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Oral Corticosteroids Versus Adrenocorticotropic Hormone for Infantile Spasms—An Unfinished Story
Accepted Manuscript Oral Corticosteroids versus ACTH for Infantile Spasms – an Unfinished Story John R. Mytinger , MD Geoffrey L. Heyer , MD PII:
S0887-8994(14)00329-4
DOI:
10.1016/j.pediatrneurol.2014.05.025
Reference:
PNU 8381
To appear in:
Pediatric Neurology
Please cite this article as: Mytinger JR, Heyer GL, Oral Corticosteroids versus ACTH for Infantile Spasms – an Unfinished Story, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
EDITORIAL
John R. Mytinger, MD, Geoffrey L. Heyer, MD
The Ohio State University
SC
Division of Pediatric Neurology
Nationwide Children’s Hospital
TE D
M AN U
Columbus, Ohio, USA
AC C
EP
Contact information: John R. Mytinger, M.D. Nationwide Children’s Hospital The Ohio State University College of Medicine Division of Pediatric Neurology 700 Children’s Drive Columbus, Ohio 43205 Telephone: 614-722-4625 Telefax: 614-722-4633 [email protected]
RI PT
Oral Corticosteroids versus ACTH for Infantile Spasms – an Unfinished Story
ACCEPTED MANUSCRIPT
Sorel and Dusaucy-Bauloye first reported the effectiveness of adrenocorticotropic hormone (ACTH) for infantile spasms in 1958.1 In 2010, after 50 years of off-label use, the FDA (Food & Drug Administration) approved the use of ACTH (H.P. Acthar® gel) for the treatment of infantile spasms in the United States.
RI PT
The use of ACTH is supported by a small Class I randomized controlled trial (RCT) in which electroclinical remission was documented in 13 of 15 (86.6%) patients receiving 150 U/m2/day of natural ACTH and in 4 of 14 (28.6%) patients receiving 2 mg/kg/day of oral corticosteroids (prednisone).2 After
M AN U
commonly used treatment for infantile spasms in the United States.3
SC
excluding patients with tuberous sclerosis (who often receive vigabatrin), ACTH continues to be the most
For many clinicians, the Class I study noted above was enough to ‘close the book’ on oral corticosteroids. However, a critical question about hormone therapy for infantile spasms has lingered – is 2 mg/kg/day of prednisone comparable to an ACTH dose of 150 U/m2/day? In other words, does the response rate increase with higher doses of oral corticosteroids? A Class III RCT by Lux and colleagues utilizing high-
TE D
dose prednisolone at 40-60 mg/day (in 3-4 divided doses) reported a clinical remission rate of 70% (compared to 76% for synthetic ACTH at 40 IU/every other day).4 Unfortunately, this study was not powered to detect a difference between hormone treatments and did not confirm electroclinical remission
EP
by electroencephalography (EEG). Despite these shortcomings, this study has changed practice for some
AC C
clinicians5 and has led to further questions about the superiority of ACTH over oral corticosteroids.
Despite its lack of FDA approval for this indication, oral corticosteroids are the second most commonly used treatment for infantile spasms (in individuals without tuberous sclerosis complex) in the United States.3 Prednisone and prednisolone are most frequently used and are equipotent with the only notable difference between them being that prednisone (the prodrug) is converted to prednisolone (the active form) after ingestion. In addition to the study by Lux and colleagues, several factors have influenced the use of oral corticosteroids. First of all, oral corticosteroids are one of three treatment options with greater than Class IV evidence to support their use (the others being ACTH and vigabatrin).6 The response rates
ACCEPTED MANUSCRIPT
from Class II and III studies with oral corticosteroids range from 29% to 70%, although the definition of treatment ‘response’ has varied.6 Secondly, some children who fail to respond to ACTH will respond to oral corticosteroids (and vice versa).7 Finally, natural ACTH in the United States is expensive (exceeding
RI PT
$50,000 for a one month course), it is administered by intramuscular injection which requires caregiver instruction, and prior authorization by insurance is necessary. In contrast, oral corticosteroids are
inexpensive (less than $40 for a one month course), easy to administer, and readily available without the
SC
need for prior authorization by insurance.
