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April 4, 2018

Getting serious about the early-life epilepsies
Lessons from the world of pediatric oncology

May 1, 2018 issue
90 (18) 842-848

Abstract

Early-life epilepsies represent a group of many individually rare and often complex developmental brain disorders associated with lifelong devastating consequences and high risk for early mortality. The quantity and quality of evidence needed to guide the evaluation and treatment to optimize outcomes of affected children is minimal; most children are treated within an evidence-free practice zone based solely on anecdote and lore. The remarkable advances in diagnostics and therapeutics are implemented haphazardly with no systematic effort to understand their effects and value. This stands in stark contrast to the evidence-rich practice of the Children's Oncology Group, where standard of care treatments are identified through rigorous, multicenter research studies, and the vast majority of patients are treated on protocols developed from that research. As a consequence, overall mortality for childhood cancers has declined from ∼90% in the 1950s to ∼20% today. The situations of these 2 rare disease specialties are contrasted, and some suggestions for moving early-life epilepsy onto a fast track for success are offered. Chief amongst these is that early-life epilepsy should be treated with the same urgency as pediatric cancer. The best diagnostics and evidence-based treatments should be used in a systematic fashion right from the start, not after the child and family have been subjected to the ravages of the disorder for months or years. This will require unity and cooperation among physicians, researchers, and institutions across state and national borders.

