowledge, this is the largest study to evaluate felbamate for treatment of epileptic spasms, and it is distinguished by reliance on relatively strict criteria for response and careful quantification of felbamate exposure. Although our observed response rate was low, and indistinguishable from the rate of spontaneous remission of epileptic spasms observed in two natural history studies (Hrachovy et al., 1991; Jeavons and Bower, 1961), there is reason to believe felbamate may nevertheless be effective. Firstly, we believe to some extent that our low response rates reflect the highly refractory character of the study population. Indeed, the vast majority of children in our series had failed a first-line therapy prior to felbamate exposure and latency from epileptic spasms onset to felbamate initiation was typically years in duration. Conversely, it is noteworthy that 4 of 5 clinical responders received felbamate within 12 months of epileptic spasms onset. Secondly, we speculate that response rates might have been higher if we had utilized higher dosage or more rapid titration. Although the dosage used in our series was largely guided by the recommended dosage for treatment of children with Lennox-Gastaut syndrome (45 mg/kg/day) (The Felbamate study group, 1993), several investigators have observed higher efficacy with dosage approaching 100 mg/kg/day (Zupanc et al., 2010). Similarly, peak felbamate dosage in prior studies of epileptic spasms has ranged from 15 to 120 mg/kg/day (Dozières-Puyravel et al., 2019; Espe-Lillo et al., 1993; Hosain et al., 1997; Hurst and Rolan, 1995; Stafstrom, 1996). 3
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Table 2 Summary of prior studies. Study
Sample size (n)
Peak dosage (mg/kg/day)
Resolution of epileptic spasms (%)
50% responder rate (%)a
Espe-Lillo et al., 1993 Hurst and Rolan, 1995 Stafstrom, 1996 Hosain et al., 1997 Dozières-Puyravel et al., 2019 Present study
3 4 3 11 29 62
45 15-30 90-120 15-75 37 (25–45)b 47 (38–64)c
0 75 0 9 28 8
100 75 No data 91 No data No data
a b c
The percentage of patients with at least 50% reduction in seizure-frequency. Mean (range). Median (interquartile range).
that felbamate is generally safe and well-tolerated, especially relative to hormonal therapy and vigabatrin. Still, we acknowledge that our method to quantify adverse events was limited. It is likely that some side effects were poorly documented in the medical record, and that we have underestimated adverse event rates as a consequence. Nonetheless, successful management of side effects is critical in the use of felbamate, especially when practitioners employ high dose regimens. In two recent studies, discontinuation rates ranged from 6 to 25%, and seemed to vary as a function of specific side effect mitigation strategies (Heyman et al., 2014; Shah et al., 2016). Given consensus that hormonal therapy and vigabatrin should be used first-line for treatment of infantile spasms (Go et al., 2012; Knupp et al., 2016a; Pellock et al., 2010), this study provides limited support for consideration of felbamate after failure of first-line therapies. However, there are no adequate studies that directly compare felbamate with other candidate treatment options, such as the ketogenic diet, topiramate, zonisamide, various benzodiazepines, and cannabidiol. To this end, further study is needed to better evaluate and prioritize all candidate therapies for treatment of patients with refractory epileptic spasms. As part of this effort, we believe a methodologicallysuperior prospective study of felbamate is warranted, ideally with implementation of (1) a higher target dosage and/or more rapid dose titration schedule, (2) a cohort with shorter duration of epileptic spasms, (3) an appropriate control group, and (4) more robust outcome measures such as blinded review of pre- and post-treatment video-EEG.
