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Practice Experience in the Treatment of Infantile Spasms at a Tertiary Care Center
Pediatric Neurology xxx (2014) 1e5
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Practice Experience in the Treatment of Infantile Spasms at a Tertiary Care Center Drew Thodeson MD a, *, Yoshimi Sogawa MD a, b a b
Division of Child Neurology/Epilepsy, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania Department of Neurology and Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
abstract BACKGROUND: The current treatment guidelines for treatment of infantile spasms is ambiguous regarding individuals with known etiology and is backed by limited evidence. Recently published survey data reveal diverse treatment variation for infantile spasms. We conducted a retrospective medical record review to better understand the clinical variables which affect treatment selection for new-onset infantile spasms. METHODS: We systematically extracted demographic data and treatment response of children with new onset infantile spasms over a 3-year period at a single institution. Treatment was divided into three groups: vigabatrin, hormone treatment, and other therapies. RESULTS: Our final cohort had 65 patients; 74% had a known etiology. Sixty-two percent were initially treated with vigabatrin. Other therapies were used more often in known etiology than in unknown etiology as initial treatment (40% vs 6%; P ¼ 0.002). Treatment response at 3 months was not statistically different between unknown etiology and known etiology groups (71% vs 46%; P ¼ 0.08). Overall, initial treatment choice was effective in 35% (23 of 65). Eighty-six percent (37 of 42) who failed the initial medication had subsequent medication trials within 3 months. CONCLUSIONS: Etiology was strongly associated with initial treatment choice. The variation in treatment choice at our center reflects the limited evidence derived from well-designed clinical trials. Keywords: infantile spasms, treatment, vigabatrin, ACTH, epilepsy
Pediatr Neurol 2014; -: 1-5 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Infantile spasms (IS) is a childhood epileptic encephalopathy which generally carries a poor prognosis. The American Academy of Neurology and Child Neurology Society practice guidelines regarding the best practice for short-term medical treatment of IS have concluded that adrenocorticotropic hormone (ACTH) is probably effective (level B), vigabatrin (VGB) is possibly effective (level C), and ACTH may be offered over VGB in cryptogenic patients to improve developmental outcome (level C). Evidence was insufficient to establish the efficacy of oral steroids, ketogenic diet, and other anticonvulsants (level U).1 A recent Article History: Received May 3, 2014; Accepted in final form July 13, 2014 * Communications should be addressed to: Dr. Thodeson; Division of Child Neurology; Children’s Hospital of Pittsburgh of UPMC; 45th Street and Penn Avenue; Pittsburgh, Pennsylvania 15201. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.019
survey of child neurologists in the United States revealed diverse treatment practice and found that that some physicians are choosing therapies other than ACTH or VGB in certain patient populations.2 The practice parameter mentions little about treatment of patients with known etiology. Moreover, it does not mention further treatment choices after medication failure or in case of relapse. To understand the clinical variables which affect treatment selection, we conducted a retrospective medical record review. Materials and Methods The Children’s Hospital of Pittsburgh of UPMC is the only tertiary care children’s hospital in southwestern Pennsylvania, serving a catchment area of approximately three million people. Almost all children with newly diagnosed IS are admitted to our hospital for evaluation and treatment. Our institution employs 22 board-certified child neurologists including seven who specialize in epilepsy. Until recently, there was no consensus or institutional protocol for the treatment of IS. Treatment was chosen by an individual physician when the patient was admitted.
