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Vigabatrin as First-Line Treatment for Infantile Spasms Not Related to Tuberous Sclerosis Complex
Pediatric Neurology 53 (2015) 141e145
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Vigabatrin as First-Line Treatment for Infantile Spasms Not Related to Tuberous Sclerosis Complex Kevin Jones MD, FRCPC a, *, Cristina Go MD, ABPN b, Jennifer Boyd RN, MHSc, CNN(C), MSCN b, Ayako Ochi PhD b, Blathnaid McCoy MBBCh, MRCPI b, Klajdi Puka HBSc c, O. Carter Snead III MD, FRCPC b a
The Division of Neurology, Department of Pediatrics, McMaster Children’s Hospital, Hamilton, Ontario, Canada The Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada c The Division of Psychology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada b
abstract BACKGROUND: Infantile spasms are a rare, catastrophic, age-specific seizure disorder of infancy. Adrenocorticotropic hormone or vigabatrin have been recommended for the short-term treatment of infantile spasms by the Child Neurology Society/American Academy of Neurology practice parameter. OBJECTIVE: This retrospective study reviewed the Hospital for Sick Children’s experience with the short-term efficacy of vigabatrin as first-line treatment for infantile spasms not related to tuberous sclerosis complex. METHOD: We performed a single-center, retrospective analysis of all cases of newly diagnosed infantile spasms between January 2010 and September 2013. Duration of follow-up was at least 6 months from treatment initiation. RESULTS: Eighteen of the 61 infants (30%) had a clinical and electrographic response to vigabatrin therapy within 4 weeks of treatment. Of the vigabatrin responders, 2/18 (11%) relapsed. At final follow-up after initiation of vigabatrin therapy, 17/61 (27%) of the vigabatrin responders were free of all clinical seizure types. Normal development at the time of infantile spasms diagnosis was statistically associated with vigabatrin response. CONCLUSION: These findings do not support our hypothesis that vigabatrin is effective as first-line, short-term treatment of infantile spasms in non-tuberous sclerosis complex patients. However, when used in this setting, vigabatrin is most effective in children with normal development at the time of diagnosis. These findings may assist clinicians in the optimal treatment choice for children at the first presentation of infantile spasms not related to tuberous sclerosis complex. Keywords: epileptic encephalopathy, infantile spasms, vigabatrin, nontuberous sclerosis complex, efficacy, predictors
Pediatr Neurol 2015; 53: 141-145 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Infantile spasms are a rare, catastrophic age-specific, seizure disorder characterized clinically by epileptic spasms, often accompanied by developmental regression
Article History: Received January 25, 2015; Accepted in final form April 25, 2015 * Communications should be addressed to: Dr. Jones; The Division of Neurology; Department of Pediatrics; McMaster Children’s Hospital; 3A Health Sciences Centre; 1280 Main Street West; Hamilton, ON L8S 4K1. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.04.012
and a characteristic interictal electroencephalography (EEG) pattern called hypsarrhythmia.1 When all three of these features are present, the term “West syndrome” is used.1 The initial age of onset in 90% of cases is before 12 months of life, with peak onset at 6 months. The incidence is 2-3 per 10,000 live births with a lifetime prevalence of 1.5-2 per 10,000 children. It is slightly more common in males, and a family history exists in 3%-6% of cases.2-4 The etiology of infantile spasms can be categorized as structural, metabolic, or genetic.5 In up to 40% of patients, no cause can be determined and these are defined as
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unknown.6 The spontaneous remission rate of infantile spasms in limited natural history studies is 25% at 12 months after the onset of infantile spasms7 The considerable variation in the management of infantile spasms, has led to the publication of treatment surveys, consensus statements, practice parameters, and reviews of the subject.8-16 A survey on the evaluation and treatment of infantile spasms among members of the Child Neurology Society reported that the majority of neurologists surveyed use adrenocorticotrophic hormone (ACTH) as the first-line treatment of infantile spasms not caused by tuberous sclerosis complex and vigabatrin as the first-line treatment of infantile spasms caused by tuberous sclerosis complex.13 The 2004 American Academy of Neurology and Child Neurology Society practice parameter on the medical treatment of infantile spasms and the 2012 update of this evidence-based guideline concluded that ACTH or vigabatrin may be useful for the short-term treatment of infantile spasms, with ACTH being more effective than vigabatrin excluding patients with tuberous sclerosis complex.8,12 Vigabatrin is an irreversible, enzyme-activated, selective inhibitor of gamma aminobutyric acid transaminase. By inhibiting gamma aminobutyric acid transaminase catabolism, there is increased availability of gamma aminobutyric acid within the synaptic cleft, increasing the effect of inhibitory interneurons.17 Another mechanism of action may be via the mammalian target of rapamycin (mTOR) pathway, a key signaling pathway that is dysregulated in tuberous sclerosis complex. Animal studies have shown that vigabatrin partially inhibited mTOR pathway activity and glial proliferation in the tuberous sclerosis complex 1 knock-out mice In Vitro as well as reduced mTOR pathway activation in cultured astrocytes from both knock-out and control mice. This may account for the unique efficacy of vigabatrin in tuberous sclerosis complex.18 At our institution, vigabatrin is the preferred first-line treatment for all patients with newly diagnosed infantile spasms because of its relative ease of use and better shortterm side effect profile compared with ACTH. However, concerns regarding the retinal toxicity of vigabatrin require patients to have regular monitoring with electroretinographs, which, in this population, is performed under sedation.19-21 Also, vigabatrin -related magnetic resonance imaging changes are seen in 22%-32% of children treated for infantile spasms, and although these changes are mostly asymptomatic and typically resolve even when vigabatrin is continued, there is concern that the changes reflect a medication-related neurotoxicity.19,22,23 For patients who do not have a complete resolution of clinical spasms and electrographic hypsarrhythmia when treated with vigabatrin for 2 weeks, we prescribe a 6-week course of synthetic ACTH (Synacthen) intramuscularly on alternate days as a second-line agent. This rigorous protocol of using vigabatrin as the first-line drug for the first 2 weeks, followed by high-dose ACTH in those children who fail to have both a clinical resolution of spasms and an EEG resolution of hypsarrhythmia leads to seizure control in 96% of patients.24 For those children who responded to vigabatrin, a 6-month course of the drug was administered. This time was chosen because of our experience indicating that the incidence of retinal toxicity starts to increase after 6 months of vigabatrin therapy.21