In this issue of Pediatric Neurology, Wanigasinghe and colleagues report their randomized, parallel,
M AN U
investigator-blind clinical trial comparing ACTH and prednisolone for the treatment of infantile spasms.8 Ninety two patients were randomized to either 40-60 IU/every other day of synthetic ACTH or 40-60 mg/day of prednisolone for two weeks; 40 patients in each clinical arm were analyzed. An EEG of 35 minutes duration was performed 14 days after the start of treatment. The primary outcome measure was
TE D
change in the hypsarrhythmia severity score developed by Kramer and colleagues.9 Clinical remission of spasms was not reported. The authors found greater improvement in the mean hypsarrhythmia severity score in the prednisolone group (the score falling by nearly 8 points) compared to the ACTH group (the
EP
score falling by 6 points). In addition, there were significantly fewer electrographic spikes and sharp waves present on the post-treatment EEG in the prednisolone group compared to the ACTH group
AC C
(p=0.002).
In validating their scale, Kramer et al detected a significant correlation between higher hypsarrhythmia severity scores on pre-treatment EEG and poorer outcomes.9 Good outcomes occurred in 38% of subjects with scores below 10 and in 16% of those with scores above 10. Notably, this means that 62% of children had bad outcomes despite more ‘favorable’ severity scores. The authors go on to state that “…although the relationship between the hypsarrhythmia score and outcome is statistically significant, it remains uncertain how clinically useful it will be, in view of the wide scatter.”9 Thus, this scale may not
ACCEPTED MANUSCRIPT
be an optimal outcome measure. Furthermore, in the study by Wanigasinghe et al, the primary outcome measure was the mean change in the severity score between the pre-treatment and post-treatment EEG. However, the study by Kramer and colleagues was not designed to validate the significance of a change in
RI PT
the hypsarrhythmia severity score in regard to outcome. So while statistically significant, the clinical significance of a two point greater improvement in one group over the other is not clear, especially with the mean post-treatment score of both groups falling within the ‘favorable’ range (2.61 for prednisolone
SC
and 4.33 for ACTH).
M AN U
Other study limitations include the brevity of the post-treatment EEG in general, the limited electrographic assessment of sleep using a selected EEG sample of only 10 seconds for some data points, and the use of a single EEG reviewer. Intra-rater reliability was assessed by correlation and found to be acceptable (0.75), but inter-rater reliability (reliability between different interpreters) can be poor when
TE D
assessing the EEG background of children with infantile spasms.10
Despite these shortcomings, the study by Wanigasinghe and colleagues suggests that the electrographic improvement with prednisolone may be at least as good as with synthetic ACTH. The authors should be
EP
congratulated on their effort. A future report of clinical and developmental outcomes in this cohort would strengthen their findings. Unfortunately, for now, the question of superiority, or even equality, between
AC C
natural or synthetic ACTH and oral corticosteroids in regard to efficacy for infantile spasms remains unanswered. Optimizing hormone therapy has important implications, not the least of which is drug expense. Future infantile spasm treatment studies must incorporate electroclinical and developmental outcomes.
References 1.
Sorel L, Dusaucy-Bauloye A. [Findings in 21 cases of Gibbs' hypsarrhythmia; spectacular effectiveness of ACTH]. Acta neurologica et psychiatrica Belgica. Feb 1958;58(2):130-141.
ACCEPTED MANUSCRIPT
7. 8.
9. 10.
RI PT
SC
6.
M AN U
5.
TE D
4.
EP
3.
Baram TZ, Mitchell WG, Tournay A, Snead OC, Hanson RA, Horton EJ. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics. Mar 1996;97(3):375-379. Mytinger JR, Joshi S. The current evaluation and treatment of infantile spasms among members of the Child Neurology Society. Journal of child neurology. Oct 2012;27(10):1289-1294. 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. Nov 13-19 2004;364(9447):1773-1778. Mohamed BP, Scott RC, Desai N, Gutta P, Patil S. Seizure outcome in infantile spasms--a retrospective study. Epilepsia. Apr 2011;52(4):746-752. 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. Jun 12 2012;78(24):1974-1980. Hrachovy RA, Frost JD, Jr., Kellaway P, Zion TE. Double-blind study of ACTH vs prednisone therapy in infantile spasms. The Journal of pediatrics. Oct 1983;103(4):641-645. Wanigasinghe J, Arambepola C. Ranganathan S, Sumanasena S, Muhandiram E. The efficacy of moderate to high dose oral prednisolone versus low to moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial. Pediatric neurology. 2014;In Press. Kramer U, Sue WC, Mikati MA. Hypsarrhythmia: frequency of variant patterns and correlation with etiology and outcome. Neurology. Jan 1997;48(1):197-203. Kwong G MJ, Lerner JT, Wu JY, Sankar R, Hussain SA. Inter-rater reliability of the assessment of hypsarrhythmia. Epilepsy Currents. 2014;14(Suppl 1)(32).