Prior studies of felbamate for treatment of epileptic spasms provide only a limited guide for practitioners. In Table 2, we have summarized the diverse response rates and dosage regimens utilized in these reports and placed the current study in this context. Importantly, we must acknowledge that it is challenging to compare and contrast these studies given the relatively small size of each study, and the implementation of highly varied criteria for patient inclusion and response. With this perspective in mind, our prior suggestion that higher dosage may be more efficacious is contradicted by the observation that the studies with highest dosage seem to exhibit the lowest response rates. However, it should be acknowledged that a lack of identification of a dose-response relationship may be misleading when evaluating studies in which dosage is flexible or incompletely dictated by protocol. We suspect that the inverse dose-response relationship across studies may be explained by practitioners preferentially titrating to high dose in patients with initial non-response. Indeed, none of these reports permit a rigorous within-study comparison of “low” versus “high” dose. It is also notable that although the rate of complete resolution of epileptic spasms was low in the studies of Espe-Lillo et al. (Espe-Lillo et al., 1993) and Hosain et al. (Hosain et al., 1997), both studies reported high proportions of patients with at least 50% reduction in seizure frequency (50% responder rate). In addition to our data and prior reports, there is a potential mechanistic basis for efficacy of felbamate—namely N-methyl-D-aspartate (NMDA) signaling. In particular, gain of function mutations of GRIN1 and GRIN2B (encoding the NR1 and NR2B NMDA receptor subunits, respectively) have been linked to infantile spasms (Epi4K Consortium et al., 2013; Lemke et al., 2014), and NMDA acutely provokes seizures in a contemporary model of infantile spasms (Chachua et al., 2011; Velísek et al., 2007). As such, given that felbamate blocks glutamatemediated calcium currents via the NMDA receptor (Rho et al., 1994), it is at least a logical treatment for infantile spasms. The same rationale supports the phase II clinical trial (ClinicalTrials.gov NCT02829827) of radiprodil—a negative allosteric modulator of NR2B subunit-containing NMDA receptors—for treatment of refractory infantile spasms (Mullier et al., 2017). Importantly, we must note the methodologic limitations of this study. It should be emphasized that neither this study nor any of the previous studies are randomized, double-blind, placebo-controlled studies. All of these uncontrolled, retrospective studies are vulnerable to potential biases in the parent-report of epileptic spasms resolution, as well as biases that impact the identification of hypsarrhythmia (and resolution thereof) (Hussain et al., 2015), or the decision to report results at all (publication bias). Furthermore, given the highly-refractory character of our epileptic spasms cohort, as well as our implementation of a generous time-limit (3 months) for clinical and electroclinical response, it is difficult to compare our reported response rates with other studies. In particular, there was a very limited opportunity to observe prompt resolution of hypsarrhythmia, as only one-third of children in this series exhibited ongoing hypsarrhythmia at the time of felbamate initiation. With regard to tolerability and safety, this study supports the view
Declaration of Competing Interest Dr. Hussain has received research support from the Epilepsy Therapy Project, the Milken Family Foundation, the Hughes Family Foundation, the Elsie and Isaac Fogelman Endowment, Eisai, Lundbeck, Insys, GW Pharma, UCB Biopharma, Zogenix, and the NIH (R34MH089299). He has received honoraria for service on the scientific advisory boards of Mallinckrodt, Upsher-Smith Laboratories, Insys, UCB Biopharma, and Zogenix; as a consultant to UCB, Mallinckrodt, Insys, GW Pharma, West Therapeutic Development, Aquestive Therapeutics, Shennox, and Amzell; and on the speaker’s bureau for Mallinckrodt and GW Pharmaceuticals. Dr. Rajaraman has received research support from Marinus and the International CDKL5 Research Foundation. Dr. Shrey has received research support from the Lennox-Gastaut Syndrome Foundation, UCB Biopharma, and Mallinckrodt, as well as the CHOC Children’s Physician Subspecialty Faculty Tithe Fund and the CHOC Children’s Physician Scientist Scholars Program. Dr. Sankar serves on scientific advisory boards or serves on the speaker’s bureau for and has received honoraria and funding for travel from Eisai, UCB Pharma, Sunovion, Supernus, Greenwich Biosciences, LivaNova, and on the advisory boards for Aquestive Therapeutics, West Therapeutic Development, Insys Development Company, and Zogenix; receives royalties from the publication of Pellock’s Pediatric Epilepsy, 4th ed. (Demos Publishing, 2016) and Epilepsy: Mechanisms, Models, and Translational Perspectives (CRC Press, 2011); serves on speakers’ bureaus 4
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for and has received speaker honoraria from Eisai, UCB, GlaxoSmithKline, LivaNova, Supernus, and BioMarin. He has received research support from SK Life Sciences and Insys Development Company, Inc. The remaining authors report no conflicts of interest.
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