2
D. Thodeson, Y. Sogawa / Pediatric Neurology xxx (2014) 1e5
During the study period, inpatient supervision time was divided such that each attending neurologist spent an average of 2-6 weeks on service per year. This gave a unique opportunity to evaluate physicians’ treatment choices and short-term remission rates. Children with IS were identified by the International Classification of Diseases, Ninth Revision, code for IS on discharge diagnosis from September 2009 to September 2012. Medical records were reviewed and data on demographics, medical history, neurological examinations, electroencephalography (EEG), neuroimaging, and treatment responses were extracted systematically. Patients with the clinical diagnosis of new onset IS and/or hypsarrhythmia or modified hypsarrhythmia on EEG were included. All patients had clinical seizures consistent with spasms and interictal EEG consistent with hypsarrhythmia or hypsarrhythmia variant. Individuals with clinical spasms in clusters without hypsarrhythmia on EEG were excluded. Patients born before January 1, 2008 were excluded, as they were unlikely to be new onset IS based on their age. Etiology was divided into known and unknown groups. The terms “cryptogenic,” “symptomatic,” and “idiopathic” were avoided based on revised International League Against Epilepsy classification.3 All patients with an unknown etiology had normal development before onset of spasms and negative standard work up. The known etiology group was further subdivided into six categories: (1) cortical malformation; (2) perinatal insult, defined as children with prematurity, neonatal seizures, and/or hypoxic-ischemic encephalopathy; (3) trisomy 21; (4) tuberous sclerosis complex; (5) other known etiologies associated with IS; and (6) known etiology not otherwise specified (NOS). Known etiology NOS was assigned to patients with clear developmental delay or abnormal neurological examination before the onset of IS and to patients with an abnormal etiologic evaluation not known to be associated with IS. Standard etiologic work up for IS at our institution includes magnetic resonance imaging brain, cerebrospinal fluid analysis, serum amino acid, urine organic acid, and chromosome and microarray analysis. The day that the EEG confirmed the presence of hypsarrhythmia was used as the date of diagnosis. Treatment lag was defined as the interval between the onset of spasms and the initiation of IS-specific antiepileptic medication. Treatment responder was defined as resolution of clinical spasms and resolution of hypsarrhythmia within 3 months of the initial diagnosis. Any treatment started after 3 months from the diagnosis was excluded from analysis. Treatment was divided into three groups: VGB, hormone treatment, and other therapies. VGB was titrated to goal dose of 100-150 mg/kg as tolerated. Hormone treatment group included patients treated with oral steroid and ACTH. Oral steroid used was prednisolone and doses ranged from 2 to 5 mg/kg/day for 2 weeks followed by a 4- to 6-week taper. ACTH dosing was 100-150 U/m2 for 2 weeks followed by a 4- to 6-week taper with the exception of one patient who received 50 U/m2 for 2 weeks with subsequent taper. Other therapies included all other anticonvulsants and the ketogenic diet. The preliminary results were discussed in our divisional quality assessment meeting. Descriptive analysis was performed with Stata software version 10 (StataCorp LP, College Station, TX). Student t tests were used for continuous variables, and the Pearson chi-square or Fisher exact tests were used for categorical variables. A two-sided P value of less than 0.05 was considered statistically significant. This study was approved by the Institutional Review Board of the Children’s Hospital of Pittsburgh.
Results Demographics
A total of 73 patients met inclusion criteria. Eight patients were excluded from analysis because of treatment at another facility (two) and insufficient follow-up data (six). The final cohort had 65 patients with 41 males (63%). Forty-eight patients (74%) had a known etiology (Table). The median age of onset was six months (range 0.5-20 months). All six patients (9%) with onset before 3 months had known etiology. Four of those six patients had cortical malformations. The six patients (9%) with onset after 12 months were also
TABLE. Demographics
Total number Age of onset Diagnostic lag time Known etiology
Delayed Diagnosis
65 41 males (63%) Median 6 mo (3 wk-20 mo) Median 1 mo (<1 wk-11 mo) 48 (74%) Cortical malformations Perinatal insult Trisomy 21 Tuberous sclerosis Other known etiology associated with IS: Menkes disease, ARX, KCNQ2, nonaccidental trauma, and cardiac arrest outside of neonatal period Known etiology NOS: Bilateral extra-axial CSF collections, subdural hematomas, visual impairment, genetic mutation of unknown clinical significance, and focal seizures before IS 10 (17%) Trisomy 21 Cortical malformations Perinatal insult Menkes disease Unknown
12 14 5 2 7
8
3 3 2 1 1
Abbreviations: CSF ¼ Cerebrospinal fluid IS ¼ Infantile spasms NOS ¼ Not otherwise specified
known etiology. Two patients had trisomy 21, and four patients had perinatal insult. All patients with unknown etiology presented between 4 and 8 months with the exception of one patient who presented at 3 months (Table). The median diagnostic lag time was 1 month (range, <1 week-11 months), and 85% of patients were diagnosed within 1 month of spasm onset. Nine of 10 patients with delayed diagnosis had known etiology. Initial treatment choice
The most frequently chosen initial treatment was VGB, which was used in 62% of patients, followed by other therapies in 31% and hormone treatment in 8% of patients. Initial treatment choice was strongly associated with etiology. The patients with known etiology received other therapies more often than the patients with unknown etiology (40% vs 6%; P ¼ 0.002). Other therapies used included topiramate (10), valproic acid (three), zonisamide (two), levetiracetam, phenobarbital, lacosamide, clonazepam, and ketogenic diet (one each). Patients with unknown etiology received VGB in 70% of cases and hormone therapy in 24% of cases as initial therapy (Fig 1). Short-term treatment outcome
Fifty-two percent (34 of 65) of patients achieved short-term remission within 3 months from diagnosis.