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References

1.
Camfield CS, Camfield PR, Gordon K, Wirrell E, Dooley JM. Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia 1996;37:19–23.
2.
Aaberg KM, Gunnes N, Bakken IJ, et al. Incidence and prevalence of childhood epilepsy: a nationwide cohort study. Pediatrics 2017;139.
3.
Vasconcellos E, Wyllie E, Sullivan S, et al. Mental retardation in pediatric candidates for epilepsy surgery: the role of early seizure onset. Epilepsia 2001;42:268–274.
4.
Freitag H, Tuxhorn I. Cognitive function in preschool children after epilepsy surgery: rationale for early intervention. Epilepsia 2005;46:561–567.
5.
Berg AT, Smith SN, Frobish D, et al. Longitudinal assessment of adaptive behavior in infants and young children with newly diagnosed epilepsy: influences of etiology, syndrome, and seizure control. Pediatrics 2004;114:645–650.
6.
Cormack F, Cross JH, Isaacs E, et al. The development of intellectual abilities in pediatric temporal lobe epilepsy. Epilepsia 2007;48:201–204.
7.
Vendrame M, Alexopoulos AV, Boyer K, et al. Longer duration of epilepsy and earlier age at epilepsy onset correlate with impaired cognitive development in infancy. Epilepsy Behav 2009;16:431–435.
8.
Howell KB, Harvey AS, Archer JS. Epileptic encephalopathy: use and misuse of a clinically and conceptually important concept. Epilepsia 2016;57:343–347.
9.
Berg AT, Cross JH. Towards a modern classification of the epilepsies? Lancet Neurol 2010;9:459–461.
10.
Skirrow C, Cross JH, Cormack F, Harkness W, Vargha-Khadem F, Baldeweg T. Long-term intellectual outcome after temporal lobe surgery in childhood. Neurology 2011;76:1330–1337.
11.
Jonas R, Nguyen S, Hu B, et al. Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 2004;62:1712–1721.
12.
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.
13.
Berg AT, Loddenkemper T, Baca CB. Diagnostic delays in children with early onset epilepsy: impact, reasons, and opportunities to improve care. Epilepsia 2014;55:123–132.
14.
Auvin S, Hartman AL, Desnous B, et al. Diagnosis delay in West syndrome: misdiagnosis and consequences. Eur J Pediatr 2012;171:1695–1701.
15.
Camfield P, Camfield C. Long-term prognosis for symptomatic (secondarily) generalized epilepsies: a population-based study. Epilepsia 2007;48:1128–1132.
16.
Moseley BD, Wirrell EC, Wong-Kisiel LC, Nickels K. Early onset epilepsy is associated with increased mortality: a population-based study. Epilepsy Res 2013;105:410–414.
17.
Berg AT, Shinnar S, Testa FM, Levy SR, Smith SN, Beckerman B. Mortality in childhood-onset epilepsy. Arch Pediatr Adolesc Med 2004;158:1147–1152.
18.
Sakauchi M, Oguni H, Kato I, et al. Retrospective multiinstitutional study of the prevalence of early death in Dravet syndrome. Epilepsia 2011;52:1144–1149.
19.
Riikonen R. Long-term outcome of West syndrome: a study of adults with a history of infantile spasms. Epilepsia 1996;37:367–372.
20.
Collins FS, Varmus H. A new initiative on precision medicine. New Engl J Med 2015;372:793–795.
21.
Trevathan E, Murphy CC, Yeargin-Allsopp M. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia 1999;40:748–751.
22.
Wu YW, Sullivan J, McDaniel SS, et al. Incidence of Dravet syndrome in a US population. Pediatrics 2015;136:e1310–e1315.
23.
Wolff M, Johannesen KM, Hedrich UB, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017;140:1316–1336.
24.
Brodie MJ. Antiepileptic drug therapy the story so far. Seizure 2010;19:650–655.
25.
Hirtz D, Ashwal S, Berg A, et al. Practice parameter: evaluating a first nonfebrile seizure in children: report of the quality standards subcommittee of the American Academy of Neurology, the Child Neurology Society, and the American Epilepsy Society. Neurology 2000;55:616–623.
26.
Gaillard WD, Chiron C, Cross JH, et al. Guidelines for imaging infants and children with recent-onset epilepsy. Epilepsia 2009;50:2147–2153.
27.
Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011;77:1629–1635.
28.
Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86:749–764.
29.
Kutscher EJ, Joshi SM, Patel AD, Hafeez B, Grinspan ZM. Barriers to genetic testing for pediatric Medicaid beneficiaries with epilepsy. Pediatr Neurol 2017;73:28–35.
30.
Ream MA, Patel AD. Obtaining genetic testing in pediatric epilepsy. Epilepsia 2015;56:1505–1514.
31.
Trevathan E. So what? Does the test lead to improved health outcomes? Neurology 2011;77:1586–1587.
32.
Wilmshurst JM, Gaillard WD, Vinayan KP, et al. Summary of recommendations for the management of infantile seizures: task force report for the ILAE commission of pediatrics. Epilepsia 2015;56:1185–1197.
33.
Berg AT, Coryell J, Saneto RP, et al. Early-life epilepsies and the emerging role of genetic testing. JAMA Pediatr 2017;171:863–871.
34.
Shellhaas RA, Wusthoff CJ, Tsuchida TN, et al. Profile of neonatal epilepsies: characteristics of a prospective US cohort. Neurology 2017;89:893–899.
35.
Brunklaus A, Dorris L, Ellis R, et al. The clinical utility of an SCN1A genetic diagnosis in infantile-onset epilepsy. Dev Med Child Neurol 2013;55:154–161.
36.
Labiner DM, Bagic AI, Herman ST, Fountain NB, Walczak TS, Gumnit RJ. Essential services, personnel, and facilities in specialized epilepsy centers–revised 2010 guidelines. Epilepsia 2010;51:2322–2333.
37.
Berg AT, Cross JH. Classification of epilepsies and seizures: historical perspective and future directions. Handbook Clin Neurol 2012;107:99–111.
38.
Brunklaus A, Dorris L, Zuberi SM. Comorbidities and predictors of health-related quality of life in Dravet syndrome. Epilepsia 2011;52:1476–1482.
39.
Pastor PN, Reuben CA, Kobau R, Helmers SL, Lukacs S. Functional difficulties and school limitations of children with epilepsy: findings from the 2009-2010 National Survey of Children with Special Health Care Needs. Disabil Health J 2015;8:231–239.
40.
Cui W, Kobau R, Zack MM, Helmers S, Yeargin-Allsopp M. Seizures in children and adolescents aged 6-17 years: United States, 2010-2014. MMWR Morb Mortal Wkly Rep 2015;64:1209–1214.
41.
Berg AT, Tarquinio D, Koh S. Epilepsy is a co-expression of developmental brain disorders. Semin Pediatr Neurol 2017;2017:251–263.
42.
Berg AT, Nickels K, Wirrell EC, et al. Mortality risks in new-onset childhood epilepsy. Pediatrics 2013;132:124–131.
43.
FDA. Rare diseases: common issues in drug development, guidance for industry [online]. Available at: fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM458485.pdf. Accessed March 14, 2017.
44.
Barnes KV, Coughlin FR, O'Leary HM, et al. Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales. J Neurodev Disord 2015;7:30.
45.
Downs J, Bebbington A, Kaufmann WE, Leonard H. Longitudinal hand function in Rett syndrome. J Child Neurol 2011;26:334–340.
46.
Downs JA, Bebbington A, Jacoby P, et al. Gross motor profile in Rett syndrome as determined by video analysis. Neuropediatrics 2008;39:205–210.
47.
Kaufmann WE, Tierney E, Rohde CA, et al. Social impairments in Rett syndrome: characteristics and relationship with clinical severity. J Intellect Disabil Res 2012;56:233–247.
48.
O'Leary M, Krailo M, Anderson JR, Reaman GH. Progress in childhood cancer: 50 years of research collaboration, a report from the Children's Oncology Group. Semin Oncol 2008;35:484–493.
49.
American Cancer Society. Cancer in children and adolescents [online]. Available at: cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2014.html. Accessed October 23, 2017.
50.
Perry MS. Meaningful results in a jiffy: a PERC of multicenter collaborations. Epilepsy Curr 2016;16:299–301.
51.
Knupp KG, Coryell J, Nickels KC, et al. Response to treatment in a prospective national infantile spasms cohort. Ann Neurol 2016;79:475–484.
52.
US Cancer Statistics Working Group. United States Cancer Statistics: 1999–2014 Incidence and Mortality Web-based Report. Atlanta: US Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2017. Available at: cdc.gov/uscs. Accessed October 23, 2017.
53.
Verhaart IEC, Robertson A, Wilson IJ, et al. Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy: a literature review. Orphanet J Rare Dis 2017;12:124.
54.
Genetics Home Reference. Duchenne and Becker muscular dystrophy [online]. Available at: ghr.nlm.nih.gov/condition/duchenne-and-becker-muscular-dystrophy. Accessed October 24, 2017.
55.
Genetics Home Reference. CLN2 disease [online]. Available at: ghr.nlm.nih.gov/condition/cln2-disease. Accessed October 24, 2017.
56.
Shellhaas RA, Chang T, Wusthoff CJ, et al. Treatment duration after acute symptomatic seizures in neonates: a multicenter cohort study. J Pediatr 2017;181:298–301.
57.
Shellhaas RA, Berg AT, Grinspan ZM, et al. Initial treatment for nonsyndromic early-life epilepsy: an unexpected consensus. Pediatr Neurol 2017;75:73–79.
58.
Knupp KG, Leister E, Coryell J, et al. Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort. Epilepsia 2016;57:1834–1842.
59.
Fernandez CV, Ruccione K, Wells RJ, et al. Recommendations for the return of research results to study participants and guardians: a report from the Children's Oncology Group. J Clin Oncol 2012;30:4573–4579.
60.
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.
61.
Wang CJ, Jonas R, Fu CM, Ng CY, Douglass L. Quality-of-care indicators for infantile spasms. J Child Neurol 2013;28:13–20.
62.
Patel AD, Berg AT, Billinghurst L, et al. Quality improvement in neurology: child neurology quality measure set: executive summary. Neurology 2018;90:67–73.