Objective
This study aimed to retrospectively review the Hospital for Sick Children’s experience of the first-line, short-term effectiveness of vigabatrin in the treatment of infantile spasms, not related to tuberous sclerosis complex. This was measured by clinical and EEG response at 14 days. Our hypothesis was that vigabatrin is effective as first-line, shortterm treatment of infantile spasms. The study also aimed to identify potential predictors of the response to treatment. Methods We performed a single-center, retrospective, health record analysis of all patients with newly diagnosed infantile spasms at the Hospital for Sick Children between January 2010 and September 2013. All patients used the treatment regimen as per the Hospital for Sick Children’s infantile spasms treatment guidelines. The vigabatrin regimen used in this study is summarized in Table 1. All patients were followed for at least 6 months from diagnosis and treatment initiation. Seven patients in this study were previously included in a retrospective case series of children who failed to respond to vigabatrin and were subsequently treated with either ACTH or prednisolone.25 This study was approved by the Hospital for Sick Children’s Research Ethics Board (REB Application Number: 1000042004).
Inclusion criteria The inclusion criteria used for the study were as follows: a diagnosis of clinical epileptic spasms and an initial EEG demonstrating features of hypsarrhythmia or modified hypsarrhythmia in children between the ages of 2 and 24 months.
Exclusion criteria The exclusion criteria included the following: children without an initial EEG demonstrating features of hypsarrhythmia or modified hypsarrhythmia; children with tuberous sclerosis complex; children previously treated with vigabatrin or hormonal treatments within 28 days; and no follow-up visit or no follow-up EEG and enrolment in a concurrent treatment trial that might affect the outcome. The rationale for the age range and previous treatment exclusions was to limit the effect of confounding variables including outlying age and previous treatment with vigabatrin or hormonal therapy on the results of the study.
Outcome measures The primary outcome of the study was: response rate, defined as the complete cessation of infantile spasms for at least 48 hours based on parental report within 2 weeks of treatment initiation and resolution of hypsarrhythmia or modified hypsarrhythmia pattern on follow-up 1-hour video EEG with sleep, with extra electromyelograph channels on the bilateral deltoid muscles to look for subtle spasms performed between 2 and 4 weeks after starting vigabatrin. Resolution of
TABLE 1. Vigabatrin Regimen
Day 1 Day 2 Day 3 Day 4 Day 5 Continued for 6 months
50 mg/kg/day 75 mg/kg/day 100 mg/kg/day 125 mg/kg/day 150 mg/kg/day 150 mg/kg/day
The vigabatrin dose was titrated to the maximum dose over 5 days. For those patients who responded to vigabatrin, the course was continued at this dose for 6 months.
K. Jones et al. / Pediatric Neurology 53 (2015) 141e145 hypsarrhythmia or modified hypsarrhythmia patterns was defined as the disappearance of the characteristic features of hypsarrhythmia or modified hypsarrhythmia and did not include complete normalization of the background EEG. The secondary outcome measures included: clinical relapse, which was defined as any spasm reoccurrence after 2 weeks and before the final clinical assessment in an infant who previously had cessation of spasms; EEG relapse defined as a recurrence of hypsarrhythmia or modified hypsarrhythmia pattern after one previous EEG showed resolution of hypsarrhythmia; and resolution of all clinical seizure types at final follow-up. The following variables were included in the analysis: sex; age at diagnosis of infantile spasms; treatment lag time; etiology of infantile spasms; development at diagnosis of infantile spasms; birth history; family history of epilepsy or developmental delay; seizures before infantile spasms; adverse effects of vigabatrin; relapse of infantile spasms; and resolution of all seizure types at final follow-up. Development at diagnosis of infantile spasms was assessed clinically by the neurologist and was based on the child’s history and examination. A standardized developmental scale was not used. The investigations reviewed included: neuroimagingdmagnetic resonance imaging or computed tomography; blooddcomplete blood count and differential, Na, K, Cl, HCO3, pH, lactate, NH4, blood urea nitrogen, creatinine, glucose, creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, Ca, Mg, PO4, serum amino acid screen, cytomegalovirus and toxoplasmosis serology, and/or polymerase chain reaction studies; urinedamino acid screen, organic acid screen, cytomegalovirus culture or polymerase chain reaction; and genetic test resultsdchromosomal microarray and or epilepsy encephalopathy panel or infantile spasms panel. The patients were followed at the Hospital for Sick Children. The frequency of follow-up was variable and at the discretion of the attending neurologist. The patients were followed for a mean of 16.75 months after the diagnosis of infantile spasms with a standard deviation of 9.7 months. There was no statistically significant difference between the duration of follow-up of the vigabatrin responder and nonresponder cohorts. The first follow-up EEG was performed within 28 days of treatment initiation with vigabatrin. The EEGs that followed were performed at a mean interval of 3 months, with a median of 2 months and range of up to 20 months.