D. Thodeson, Y. Sogawa / Pediatric Neurology xxx (2014) 1e5
30
60
28
50
25
40
19
20
Known 15
Unknown
12
10
31 Failure
30
Success
20
4
0
1
1 Hormone
VGB
Other
FIGURE 1. Initial treatment choice by etiology. Differences in initial treatment by etiology were statistically significant (P ¼ 0.002). VGB, vigabatrin.
The patients with unknown etiology had higher response rate than the patients with known etiology, but this did not reach statistical significance (71% vs 46%; P ¼ 0.08). Within the group with known etiology, responder rate was 42% (five of 12) in cortical malformation, 50% (seven of 14) in perinatal insult, 20% (one of five) in trisomy 21, 100% (two of two) in tuberous sclerosis complex, 14% (one of seven) in other known etiology associated with IS, and 75% (six of eight) in known etiology NOS. Initial treatment choice was effective in 35% (23 of 65) of patients. VGB was effective as an initial treatment in 48% (19 of 40); hormone treatment was effective in 80% (four of five, three with ACTH and one with prednisolone). The difference in efficacy between VGB and hormone therapy as initial therapy was not statistically significant (P ¼ 0.35). Other therapies as initial treatment choices were ineffective in all 20 cases. Eighty-six percent (37 of 42) of patients who failed the initial medication had subsequent medication trials within 3 months of diagnosis. Four of the five patients who were not tried on a second medication within 3 months after medication failure had known etiology. Treatment response regardless of order of treatment received was analyzed (Fig 2). VGB was effective in 44% (24 of 55) of patients, and response rates were similar in patients with unknown etiology and known etiology (46% [six of 13] vs 43% [18 of 42]; P ¼ 0.83). Hormone therapy was effective in 67% (14 of 21) of patients. Response rates were better in unknown etiology but did not reveal a statistically significant difference (82% [nine of 11] vs 50% [five of 10]; P ¼ 0.12). Treatment responses were similar between ACTH and prednisolone (69% [nine of 13] vs 63% [five of eight]; P ¼ 0.88). Other therapies were effective in 9% (three of 34) of patients. Two patients responded to the ketogenic diet, and one patient responded to valproic acid. When all three treatments were compared, hormone and VGB were superior to other therapies (P < 0.001 and P < 0.001, respectively). There was no statistical difference between hormone and VGB (P ¼ 0.12).
31
7
10
5 0
3
14
24 3
Hormone
VGB
Other
FIGURE 2. Treatment response by medication, regardless of initial treatment. Hormone and VGB were superior to other therapies (P < 0.001 and P < 0.001, respectively). There was no statistical difference between hormone and VGB (P ¼ 0.12). VGB, vigabatrin.
Discussion
Overall demographic characteristics are consistent with previously published samples. Known etiology was subdivided according to the revised International League Against Epilepsy classification.3,4 Patients with known etiology have been lumped together for analysis in most published studies, with exception of tuberous sclerosis complex and trisomy 21. Our results suggest an importance of subdividing this group. We created a “known etiology NOS” category for patients with an abnormal etiologic evaluation which was not classically associated with IS. Some of the findings in this group are isolated subdural hematoma, visual impairment, heterozygous carrier on CLN5 gene, and mosaic mutation of 1p36 deletion. This group had 75% responder rate at 3 months, which is similar to patients with unknown etiology. Most patients with atypical age presentation were of known etiology. Patients with IS onset at less than 3 months of age had overrepresentation of cortical malformations. Patients with IS onset at greater than 12 months of age had overrepresentation of trisomy 21 or perinatal insult. Patients with unknown etiology typically presented between 4 and 8 months of age. We paid special attention to diagnostic lag because treatment initiation within 3 weeks of spasm onset has been reported to be associated with improved developmental outcome.5 Diagnostic lag time was excellent, with most of the patients diagnosed within 1 month of spasm onset. Of note, three of five patients with trisomy 21 had diagnostic lag of more than 1 month, which could have been influenced by the atypical age presentation in this population. Regarding treatment choice, we found that patients with known etiology were statistically more likely to receive other therapies as initial treatment than those with unknown etiology. Given the retrospective nature of this study, it is impossible to determine the precise reasons respective treatments were chosen for individual patients. Certainly, physician and parental preferences played important roles. During our quality assessment
4
D. Thodeson, Y. Sogawa / Pediatric Neurology xxx (2014) 1e5
meeting to discuss preliminary data, some physicians expressed concerns about higher relative toxicity of hormone therapy citing anecdotal reports of hypertensive cerebral hemorrhage and overwhelming sepsis as index cases. However, rates of these severe adverse effects were not known, and the cases cited during conference were not from the cohort analyzed for this study. Treatment cost was also cited as a concern. A 2007 increase in the cost of ACTH may have influenced physician therapy choice.6 However, we did not find that patients were denied ACTH solely based on cost, regardless of patient financial status. The relative ineffectiveness of any treatment in patients with known etiology was mentioned as a possibility for choosing a more conventional anticonvulsant. It was not clear whether this opinion was held in regards to short-term treatment, long-term developmental