AC C
2.
S0887-8994(14)00329-4
DOI:
10.1016/j.pediatrneurol.2014.05.025
Reference:
PNU 8381
To appear in:
Pediatric Neurology
Please cite this article as: Mytinger JR, Heyer GL, Oral Corticosteroids versus ACTH for Infantile Spasms – an Unfinished Story, Pediatric Neurology (2014), doi: 10.1016/j.pediatrneurol.2014.05.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
EDITORIAL
John R. Mytinger, MD, Geoffrey L. Heyer, MD
The Ohio State University
SC
Division of Pediatric Neurology
Nationwide Children’s Hospital
TE D
M AN U
Columbus, Ohio, USA
AC C
EP
Contact information: John R. Mytinger, M.D. Nationwide Children’s Hospital The Ohio State University College of Medicine Division of Pediatric Neurology 700 Children’s Drive Columbus, Ohio 43205 Telephone: 614-722-4625 Telefax: 614-722-4633 [email protected]
RI PT
Oral Corticosteroids versus ACTH for Infantile Spasms – an Unfinished Story
ACCEPTED MANUSCRIPT
Sorel and Dusaucy-Bauloye first reported the effectiveness of adrenocorticotropic hormone (ACTH) for infantile spasms in 1958.1 In 2010, after 50 years of off-label use, the FDA (Food & Drug Administration) approved the use of ACTH (H.P. Acthar® gel) for the treatment of infantile spasms in the United States.
RI PT
The use of ACTH is supported by a small Class I randomized controlled trial (RCT) in which electroclinical remission was documented in 13 of 15 (86.6%) patients receiving 150 U/m2/day of natural ACTH and in 4 of 14 (28.6%) patients receiving 2 mg/kg/day of oral corticosteroids (prednisone).2 After
M AN U
commonly used treatment for infantile spasms in the United States.3
SC
excluding patients with tuberous sclerosis (who often receive vigabatrin), ACTH continues to be the most
For many clinicians, the Class I study noted above was enough to ‘close the book’ on oral corticosteroids. However, a critical question about hormone therapy for infantile spasms has lingered – is 2 mg/kg/day of prednisone comparable to an ACTH dose of 150 U/m2/day? In other words, does the response rate increase with higher doses of oral corticosteroids? A Class III RCT by Lux and colleagues utilizing high-
TE D
dose prednisolone at 40-60 mg/day (in 3-4 divided doses) reported a clinical remission rate of 70% (compared to 76% for synthetic ACTH at 40 IU/every other day).4 Unfortunately, this study was not powered to detect a difference between hormone treatments and did not confirm electroclinical remission
EP
by electroencephalography (EEG). Despite these shortcomings, this study has changed practice for some
AC C
clinicians5 and has led to further questions about the superiority of ACTH over oral corticosteroids.
Despite its lack of FDA approval for this indication, oral corticosteroids are the second most commonly used treatment for infantile spasms (in individuals without tuberous sclerosis complex) in the United States.3 Prednisone and prednisolone are most frequently used and are equipotent with the only notable difference between them being that prednisone (the prodrug) is converted to prednisolone (the active form) after ingestion. In addition to the study by Lux and colleagues, several factors have influenced the use of oral corticosteroids. First of all, oral corticosteroids are one of three treatment options with greater than Class IV evidence to support their use (the others being ACTH and vigabatrin).6 The response rates
ACCEPTED MANUSCRIPT
from Class II and III studies with oral corticosteroids range from 29% to 70%, although the definition of treatment ‘response’ has varied.6 Secondly, some children who fail to respond to ACTH will respond to oral corticosteroids (and vice versa).7 Finally, natural ACTH in the United States is expensive (exceeding
RI PT
$50,000 for a one month course), it is administered by intramuscular injection which requires caregiver instruction, and prior authorization by insurance is necessary. In contrast, oral corticosteroids are
inexpensive (less than $40 for a one month course), easy to administer, and readily available without the
SC
need for prior authorization by insurance.