Statistical analysis Categorical and continuous variables were assessed using the chi square test and Student t test, respectively. The data was analyzed using a logistic regression model with SAS.
Results
Eighty-three children who presented with infantile spasms between January 2010 and September 2013 were evaluated for enrolment. Of the 83, 61 met the inclusion criteria. The study outline is depicted in Figure. Only 18 of the 61 infants (30%) had a clinical and electrographic response to vigabatrin therapy within 4 weeks of treatment. Of the vigabatrin responders, 2/18 (11%) relapsed. At final follow-up after initiation of vigabatrin therapy at a mean of 15 months with a standard deviation of 6.6 months, 17/61 (27%) of the patients were free of all clinical seizure types. Forty-three children (70%) failed to respond to vigabatrin clinically and electrographically. Of the vigabatrin nonresponders, 38/43 received second-line hormonal therapy, of which 28/38 were treated with ACTH and 10/38 were treated with prednisolone. Of these patients, 18/28 (43%) responded to ACTH, whereas only 1/10 (10%) responded to
143
FIGURE. The study profile outlines the numbers of children with infantile spasms assessed, excluded or included from the study and the numbers of children who responded or failed vigabatrin. EEG ¼ electroencephalograph; MRI ¼ magnetic resonance imaging.
prednisolone. The five patients who failed vigabatrin and did not receive hormonal therapy were offered other antiepileptic medications or nonhormonal treatment. Of these, 7/38 (18%) relapsed after initially responding to second-line hormonal therapy with adrenocorticotropic hormone or prednisolone. Twenty-five of 61 (41%) were free of all seizure types at final follow-up after initiation of vigabatrin treatment. The cohort of vigabatrin responders and vigabatrin failures were evaluated for predictors of outcome. The results are tabulated in Table 2. There were 23/61 (38%) children with normal development at the time of diagnosis and 13/ 18 (72%) children who responded to vigabatrin, with normal development at diagnosis, compared with 10/43 (23%) vigabatrin failures with normal development at diagnosis. Normal development at the time of diagnosis of infantile spasms was statistically significantly associated with vigabatrin response (P ¼ 0.001). An abnormal birth history including prematurity, hypoxic ischemic encephalopathy, structural brain abnormalities, hypotonia, antenatal drug exposure, recurrent apneas, congenital abnormalities, or dysmorphic features was statistically significantly associated with vigabatrin failure (P ¼ 0.008). There was no significant difference in response to vigabatrin when sex, age at diagnosis, treatment lag time, etiology, family history of epilepsy, or developmental delay and seizures before the onset of infantile spasms, were evaluated. Adverse events associated with vigabatrin, included dyskinesia in 3/61 (5%) children, magnetic resonance imaging changes in 10/61 (16%) children, and electroretinograph changes in 1/61 children (2%). Discussion
Effective, early medical treatment of infantile spasms reduces the number of spasms and the duration of epileptic encephalopathy. It is an important predictor of developmental and long-term seizure outcome.26 The efficacy of vigabatrin as a first-line treatment of infantile spasms or West syndrome in non-tuberous sclerosis complex patients varies from study to study, ranging from 9% to 53%24,27-29 This variability may be due to individual differences in
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TABLE 2. Comparison of the Vigabatrin Responders and Nonresponders
Variable Sex, N (%) Female Male Age at diagnosis (months); mean (SD) Treatment lag time (months); mean (SD) Etiology, N (%) Structural Metabolic Genetic Immune Unknown Normal development at diagnosis, N (%) Complication in birth history Family history of epilepsy, developmental delay Seizures before IS VGB adverse effects, N (%) MD MRI ERG Relapse, N (%) Follow-up (months), Mean (SD) Seizure resolution at end of follow-up
Entire Cohort (N ¼ 61)
VBG Responders (N ¼ 18, 30%)
VGB Nonresponders (N ¼ 43, 70%)
26 35 7.3 1.3
(43%) (57%) (3.4) (1.9)
6 12 7.75 1
(33%) (67%) (3.69) (1.1)
20 23 7 1.5
(47%) (53%) (3.27) (2.2)
25 3 15 0 21 23 26 18
(41%) (5%) (25%) (0%) (34%) (38%) (43%) (30%)
4 0 5 0 9 13 3 7
(22%) (0%) (28%) (0%) (50%) (72%) (17%) (39%)
21 3 10 0 12 10 23 11
(49%) (7%) (23%) (0%) (28%) (23%) (53%) (25%)
19 (31%) 3 10 1 10 16.75 42
(5%) (16%) (2%) (16%) (9.7) (69%)
5 (28%) 1 1 1 2 15 17
(6%) (6%) (6%) (11%) (6.6) (28%)
14 (32%) 2 9 0 8 17.25 25
(5%) (21%) (0%) (19%) (9.9) (41%)
P-value
0.34 0.46 0.40 0.054 0.7 0.1 0.001 0.008 0.29 0.71 0.13
0.47 0.38 0.12