potential, or long-term epilepsy risk. This is an important point for future education because previous well-designed studies have not revealed statistically significant difference in efficacy or complications based on etiology.7-9 Moreover, in a Finnish longitudinal study on adults with history of IS, those with normal or nearnormal IQ after IS were not invariably those with normal developmental quotients or unknown etiology before treatment.10 Initial therapeutic choices revealed efficacy in less than 40% of cases, which is lower than previously published studies.7-9,11 This is likely skewed because of the use of other treatments as first-line therapies in many cases. Although there have been small open-label studies describing efficacy of treatments other than hormone or VGB as first-line therapy for IS, these studies did not use strict criteria for clinical or EEG outcome assessment and were not blinded.12-15 Most patients had subsequent treatment trials within a short period after the initial treatment failed; however, some patients were labeled as “refractory IS” and continued on the same treatment. Refractory IS is a poorly defined concept. Generally accepted definitions of refractory epilepsy include failure of two or three appropriately chosen anticonvulsants at reasonable doses,16 but even this definition is not without controversy. We would like to reserve “refractory IS” for patients who fail both hormone treatment and VGB or for patients who relapsed and did not respond to a second treatment course. The obvious limitation of our study is its retrospective nature, which created two major challenges. First, there was very little commentary in the medical record about the treatment decision-making process between the family and the physician. Second, outcome assessment was not uniform. Some patients had to be excluded from this study because treatment response was judged solely on parental report or spasm improvement without EEG confirmation. The need for uniform outcome definition was a point of emphasis in the most recent Cochrane review on the treatment of IS. The review states that lack of well-designed randomized controlled trials, ambiguity of definitions of hypsarrhythmia, and quantification of spasm reduction as confounding factors.17 The paucity of relevant evidence is reflected in the most recent guideline, which can only provide clinicians with limited recommendations in treatment.1 In summary, careful attention to the etiology within
the known etiology group is important as each subgroup seems to have propensity for different clinical presentation and treatment response. Implementation of standardized diagnostic workup, treatment protocol, and outcome goals are necessary to maximizing short-term treatment response including succession of treatment and to understand the true incidence of intractable IS. The preliminary data of this manuscript were presented at 67th annual meeting of American Epilepsy Society Meeting. The authors thank Drs. Miya Asato and Ira Bergman for reviewing the manuscript. D.T. reviewed medical records and wrote the manuscript. Y.S. designed the study, submitted Institutional Review Board application, reviewed medical records, and analyzed data. The authors do not have conflicting or competing interests. There was no funding or financial disclosure for this article.
References 1. Go CY, Mackay MT, Weiss SK, et al. 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. 2012;78:1974-1980. http://dx.doi.org/10.1212/ WNL.0b013e318259e2cf. 2. Mytinger JR, Joshi S. The current evaluation and treatment of infantile spasms among members of the Child Neurology Society. Journal of Child Neurology. 2012;27:1289-1294. http://dx.doi.org/10. 1177/0883073812455692. 3. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-685. http://dx.doi.org/10.1111/j.15281167.2010.02522.x. 4. Scheffer IE. Epilepsy: a classification for all seasons? Epilepsia. 2012; 53(Suppl. 2):6-9. http://dx.doi.org/10.1111/j.1528-1167.2012.03551.x. 5. Rener-Primec Z, Stare J, Neubauer D. The risk of lower mental outcome in infantile spasms increases after three weeks of hypsarrhythmia duration. Epilepsia. 2006;47:2202-2205. http://dx.doi. org/10.1111/j.1528-1167.2006.00888.x. 6. Gettig J, Cummings JP, Matuszewski KHP. Acthar gel and cosyntropin review: clinical and financial implications. Pharmacy and Therapeutics. 2009;34:250-257. PMCID: PMC2697107. 7. Baram TZ, Mitchell WG, Tournay A, Snead III OC, Hanson RA, Horton EJ. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics. 1996;97:375-379. PMCID: PMC3100715. 8. 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. http://dx.doi.org/10.1016/ S0140-6736(04)17400-X. 9. Vigevano F, Cilio MR. Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study. Epilepsia. 1997;38:1270-1274. http://dx.doi.org/10.1111/j.1528-1157.1997. tb00063.x. 10. Riikonen R. Long-term outcome of West syndrome: a study of adults with a history of infantile spasms. Epilepsia. 1996;37: 367-372. http://dx.doi.org/10.1111/j.1528-1157.1996.tb00573.x. 11. Hrachovy RA, Frost Jr JD, Glaze DG. High-dose, long-duration versus low-dose, short-duration corticotropin therapy for infantile spasms. Journal of Pediatrics. 1994;124:803-806. http://dx.doi.org/10.1016/ S0022-3476(05)81379-4. 12. Kwon YS, Jun YH, Hong YJ, Son BK. Topiramate monotherapy in infantile spasm. Yonsei Medical Journal. 2006;47:498-504. http://dx. doi.org/10.3349/ymj.2006.47.4.498. 13. Lotze TE, Wilfong AA. Zonisamide treatment for symptomatic infantile spasms. Neurology. 2004;62:296-298. http://dx.doi.org/10. 1212/01.WNL.0000103284.73495.35. 14. Glauser TA, Clark PO, Strawsburg R. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia. 1998;39:1324-1328. http://dx.doi.org/10.1111/j.1528-1157.1998.tb01331.x.