Information & Authors

Information

Published In

Neurology®
Volume 90Number 18May 1, 2018
Pages: 842-848
PubMed: 29618625

Publication History

Received: November 1, 2017
Accepted: February 15, 2018
Published online: April 4, 2018
Published in print: May 1, 2018

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Disclosure

A. Berg has received funding from the NINDS, Pediatric Epilepsy Research Foundation, The Centers for Disease Control (subcontract from Case Western Reserve), and The Goizuetta Foundation through Children's Healthcare of Atlanta. Dr. Berg received speaking honoraria from Oklahoma Medical Center and Washington University, St, Louis, MO. S. Goldman reports funding from the National Cancer Institute. Go to Neurology.org/N for full disclosures.

Study Funding

No targeted funding reported.

Authors

Affiliations & Disclosures

Anne T. Berg, PhD
From the Epilepsy Center, Neurology (A.T.B.), and Hematology-Oncology (S.G.), Ann & Robert H Lurie Children's Hospital of Chicago, IL.
Disclosure
Scientific Advisory Boards:
1.
CURE, Infantile Spasms Initiative
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Epilepsy and Behavior 2009 - current Neurology 2012 - current Editorial board for both
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NINDS R37 NS31146 2002-2016 CDC SIP 2014-2016
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
Pediatric Epilepsy Research Foundation (PERF) current Dravet Syndrome Foundation completed 2016
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
Dow Agro Science 2006-2010 Busch&Blackwell - currently in progress- Completed 2016
Stewart Goldman, MD
From the Epilepsy Center, Neurology (A.T.B.), and Hematology-Oncology (S.G.), Ann & Robert H Lurie Children's Hospital of Chicago, IL.
Disclosure
Scientific Advisory Boards:
1.
1) Commercial -- Novartis CAR-T advisory board
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. Berg [email protected]
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

Author Contributions

Dr. Berg drafted the manuscript. Dr. Goldman critically reviewed, revised, and drafted additional portions.

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