The P values in bold represent the statistically significant values. Abbreviations: IS ¼ Infantile spasms ERG ¼ Electroretinograph MD ¼ Movement disorders MRI ¼ Magnetic resonance imaging SD ¼ Standard deviation VGB ¼ Vigabatrin
case definitions and methodology. The efficacy of vigabatrin leading to the clinical cessation of infantile spasms in non-tuberous sclerosis complex patients was 36/55 (48%) in the combined studies by Vigevano and Lux.28,29 However, in the study by Lux, all patients did not have a follow-up EEG, and the electrographical resolution rate was 20/36 (55%).28 The study by Eltermann et al. reported the lowest efficacy of vigabatrin leading to cessation of spasms in non-tuberous sclerosis complex patients at 17/183 (9%).27 There was no statistically significant difference in the primary end point response rates for etiology in this study, although the highest observed response rate occurred in infants with tuberous sclerosis complex. The response rate in the high-dose, tuberous sclerosis symptomatic group was 25%, whereas the response rates in the high-dose symptomatic other group was 13.3% and the high-dose cryptogenic group was 14.8%.27 Bitton et al. measured vigabatrin efficacy by both clinical resolution of infantile spasms and electrographic resolution of hypsarrhythmia in all patients within 2 weeks and reported an electroclinical response to vigabatrin in 43/68 (63%) children.24 Their definition of resolution was similar to that used in our study, however their study included five patients with tuberous sclerosis complex. When these patients were excluded, the vigabatrin response rate was reduced to 52%. The efficacy in our study was lower, with complete response recorded in only 18/61 (30%) infants. This may be due to differences in the number of cases of symptomatic versus cryptogenic etiologies between the studies. The response rate in this study is likely less than the
37/57 (65%) previously reported in our retrospective case series of children who failed to respond to vigabatrin and were subsequently treated with either adrenocorticotrophic hormone or prednisolone, since tuberous sclerosis complex was not considered as an exclusion criteria in that study.25 We found a statistically significant association between normal neurodevelopment at the time of diagnosis of infantile spasms and resolution of spasms in response to vigabatrin therapy. Developmental delay at initial diagnosis of infantile spasms and a complicated birth history were associated with vigabatrin failure. These findings emphasize the importance of identifying biomarkers of medication efficacy, which would enable clinicians to choose the most appropriate first-line medication for each patient. This may expedite treatment response, minimize the duration of epileptic encephalopathy, and improve the long-term developmental outcome of children with infantile spasms. This uncontrolled, nonrandomized, retrospective singlecenter study is limited by the relatively small sample size, absence of an independent, objective EEG reviewer, and the use of a standardized developmental outcome scale e.g., the Vineland Adaptive Behavior Scale 2nd edition.30 Conclusions
This retrospective case series of children with infantile spasms not related to tuberous sclerosis complex reported a clinical and electrographical response to vigabatrin in only
K. Jones et al. / Pediatric Neurology 53 (2015) 141e145
18/61 (30%) of patients within 4 weeks of treatment. However, vigabatrin is most likely to be effective in the firstline treatment of infantile spasms, not related to tuberous sclerosis complex in children with normal development at the time of diagnosis. The variability in vigabatrin efficacy in the first-line treatment of infantile spasms not related to tuberous sclerosis complex may be due to differences in case definitions, methodology, and etiology between studies. These findings do not support our hypothesis that vigabatrin is effective as first-line, short-term treatment of infantile spasms in nontuberous sclerosis complex patients. The results of this study may assist clinicians in the optimal treatment choice for children at the first presentation of infantile spasms not related to tuberous sclerosis complex.
12.
13.
14. 15. 16. 17. 18.
This study was performed at the Hospital for Sick Children, University of Toronto and presented as a poster at the American Epilepsy Society Annual Meeting in 2014. We would like to thank the clinicians who cared for the patients and their families. Author contributions: KJ collected the data and wrote the first draft of the manuscript. All authors reviewed the data and manuscript and were involved in editing the final article. Conflicts of Interest: The authors declared no potential conflicts of interest with regards to the publication of this article. Funding: The authors received no financial support for the research or publication of this article.
19.
20.
21.
22.