D. Thodeson, Y. Sogawa / Pediatric Neurology xxx (2014) 1e5 15. Kossoff EH, Hedderick EF, Turner Z, Freeman JM. A case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile spasms. Epilepsia. 2008;49:1504-1509. http://dx.doi.org/10. 1111/j.1528-1167.2008.01606.x. 16. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE
5
Commission on Therapeutic Strategies. Epilepsia. 2010;51: 1069-1077. http://dx.doi.org/10.1111/j.1528-1167.2009.02397.x. 17. Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database of Systematic Reviews 2008;(Issue 4): Art. No. CD001770. http://dx.doi.org/10.1002/14651858. CD001770.pub2.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Practice Experience in the Treatment of Infantile Spasms at a Tertiary Care Center Drew Thodeson MD a, *, Yoshimi Sogawa MD a, b a b
Division of Child Neurology/Epilepsy, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania Department of Neurology and Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania
abstract BACKGROUND: The current treatment guidelines for treatment of infantile spasms is ambiguous regarding individuals with known etiology and is backed by limited evidence. Recently published survey data reveal diverse treatment variation for infantile spasms. We conducted a retrospective medical record review to better understand the clinical variables which affect treatment selection for new-onset infantile spasms. METHODS: We systematically extracted demographic data and treatment response of children with new onset infantile spasms over a 3-year period at a single institution. Treatment was divided into three groups: vigabatrin, hormone treatment, and other therapies. RESULTS: Our final cohort had 65 patients; 74% had a known etiology. Sixty-two percent were initially treated with vigabatrin. Other therapies were used more often in known etiology than in unknown etiology as initial treatment (40% vs 6%; P ¼ 0.002). Treatment response at 3 months was not statistically different between unknown etiology and known etiology groups (71% vs 46%; P ¼ 0.08). Overall, initial treatment choice was effective in 35% (23 of 65). Eighty-six percent (37 of 42) who failed the initial medication had subsequent medication trials within 3 months. CONCLUSIONS: Etiology was strongly associated with initial treatment choice. The variation in treatment choice at our center reflects the limited evidence derived from well-designed clinical trials. Keywords: infantile spasms, treatment, vigabatrin, ACTH, epilepsy
Pediatr Neurol 2014; -: 1-5 Ó 2014 Elsevier Inc. All rights reserved.
Introduction
Infantile spasms (IS) is a childhood epileptic encephalopathy which generally carries a poor prognosis. The American Academy of Neurology and Child Neurology Society practice guidelines regarding the best practice for short-term medical treatment of IS have concluded that adrenocorticotropic hormone (ACTH) is probably effective (level B), vigabatrin (VGB) is possibly effective (level C), and ACTH may be offered over VGB in cryptogenic patients to improve developmental outcome (level C). Evidence was insufficient to establish the efficacy of oral steroids, ketogenic diet, and other anticonvulsants (level U).1 A recent Article History: Received May 3, 2014; Accepted in final form July 13, 2014 * Communications should be addressed to: Dr. Thodeson; Division of Child Neurology; Children’s Hospital of Pittsburgh of UPMC; 45th Street and Penn Avenue; Pittsburgh, Pennsylvania 15201. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.07.019
survey of child neurologists in the United States revealed diverse treatment practice and found that that some physicians are choosing therapies other than ACTH or VGB in certain patient populations.2 The practice parameter mentions little about treatment of patients with known etiology. Moreover, it does not mention further treatment choices after medication failure or in case of relapse. To understand the clinical variables which affect treatment selection, we conducted a retrospective medical record review. Materials and Methods The Children’s Hospital of Pittsburgh of UPMC is the only tertiary care children’s hospital in southwestern Pennsylvania, serving a catchment area of approximately three million people. Almost all children with newly diagnosed IS are admitted to our hospital for evaluation and treatment. Our institution employs 22 board-certified child neurologists including seven who specialize in epilepsy. Until recently, there was no consensus or institutional protocol for the treatment of IS. Treatment was chosen by an individual physician when the patient was admitted.