In this issue of Pediatric Neurology, Wanigasinghe and colleagues report their randomized, parallel,
M AN U
investigator-blind clinical trial comparing ACTH and prednisolone for the treatment of infantile spasms.8 Ninety two patients were randomized to either 40-60 IU/every other day of synthetic ACTH or 40-60 mg/day of prednisolone for two weeks; 40 patients in each clinical arm were analyzed. An EEG of 35 minutes duration was performed 14 days after the start of treatment. The primary outcome measure was
TE D
change in the hypsarrhythmia severity score developed by Kramer and colleagues.9 Clinical remission of spasms was not reported. The authors found greater improvement in the mean hypsarrhythmia severity score in the prednisolone group (the score falling by nearly 8 points) compared to the ACTH group (the
EP
score falling by 6 points). In addition, there were significantly fewer electrographic spikes and sharp waves present on the post-treatment EEG in the prednisolone group compared to the ACTH group
AC C
(p=0.002).
In validating their scale, Kramer et al detected a significant correlation between higher hypsarrhythmia severity scores on pre-treatment EEG and poorer outcomes.9 Good outcomes occurred in 38% of subjects with scores below 10 and in 16% of those with scores above 10. Notably, this means that 62% of children had bad outcomes despite more ‘favorable’ severity scores. The authors go on to state that “…although the relationship between the hypsarrhythmia score and outcome is statistically significant, it remains uncertain how clinically useful it will be, in view of the wide scatter.”9 Thus, this scale may not
ACCEPTED MANUSCRIPT
be an optimal outcome measure. Furthermore, in the study by Wanigasinghe et al, the primary outcome measure was the mean change in the severity score between the pre-treatment and post-treatment EEG. However, the study by Kramer and colleagues was not designed to validate the significance of a change in
RI PT
the hypsarrhythmia severity score in regard to outcome. So while statistically significant, the clinical significance of a two point greater improvement in one group over the other is not clear, especially with the mean post-treatment score of both groups falling within the ‘favorable’ range (2.61 for prednisolone
SC
and 4.33 for ACTH).
M AN U
Other study limitations include the brevity of the post-treatment EEG in general, the limited electrographic assessment of sleep using a selected EEG sample of only 10 seconds for some data points, and the use of a single EEG reviewer. Intra-rater reliability was assessed by correlation and found to be acceptable (0.75), but inter-rater reliability (reliability between different interpreters) can be poor when
TE D
assessing the EEG background of children with infantile spasms.10
Despite these shortcomings, the study by Wanigasinghe and colleagues suggests that the electrographic improvement with prednisolone may be at least as good as with synthetic ACTH. The authors should be
EP
congratulated on their effort. A future report of clinical and developmental outcomes in this cohort would strengthen their findings. Unfortunately, for now, the question of superiority, or even equality, between
AC C
natural or synthetic ACTH and oral corticosteroids in regard to efficacy for infantile spasms remains unanswered. Optimizing hormone therapy has important implications, not the least of which is drug expense. Future infantile spasm treatment studies must incorporate electroclinical and developmental outcomes.
References 1.
Sorel L, Dusaucy-Bauloye A. [Findings in 21 cases of Gibbs' hypsarrhythmia; spectacular effectiveness of ACTH]. Acta neurologica et psychiatrica Belgica. Feb 1958;58(2):130-141.
ACCEPTED MANUSCRIPT
7. 8.
9. 10.
RI PT
SC
6.
M AN U
5.
TE D
4.
EP
3.
Baram TZ, Mitchell WG, Tournay A, Snead OC, Hanson RA, Horton EJ. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics. Mar 1996;97(3):375-379. Mytinger JR, Joshi S. The current evaluation and treatment of infantile spasms among members of the Child Neurology Society. Journal of child neurology. Oct 2012;27(10):1289-1294. 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. Nov 13-19 2004;364(9447):1773-1778. Mohamed BP, Scott RC, Desai N, Gutta P, Patil S. Seizure outcome in infantile spasms--a retrospective study. Epilepsia. Apr 2011;52(4):746-752. 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. Jun 12 2012;78(24):1974-1980. Hrachovy RA, Frost JD, Jr., Kellaway P, Zion TE. Double-blind study of ACTH vs prednisone therapy in infantile spasms. The Journal of pediatrics. Oct 1983;103(4):641-645. Wanigasinghe J, Arambepola C. Ranganathan S, Sumanasena S, Muhandiram E. The efficacy of moderate to high dose oral prednisolone versus low to moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial. Pediatric neurology. 2014;In Press. Kramer U, Sue WC, Mikati MA. Hypsarrhythmia: frequency of variant patterns and correlation with etiology and outcome. Neurology. Jan 1997;48(1):197-203. Kwong G MJ, Lerner JT, Wu JY, Sankar R, Hussain SA. Inter-rater reliability of the assessment of hypsarrhythmia. Epilepsy Currents. 2014;14(Suppl 1)(32).
AC C
2.