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consensus statement of the West Delphi group. Epilepsia. 2004;45: 1416-1428. Mackay MT, Weiss SK, Adams-Webber T, et al. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology. 2004;62:1668-1681. Mytinger JR, Quigg M, Taft WC, Buck ML, Rust RS. Outcomes in treatment of infantile spasms with pulse methylprednisolone. J Child Neurol. 2010;25:948-953. Pellock JM, Hrachovy R, Shinnar S, et al. Infantile spasms: a U.S. consensus report. Epilepsia. 2010;51:2175-2189. Riikonen R. Recent advances in the pharmacotherapy of infantile spasms. CNS Drugs. 2014;28:279-290. Wang CJ, Jonas R, Fu CM, Ng CY, Douglass L. Quality-of-care indicators for infantile spasms. J Child Neurol. 2013;28:13-20. Ben-Menachem E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol Scand Suppl. 2011;124(192):5-15. Zhang B, McDaniel SS, Rensing NR, Wong M. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLoS One. 2013;8:e57445. Vanhatalo S, Nousiainen I, Eriksson K, et al. Visual field constriction in 91 Finnish children treated with vigabatrin. Epilepsia. 2002;43: 748-756. Westall CA, Nobile R, Morong S, Buncic JR, Logan WJ, Panton CM. Changes in the electroretinogram resulting from discontinuation of vigabatrin in children. Doc Ophthalmol. 2003; 107:299-309. Westall CA, Wright T, Cortese F, Kumarappah A, Snead 3rd OC, Buncic JR. Vigabatrin retinal toxicity in children with infantile spasms: An observational cohort study. Neurology. 2014;83: 2262-2268. Simao GN, Zarei Mahmoodabadi S, Snead OC, Go C, Widjaja E. Abnormal axial diffusivity in the deep gray nuclei and dorsal brain stem in infantile spasm treated with vigabatrin. AJNR Am J Neuroradiol. 2011;32:199-203. Wheless JW, Carmant L, Bebin M, et al. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia. 2009;50:195-205. Bitton JY, Sauerwein HC, Weiss SK, et al. A randomized controlled trial of flunarizine as add-on therapy and effect on cognitive outcome in children with infantile spasms. Epilepsia. 2012;53: 1570-1576. Jones K, Snead 3rd OC, Boyd J, Go C. Adrenocorticotropic hormone versus prednisolone in the treatment of infantile spasms post vigabatrin failure. J Child Neurol. 2015;30:595-600. O’Callaghan FJ, Lux AL, Darke K, et al. 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. 2011;52:1359-1364. Elterman RD, Shields WD, Bittman RM, Torri SA, Sagar SM, Collins SD. Vigabatrin for the treatment of infantile spasms: final report of a randomized trial. J Child Neurol. 2010;25: 1340-1347. Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. 2004;364:1773-1778. Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia. 1997;38:1270-1274. Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial. Lancet Neurol. 2005;4: 712-717.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Vigabatrin as First-Line Treatment for Infantile Spasms Not Related to Tuberous Sclerosis Complex Kevin Jones MD, FRCPC a, *, Cristina Go MD, ABPN b, Jennifer Boyd RN, MHSc, CNN(C), MSCN b, Ayako Ochi PhD b, Blathnaid McCoy MBBCh, MRCPI b, Klajdi Puka HBSc c, O. Carter Snead III MD, FRCPC b a
The Division of Neurology, Department of Pediatrics, McMaster Children’s Hospital, Hamilton, Ontario, Canada The Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada c The Division of Psychology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada b
abstract BACKGROUND: Infantile spasms are a rare, catastrophic, age-specific seizure disorder of infancy. Adrenocorticotropic hormone or vigabatrin have been recommended for the short-term treatment of infantile spasms by the Child Neurology Society/American Academy of Neurology practice parameter. OBJECTIVE: This retrospective study reviewed the Hospital for Sick Children’s experience with the short-term efficacy of vigabatrin as first-line treatment for infantile spasms not related to tuberous sclerosis complex. METHOD: We performed a single-center, retrospective analysis of all cases of newly diagnosed infantile spasms between January 2010 and September 2013. Duration of follow-up was at least 6 months from treatment initiation. RESULTS: Eighteen of the 61 infants (30%) had a clinical and electrographic response to vigabatrin therapy within 4 weeks of treatment. Of the vigabatrin responders, 2/18 (11%) relapsed. At final follow-up after initiation of vigabatrin therapy, 17/61 (27%) of the vigabatrin responders were free of all clinical seizure types. Normal development at the time of infantile spasms diagnosis was statistically associated with vigabatrin response. CONCLUSION: These findings do not support our hypothesis that vigabatrin is effective as first-line, short-term treatment of infantile spasms in non-tuberous sclerosis complex patients. However, when used in this setting, vigabatrin is most effective in children with normal development at the time of diagnosis. These findings may assist clinicians in the optimal treatment choice for children at the first presentation of infantile spasms not related to tuberous sclerosis complex. Keywords: epileptic encephalopathy, infantile spasms, vigabatrin, nontuberous sclerosis complex, efficacy, predictors
Pediatr Neurol 2015; 53: 141-145 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Infantile spasms are a rare, catastrophic age-specific, seizure disorder characterized clinically by epileptic spasms, often accompanied by developmental regression
Article History: Received January 25, 2015; Accepted in final form April 25, 2015 * Communications should be addressed to: Dr. Jones; The Division of Neurology; Department of Pediatrics; McMaster Children’s Hospital; 3A Health Sciences Centre; 1280 Main Street West; Hamilton, ON L8S 4K1. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.04.012
and a characteristic interictal electroencephalography (EEG) pattern called hypsarrhythmia.1 When all three of these features are present, the term “West syndrome” is used.1 The initial age of onset in 90% of cases is before 12 months of life, with peak onset at 6 months. The incidence is 2-3 per 10,000 live births with a lifetime prevalence of 1.5-2 per 10,000 children. It is slightly more common in males, and a family history exists in 3%-6% of cases.2-4 The etiology of infantile spasms can be categorized as structural, metabolic, or genetic.5 In up to 40% of patients, no cause can be determined and these are defined as