2
D. Thodeson, Y. Sogawa / Pediatric Neurology xxx (2014) 1e5
During the study period, inpatient supervision time was divided such that each attending neurologist spent an average of 2-6 weeks on service per year. This gave a unique opportunity to evaluate physicians’ treatment choices and short-term remission rates. Children with IS were identified by the International Classification of Diseases, Ninth Revision, code for IS on discharge diagnosis from September 2009 to September 2012. Medical records were reviewed and data on demographics, medical history, neurological examinations, electroencephalography (EEG), neuroimaging, and treatment responses were extracted systematically. Patients with the clinical diagnosis of new onset IS and/or hypsarrhythmia or modified hypsarrhythmia on EEG were included. All patients had clinical seizures consistent with spasms and interictal EEG consistent with hypsarrhythmia or hypsarrhythmia variant. Individuals with clinical spasms in clusters without hypsarrhythmia on EEG were excluded. Patients born before January 1, 2008 were excluded, as they were unlikely to be new onset IS based on their age. Etiology was divided into known and unknown groups. The terms “cryptogenic,” “symptomatic,” and “idiopathic” were avoided based on revised International League Against Epilepsy classification.3 All patients with an unknown etiology had normal development before onset of spasms and negative standard work up. The known etiology group was further subdivided into six categories: (1) cortical malformation; (2) perinatal insult, defined as children with prematurity, neonatal seizures, and/or hypoxic-ischemic encephalopathy; (3) trisomy 21; (4) tuberous sclerosis complex; (5) other known etiologies associated with IS; and (6) known etiology not otherwise specified (NOS). Known etiology NOS was assigned to patients with clear developmental delay or abnormal neurological examination before the onset of IS and to patients with an abnormal etiologic evaluation not known to be associated with IS. Standard etiologic work up for IS at our institution includes magnetic resonance imaging brain, cerebrospinal fluid analysis, serum amino acid, urine organic acid, and chromosome and microarray analysis. The day that the EEG confirmed the presence of hypsarrhythmia was used as the date of diagnosis. Treatment lag was defined as the interval between the onset of spasms and the initiation of IS-specific antiepileptic medication. Treatment responder was defined as resolution of clinical spasms and resolution of hypsarrhythmia within 3 months of the initial diagnosis. Any treatment started after 3 months from the diagnosis was excluded from analysis. Treatment was divided into three groups: VGB, hormone treatment, and other therapies. VGB was titrated to goal dose of 100-150 mg/kg as tolerated. Hormone treatment group included patients treated with oral steroid and ACTH. Oral steroid used was prednisolone and doses ranged from 2 to 5 mg/kg/day for 2 weeks followed by a 4- to 6-week taper. ACTH dosing was 100-150 U/m2 for 2 weeks followed by a 4- to 6-week taper with the exception of one patient who received 50 U/m2 for 2 weeks with subsequent taper. Other therapies included all other anticonvulsants and the ketogenic diet. The preliminary results were discussed in our divisional quality assessment meeting. Descriptive analysis was performed with Stata software version 10 (StataCorp LP, College Station, TX). Student t tests were used for continuous variables, and the Pearson chi-square or Fisher exact tests were used for categorical variables. A two-sided P value of less than 0.05 was considered statistically significant. This study was approved by the Institutional Review Board of the Children’s Hospital of Pittsburgh.
Results Demographics
A total of 73 patients met inclusion criteria. Eight patients were excluded from analysis because of treatment at another facility (two) and insufficient follow-up data (six). The final cohort had 65 patients with 41 males (63%). Forty-eight patients (74%) had a known etiology (Table). The median age of onset was six months (range 0.5-20 months). All six patients (9%) with onset before 3 months had known etiology. Four of those six patients had cortical malformations. The six patients (9%) with onset after 12 months were also
TABLE. Demographics
Total number Age of onset Diagnostic lag time Known etiology
Delayed Diagnosis
65 41 males (63%) Median 6 mo (3 wk-20 mo) Median 1 mo (<1 wk-11 mo) 48 (74%) Cortical malformations Perinatal insult Trisomy 21 Tuberous sclerosis Other known etiology associated with IS: Menkes disease, ARX, KCNQ2, nonaccidental trauma, and cardiac arrest outside of neonatal period Known etiology NOS: Bilateral extra-axial CSF collections, subdural hematomas, visual impairment, genetic mutation of unknown clinical significance, and focal seizures before IS 10 (17%) Trisomy 21 Cortical malformations Perinatal insult Menkes disease Unknown
12 14 5 2 7
8
3 3 2 1 1
Abbreviations: CSF ¼ Cerebrospinal fluid IS ¼ Infantile spasms NOS ¼ Not otherwise specified
known etiology. Two patients had trisomy 21, and four patients had perinatal insult. All patients with unknown etiology presented between 4 and 8 months with the exception of one patient who presented at 3 months (Table). The median diagnostic lag time was 1 month (range, <1 week-11 months), and 85% of patients were diagnosed within 1 month of spasm onset. Nine of 10 patients with delayed diagnosis had known etiology. Initial treatment choice
The most frequently chosen initial treatment was VGB, which was used in 62% of patients, followed by other therapies in 31% and hormone treatment in 8% of patients. Initial treatment choice was strongly associated with etiology. The patients with known etiology received other therapies more often than the patients with unknown etiology (40% vs 6%; P ¼ 0.002). Other therapies used included topiramate (10), valproic acid (three), zonisamide (two), levetiracetam, phenobarbital, lacosamide, clonazepam, and ketogenic diet (one each). Patients with unknown etiology received VGB in 70% of cases and hormone therapy in 24% of cases as initial therapy (Fig 1). Short-term treatment outcome
Fifty-two percent (34 of 65) of patients achieved short-term remission within 3 months from diagnosis.
D. Thodeson, Y. Sogawa / Pediatric Neurology xxx (2014) 1e5
30
60
28
50
25
40
19
20
Known 15
Unknown
12
10
31 Failure
30
Success
20
4
0
1
1 Hormone
VGB
Other
FIGURE 1. Initial treatment choice by etiology. Differences in initial treatment by etiology were statistically significant (P ¼ 0.002). VGB, vigabatrin.
The patients with unknown etiology had higher response rate than the patients with known etiology, but this did not reach statistical significance (71% vs 46%; P ¼ 0.08). Within the group with known etiology, responder rate was 42% (five of 12) in cortical malformation, 50% (seven of 14) in perinatal insult, 20% (one of five) in trisomy 21, 100% (two of two) in tuberous sclerosis complex, 14% (one of seven) in other known etiology associated with IS, and 75% (six of eight) in known etiology NOS. Initial treatment choice was effective in 35% (23 of 65) of patients. VGB was effective as an initial treatment in 48% (19 of 40); hormone treatment was effective in 80% (four of five, three with ACTH and one with prednisolone). The difference in efficacy between VGB and hormone therapy as initial therapy was not statistically significant (P ¼ 0.35). Other therapies as initial treatment choices were ineffective in all 20 cases. Eighty-six percent (37 of 42) of patients who failed the initial medication had subsequent medication trials within 3 months of diagnosis. Four of the five patients who were not tried on a second medication within 3 months after medication failure had known etiology. Treatment response regardless of order of treatment received was analyzed (Fig 2). VGB was effective in 44% (24 of 55) of patients, and response rates were similar in patients with unknown etiology and known etiology (46% [six of 13] vs 43% [18 of 42]; P ¼ 0.83). Hormone therapy was effective in 67% (14 of 21) of patients. Response rates were better in unknown etiology but did not reveal a statistically significant difference (82% [nine of 11] vs 50% [five of 10]; P ¼ 0.12). Treatment responses were similar between ACTH and prednisolone (69% [nine of 13] vs 63% [five of eight]; P ¼ 0.88). Other therapies were effective in 9% (three of 34) of patients. Two patients responded to the ketogenic diet, and one patient responded to valproic acid. When all three treatments were compared, hormone and VGB were superior to other therapies (P < 0.001 and P < 0.001, respectively). There was no statistical difference between hormone and VGB (P ¼ 0.12).
31
7
10
5 0
3
14
24 3
Hormone
VGB
Other
FIGURE 2. Treatment response by medication, regardless of initial treatment. Hormone and VGB were superior to other therapies (P < 0.001 and P < 0.001, respectively). There was no statistical difference between hormone and VGB (P ¼ 0.12). VGB, vigabatrin.