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unknown.6 The spontaneous remission rate of infantile spasms in limited natural history studies is 25% at 12 months after the onset of infantile spasms7 The considerable variation in the management of infantile spasms, has led to the publication of treatment surveys, consensus statements, practice parameters, and reviews of the subject.8-16 A survey on the evaluation and treatment of infantile spasms among members of the Child Neurology Society reported that the majority of neurologists surveyed use adrenocorticotrophic hormone (ACTH) as the first-line treatment of infantile spasms not caused by tuberous sclerosis complex and vigabatrin as the first-line treatment of infantile spasms caused by tuberous sclerosis complex.13 The 2004 American Academy of Neurology and Child Neurology Society practice parameter on the medical treatment of infantile spasms and the 2012 update of this evidence-based guideline concluded that ACTH or vigabatrin may be useful for the short-term treatment of infantile spasms, with ACTH being more effective than vigabatrin excluding patients with tuberous sclerosis complex.8,12 Vigabatrin is an irreversible, enzyme-activated, selective inhibitor of gamma aminobutyric acid transaminase. By inhibiting gamma aminobutyric acid transaminase catabolism, there is increased availability of gamma aminobutyric acid within the synaptic cleft, increasing the effect of inhibitory interneurons.17 Another mechanism of action may be via the mammalian target of rapamycin (mTOR) pathway, a key signaling pathway that is dysregulated in tuberous sclerosis complex. Animal studies have shown that vigabatrin partially inhibited mTOR pathway activity and glial proliferation in the tuberous sclerosis complex 1 knock-out mice In Vitro as well as reduced mTOR pathway activation in cultured astrocytes from both knock-out and control mice. This may account for the unique efficacy of vigabatrin in tuberous sclerosis complex.18 At our institution, vigabatrin is the preferred first-line treatment for all patients with newly diagnosed infantile spasms because of its relative ease of use and better shortterm side effect profile compared with ACTH. However, concerns regarding the retinal toxicity of vigabatrin require patients to have regular monitoring with electroretinographs, which, in this population, is performed under sedation.19-21 Also, vigabatrin -related magnetic resonance imaging changes are seen in 22%-32% of children treated for infantile spasms, and although these changes are mostly asymptomatic and typically resolve even when vigabatrin is continued, there is concern that the changes reflect a medication-related neurotoxicity.19,22,23 For patients who do not have a complete resolution of clinical spasms and electrographic hypsarrhythmia when treated with vigabatrin for 2 weeks, we prescribe a 6-week course of synthetic ACTH (Synacthen) intramuscularly on alternate days as a second-line agent. This rigorous protocol of using vigabatrin as the first-line drug for the first 2 weeks, followed by high-dose ACTH in those children who fail to have both a clinical resolution of spasms and an EEG resolution of hypsarrhythmia leads to seizure control in 96% of patients.24 For those children who responded to vigabatrin, a 6-month course of the drug was administered. This time was chosen because of our experience indicating that the incidence of retinal toxicity starts to increase after 6 months of vigabatrin therapy.21
Objective
This study aimed to retrospectively review the Hospital for Sick Children’s experience of the first-line, short-term effectiveness of vigabatrin in the treatment of infantile spasms, not related to tuberous sclerosis complex. This was measured by clinical and EEG response at 14 days. Our hypothesis was that vigabatrin is effective as first-line, shortterm treatment of infantile spasms. The study also aimed to identify potential predictors of the response to treatment. Methods We performed a single-center, retrospective, health record analysis of all patients with newly diagnosed infantile spasms at the Hospital for Sick Children between January 2010 and September 2013. All patients used the treatment regimen as per the Hospital for Sick Children’s infantile spasms treatment guidelines. The vigabatrin regimen used in this study is summarized in Table 1. All patients were followed for at least 6 months from diagnosis and treatment initiation. Seven patients in this study were previously included in a retrospective case series of children who failed to respond to vigabatrin and were subsequently treated with either ACTH or prednisolone.25 This study was approved by the Hospital for Sick Children’s Research Ethics Board (REB Application Number: 1000042004).
Inclusion criteria The inclusion criteria used for the study were as follows: a diagnosis of clinical epileptic spasms and an initial EEG demonstrating features of hypsarrhythmia or modified hypsarrhythmia in children between the ages of 2 and 24 months.
Exclusion criteria The exclusion criteria included the following: children without an initial EEG demonstrating features of hypsarrhythmia or modified hypsarrhythmia; children with tuberous sclerosis complex; children previously treated with vigabatrin or hormonal treatments within 28 days; and no follow-up visit or no follow-up EEG and enrolment in a concurrent treatment trial that might affect the outcome. The rationale for the age range and previous treatment exclusions was to limit the effect of confounding variables including outlying age and previous treatment with vigabatrin or hormonal therapy on the results of the study.
Outcome measures The primary outcome of the study was: response rate, defined as the complete cessation of infantile spasms for at least 48 hours based on parental report within 2 weeks of treatment initiation and resolution of hypsarrhythmia or modified hypsarrhythmia pattern on follow-up 1-hour video EEG with sleep, with extra electromyelograph channels on the bilateral deltoid muscles to look for subtle spasms performed between 2 and 4 weeks after starting vigabatrin. Resolution of
TABLE 1. Vigabatrin Regimen
Day 1 Day 2 Day 3 Day 4 Day 5 Continued for 6 months
50 mg/kg/day 75 mg/kg/day 100 mg/kg/day 125 mg/kg/day 150 mg/kg/day 150 mg/kg/day
The vigabatrin dose was titrated to the maximum dose over 5 days. For those patients who responded to vigabatrin, the course was continued at this dose for 6 months.