Discussion
Overall demographic characteristics are consistent with previously published samples. Known etiology was subdivided according to the revised International League Against Epilepsy classification.3,4 Patients with known etiology have been lumped together for analysis in most published studies, with exception of tuberous sclerosis complex and trisomy 21. Our results suggest an importance of subdividing this group. We created a “known etiology NOS” category for patients with an abnormal etiologic evaluation which was not classically associated with IS. Some of the findings in this group are isolated subdural hematoma, visual impairment, heterozygous carrier on CLN5 gene, and mosaic mutation of 1p36 deletion. This group had 75% responder rate at 3 months, which is similar to patients with unknown etiology. Most patients with atypical age presentation were of known etiology. Patients with IS onset at less than 3 months of age had overrepresentation of cortical malformations. Patients with IS onset at greater than 12 months of age had overrepresentation of trisomy 21 or perinatal insult. Patients with unknown etiology typically presented between 4 and 8 months of age. We paid special attention to diagnostic lag because treatment initiation within 3 weeks of spasm onset has been reported to be associated with improved developmental outcome.5 Diagnostic lag time was excellent, with most of the patients diagnosed within 1 month of spasm onset. Of note, three of five patients with trisomy 21 had diagnostic lag of more than 1 month, which could have been influenced by the atypical age presentation in this population. Regarding treatment choice, we found that patients with known etiology were statistically more likely to receive other therapies as initial treatment than those with unknown etiology. Given the retrospective nature of this study, it is impossible to determine the precise reasons respective treatments were chosen for individual patients. Certainly, physician and parental preferences played important roles. During our quality assessment
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meeting to discuss preliminary data, some physicians expressed concerns about higher relative toxicity of hormone therapy citing anecdotal reports of hypertensive cerebral hemorrhage and overwhelming sepsis as index cases. However, rates of these severe adverse effects were not known, and the cases cited during conference were not from the cohort analyzed for this study. Treatment cost was also cited as a concern. A 2007 increase in the cost of ACTH may have influenced physician therapy choice.6 However, we did not find that patients were denied ACTH solely based on cost, regardless of patient financial status. The relative ineffectiveness of any treatment in patients with known etiology was mentioned as a possibility for choosing a more conventional anticonvulsant. It was not clear whether this opinion was held in regards to short-term treatment, long-term developmental potential, or long-term epilepsy risk. This is an important point for future education because previous well-designed studies have not revealed statistically significant difference in efficacy or complications based on etiology.7-9 Moreover, in a Finnish longitudinal study on adults with history of IS, those with normal or nearnormal IQ after IS were not invariably those with normal developmental quotients or unknown etiology before treatment.10 Initial therapeutic choices revealed efficacy in less than 40% of cases, which is lower than previously published studies.7-9,11 This is likely skewed because of the use of other treatments as first-line therapies in many cases. Although there have been small open-label studies describing efficacy of treatments other than hormone or VGB as first-line therapy for IS, these studies did not use strict criteria for clinical or EEG outcome assessment and were not blinded.12-15 Most patients had subsequent treatment trials within a short period after the initial treatment failed; however, some patients were labeled as “refractory IS” and continued on the same treatment. Refractory IS is a poorly defined concept. Generally accepted definitions of refractory epilepsy include failure of two or three appropriately chosen anticonvulsants at reasonable doses,16 but even this definition is not without controversy. We would like to reserve “refractory IS” for patients who fail both hormone treatment and VGB or for patients who relapsed and did not respond to a second treatment course. The obvious limitation of our study is its retrospective nature, which created two major challenges. First, there was very little commentary in the medical record about the treatment decision-making process between the family and the physician. Second, outcome assessment was not uniform. Some patients had to be excluded from this study because treatment response was judged solely on parental report or spasm improvement without EEG confirmation. The need for uniform outcome definition was a point of emphasis in the most recent Cochrane review on the treatment of IS. The review states that lack of well-designed randomized controlled trials, ambiguity of definitions of hypsarrhythmia, and quantification of spasm reduction as confounding factors.17 The paucity of relevant evidence is reflected in the most recent guideline, which can only provide clinicians with limited recommendations in treatment.1 In summary, careful attention to the etiology within
the known etiology group is important as each subgroup seems to have propensity for different clinical presentation and treatment response. Implementation of standardized diagnostic workup, treatment protocol, and outcome goals are necessary to maximizing short-term treatment response including succession of treatment and to understand the true incidence of intractable IS. The preliminary data of this manuscript were presented at 67th annual meeting of American Epilepsy Society Meeting. The authors thank Drs. Miya Asato and Ira Bergman for reviewing the manuscript. D.T. reviewed medical records and wrote the manuscript. Y.S. designed the study, submitted Institutional Review Board application, reviewed medical records, and analyzed data. The authors do not have conflicting or competing interests. There was no funding or financial disclosure for this article.
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