K. Jones et al. / Pediatric Neurology 53 (2015) 141e145 hypsarrhythmia or modified hypsarrhythmia patterns was defined as the disappearance of the characteristic features of hypsarrhythmia or modified hypsarrhythmia and did not include complete normalization of the background EEG. The secondary outcome measures included: clinical relapse, which was defined as any spasm reoccurrence after 2 weeks and before the final clinical assessment in an infant who previously had cessation of spasms; EEG relapse defined as a recurrence of hypsarrhythmia or modified hypsarrhythmia pattern after one previous EEG showed resolution of hypsarrhythmia; and resolution of all clinical seizure types at final follow-up. The following variables were included in the analysis: sex; age at diagnosis of infantile spasms; treatment lag time; etiology of infantile spasms; development at diagnosis of infantile spasms; birth history; family history of epilepsy or developmental delay; seizures before infantile spasms; adverse effects of vigabatrin; relapse of infantile spasms; and resolution of all seizure types at final follow-up. Development at diagnosis of infantile spasms was assessed clinically by the neurologist and was based on the child’s history and examination. A standardized developmental scale was not used. The investigations reviewed included: neuroimagingdmagnetic resonance imaging or computed tomography; blooddcomplete blood count and differential, Na, K, Cl, HCO3, pH, lactate, NH4, blood urea nitrogen, creatinine, glucose, creatine phosphokinase, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, Ca, Mg, PO4, serum amino acid screen, cytomegalovirus and toxoplasmosis serology, and/or polymerase chain reaction studies; urinedamino acid screen, organic acid screen, cytomegalovirus culture or polymerase chain reaction; and genetic test resultsdchromosomal microarray and or epilepsy encephalopathy panel or infantile spasms panel. The patients were followed at the Hospital for Sick Children. The frequency of follow-up was variable and at the discretion of the attending neurologist. The patients were followed for a mean of 16.75 months after the diagnosis of infantile spasms with a standard deviation of 9.7 months. There was no statistically significant difference between the duration of follow-up of the vigabatrin responder and nonresponder cohorts. The first follow-up EEG was performed within 28 days of treatment initiation with vigabatrin. The EEGs that followed were performed at a mean interval of 3 months, with a median of 2 months and range of up to 20 months.
Statistical analysis Categorical and continuous variables were assessed using the chi square test and Student t test, respectively. The data was analyzed using a logistic regression model with SAS.
Results
Eighty-three children who presented with infantile spasms between January 2010 and September 2013 were evaluated for enrolment. Of the 83, 61 met the inclusion criteria. The study outline is depicted in Figure. Only 18 of the 61 infants (30%) had a clinical and electrographic response to vigabatrin therapy within 4 weeks of treatment. Of the vigabatrin responders, 2/18 (11%) relapsed. At final follow-up after initiation of vigabatrin therapy at a mean of 15 months with a standard deviation of 6.6 months, 17/61 (27%) of the patients were free of all clinical seizure types. Forty-three children (70%) failed to respond to vigabatrin clinically and electrographically. Of the vigabatrin nonresponders, 38/43 received second-line hormonal therapy, of which 28/38 were treated with ACTH and 10/38 were treated with prednisolone. Of these patients, 18/28 (43%) responded to ACTH, whereas only 1/10 (10%) responded to
143
FIGURE. The study profile outlines the numbers of children with infantile spasms assessed, excluded or included from the study and the numbers of children who responded or failed vigabatrin. EEG ¼ electroencephalograph; MRI ¼ magnetic resonance imaging.
prednisolone. The five patients who failed vigabatrin and did not receive hormonal therapy were offered other antiepileptic medications or nonhormonal treatment. Of these, 7/38 (18%) relapsed after initially responding to second-line hormonal therapy with adrenocorticotropic hormone or prednisolone. Twenty-five of 61 (41%) were free of all seizure types at final follow-up after initiation of vigabatrin treatment. The cohort of vigabatrin responders and vigabatrin failures were evaluated for predictors of outcome. The results are tabulated in Table 2. There were 23/61 (38%) children with normal development at the time of diagnosis and 13/ 18 (72%) children who responded to vigabatrin, with normal development at diagnosis, compared with 10/43 (23%) vigabatrin failures with normal development at diagnosis. Normal development at the time of diagnosis of infantile spasms was statistically significantly associated with vigabatrin response (P ¼ 0.001). An abnormal birth history including prematurity, hypoxic ischemic encephalopathy, structural brain abnormalities, hypotonia, antenatal drug exposure, recurrent apneas, congenital abnormalities, or dysmorphic features was statistically significantly associated with vigabatrin failure (P ¼ 0.008). There was no significant difference in response to vigabatrin when sex, age at diagnosis, treatment lag time, etiology, family history of epilepsy, or developmental delay and seizures before the onset of infantile spasms, were evaluated. Adverse events associated with vigabatrin, included dyskinesia in 3/61 (5%) children, magnetic resonance imaging changes in 10/61 (16%) children, and electroretinograph changes in 1/61 children (2%). Discussion
Effective, early medical treatment of infantile spasms reduces the number of spasms and the duration of epileptic encephalopathy. It is an important predictor of developmental and long-term seizure outcome.26 The efficacy of vigabatrin as a first-line treatment of infantile spasms or West syndrome in non-tuberous sclerosis complex patients varies from study to study, ranging from 9% to 53%24,27-29 This variability may be due to individual differences in
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TABLE 2. Comparison of the Vigabatrin Responders and Nonresponders
Variable Sex, N (%) Female Male Age at diagnosis (months); mean (SD) Treatment lag time (months); mean (SD) Etiology, N (%) Structural Metabolic Genetic Immune Unknown Normal development at diagnosis, N (%) Complication in birth history Family history of epilepsy, developmental delay Seizures before IS VGB adverse effects, N (%) MD MRI ERG Relapse, N (%) Follow-up (months), Mean (SD) Seizure resolution at end of follow-up
Entire Cohort (N ¼ 61)
VBG Responders (N ¼ 18, 30%)
VGB Nonresponders (N ¼ 43, 70%)
26 35 7.3 1.3
(43%) (57%) (3.4) (1.9)
6 12 7.75 1
(33%) (67%) (3.69) (1.1)
20 23 7 1.5
(47%) (53%) (3.27) (2.2)
25 3 15 0 21 23 26 18
(41%) (5%) (25%) (0%) (34%) (38%) (43%) (30%)
4 0 5 0 9 13 3 7
(22%) (0%) (28%) (0%) (50%) (72%) (17%) (39%)
21 3 10 0 12 10 23 11
(49%) (7%) (23%) (0%) (28%) (23%) (53%) (25%)
19 (31%) 3 10 1 10 16.75 42
(5%) (16%) (2%) (16%) (9.7) (69%)
5 (28%) 1 1 1 2 15 17
(6%) (6%) (6%) (11%) (6.6) (28%)
14 (32%) 2 9 0 8 17.25 25
(5%) (21%) (0%) (19%) (9.9) (41%)
P-value
0.34 0.46 0.40 0.054 0.7 0.1 0.001 0.008 0.29 0.71 0.13
0.47 0.38 0.12
The P values in bold represent the statistically significant values. Abbreviations: IS ¼ Infantile spasms ERG ¼ Electroretinograph MD ¼ Movement disorders MRI ¼ Magnetic resonance imaging SD ¼ Standard deviation VGB ¼ Vigabatrin
case definitions and methodology. The efficacy of vigabatrin leading to the clinical cessation of infantile spasms in non-tuberous sclerosis complex patients was 36/55 (48%) in the combined studies by Vigevano and Lux.28,29 However, in the study by Lux, all patients did not have a follow-up EEG, and the electrographical resolution rate was 20/36 (55%).28 The study by Eltermann et al. reported the lowest efficacy of vigabatrin leading to cessation of spasms in non-tuberous sclerosis complex patients at 17/183 (9%).27 There was no statistically significant difference in the primary end point response rates for etiology in this study, although the highest observed response rate occurred in infants with tuberous sclerosis complex. The response rate in the high-dose, tuberous sclerosis symptomatic group was 25%, whereas the response rates in the high-dose symptomatic other group was 13.3% and the high-dose cryptogenic group was 14.8%.27 Bitton et al. measured vigabatrin efficacy by both clinical resolution of infantile spasms and electrographic resolution of hypsarrhythmia in all patients within 2 weeks and reported an electroclinical response to vigabatrin in 43/68 (63%) children.24 Their definition of resolution was similar to that used in our study, however their study included five patients with tuberous sclerosis complex. When these patients were excluded, the vigabatrin response rate was reduced to 52%. The efficacy in our study was lower, with complete response recorded in only 18/61 (30%) infants. This may be due to differences in the number of cases of symptomatic versus cryptogenic etiologies between the studies. The response rate in this study is likely less than the
37/57 (65%) previously reported in our retrospective case series of children who failed to respond to vigabatrin and were subsequently treated with either adrenocorticotrophic hormone or prednisolone, since tuberous sclerosis complex was not considered as an exclusion criteria in that study.25 We found a statistically significant association between normal neurodevelopment at the time of diagnosis of infantile spasms and resolution of spasms in response to vigabatrin therapy. Developmental delay at initial diagnosis of infantile spasms and a complicated birth history were associated with vigabatrin failure. These findings emphasize the importance of identifying biomarkers of medication efficacy, which would enable clinicians to choose the most appropriate first-line medication for each patient. This may expedite treatment response, minimize the duration of epileptic encephalopathy, and improve the long-term developmental outcome of children with infantile spasms. This uncontrolled, nonrandomized, retrospective singlecenter study is limited by the relatively small sample size, absence of an independent, objective EEG reviewer, and the use of a standardized developmental outcome scale e.g., the Vineland Adaptive Behavior Scale 2nd edition.30 Conclusions
This retrospective case series of children with infantile spasms not related to tuberous sclerosis complex reported a clinical and electrographical response to vigabatrin in only
K. Jones et al. / Pediatric Neurology 53 (2015) 141e145
18/61 (30%) of patients within 4 weeks of treatment. However, vigabatrin is most likely to be effective in the firstline treatment of infantile spasms, not related to tuberous sclerosis complex in children with normal development at the time of diagnosis. The variability in vigabatrin efficacy in the first-line treatment of infantile spasms not related to tuberous sclerosis complex may be due to differences in case definitions, methodology, and etiology between studies. These findings do not support our hypothesis that vigabatrin is effective as first-line, short-term treatment of infantile spasms in nontuberous sclerosis complex patients. The results of this study may assist clinicians in the optimal treatment choice for children at the first presentation of infantile spasms not related to tuberous sclerosis complex.
12.
13.
14. 15. 16. 17. 18.
This study was performed at the Hospital for Sick Children, University of Toronto and presented as a poster at the American Epilepsy Society Annual Meeting in 2014. We would like to thank the clinicians who cared for the patients and their families. Author contributions: KJ collected the data and wrote the first draft of the manuscript. All authors reviewed the data and manuscript and were involved in editing the final article. Conflicts of Interest: The authors declared no potential conflicts of interest with regards to the publication of this article. Funding: The authors received no financial support for the research or publication of this article.
19.
20.
21.
22.
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