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Explore genetic causes, targeted therapies, and outcomes in pediatric epilepsy research. Focus on CDKL5 mutations and their impact on patients with infantile spasms and seizures. Learn about the broad spectrum of seizure disorders associated with CDKL5 mutations.
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Research and Advances in Pediatric Epilepsy, 2016 Juliann M. Paolicchi, MA MD Northeastern Regional Epilepsy Group Clinical Professor, Rutgers University Medical Center
Research and Advances in Pediatric Epilepsy, 2016 Juliann M. Paolicchi, MA MD Northeastern Regional Epilepsy Group Clinical Professor, Rutgers University Medical Center • Major Focus of Pediatric Epilepsy Research: • Identifying Genetic Causes of Epilepsy • Targeting Therapies to Specific Cause of Epilepsy • Focus on Outcome: How do new therapies work best? How can we prevent further effects of epilepsy
Financial Disclosures • NINDS: Epilepsy Phenome-Genome Study • NINDS: Human Epilepsy Project • Clinical Investigator: • LundbeckPharmaceuticals • Zogenix • Acorda Pharmaceuticals • Consultant/Speaker: • Lundbeck Pharmaceuticals • Cyberonics • Quest Diagnostics
Treatment of Epilepsy with Anti-Epileptic Medications Previously Untreated Epilepsy Patients (n=470) Kwan P, Brodie MJ. NEJM 2000; 342:314-319
Epilepsy: Incidence/100,000 200 150 100 50 0 0 20 40 60 80 100 Age Hauser, Epilepsia 33:1992
polygenic inheritance Neurobiological spectrum of the epilepsies acquired cause trauma, hypoxia, vascular etc. Structural/ Metabolic Genetic single gene Age
Recent Breakthroughs in the Genetic Basis of Epilepsy Syndromes • Early Childhood Epileptic Encephalopathies: • Otahara’s Syndrome • Early Myoclonic Epilepsy • Migrating partial epilepsy of infancy • Epileptic (Infantile spasms) • Cortical dysgenesis • Neuronal Migration disorders • Zellweger’s syndrome • Walker-Warburg syndrome • Genetic Epilepsy Febrile Seizures + • Doose Syndrome • Dravet’s syndrome • Childhood Epilepsy Syndromes: • Juvenile Myoclonic Epilepsies • Progressive Myoclonic Epilepsy Syndromes • Known genetic syndromes: • Angelman’s Syndrome • Tuberous Sclerosis
AW: ES at 4 mos of age Intractable epilepsy: head drops, myoclonic seizures, GTCS PE: Global DD, nonverbal, microcephaly, bilateral esotropia, profound hypotonia, GT MRI: unremarkable Extensive metabolic w/u: - KW: Identical twin ES at 6 mos of age Intractable epilepsy: head drops, myoclonic seizures, GTCS PE: DD, consonant vocalizations, sits unsupported, microcephaly, bilateral esotropia, diffuse hyptonia Case 1: A Tale of Two Sisters
CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patientsArcher, HL, Evans J, Edwards, S, et al. J Med Genet 2006; 43(9):729-734Department of Medical Genetics, Cardiff University, University Hospital of Wales, Cardiff, UKAbstractObjective: To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group. Methods: Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed. Results: Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett-like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto-temporal predominance and high amplitudes. Conclusions: The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting. Pts with mutation: Severe DD Autistic features and tactile sensitivity Only 1 Rett-like features Normal MRI Severe epileptic encephalopathy with ES, and subsequent myoclonic epilepsy • In a group of 72 patients referred for genetic testing of CDKL5: • severe DD and epilepsy <1 yr : 7/42F (17%)
Progressive development of facial phenotype Patient at 4 months, 5 years, 16 years and 19 years Facial features: deep set eyes straight eyebrows slightly short upturned nose, relatively large ears with large earlobes and high forehead 4 mos 4 yrs 3 ½ yrs 2 ½ yrs age 2 and 2 ½ years
Dravet’s Syndrome Severe Myoclonic Epilepsy of Infancy ( SMEI) First described by C Dravetin 1982 Progressive Course: Developmentally normal or mildly delayed Febrile status epilepticus Afebrile generalized and unilateral clonic seizures Development of myoclonus, atypical absence, partial seizures Significant cognitive and developmental deterioration, eventually nonverbal and nonambulatory
Dravet’s Syndrome Severe Myoclonic Epilepsy of Infancy First described by Dravet in 1982 Progressive Course: Developmentally normal or mildly delayed Febrile status epilepticus Afebrile generalized and unilateral clonic seizures Development of myoclonus, atypical absence, partial seizures Significant cognitive and developmental deterioration, eventually nonverbal and nonambulatory Genetics: Missense and truncation mutations in SCN1A Voltage gated Na channel subunit gene Present in >80% of patients
Sodium channel SCN1A and epilepsy:Mutations and mechanisms*Andrew Escayg and yAlan L. GoldinEmory University, Atlanta, Georgia, University of California, Irvine, California, U.S.A.Epilepsia 2010;51(9): 1650-58 SCN1A: dominantly inherited mutations Dravet syndrome: mutations cause loss of function GEFS+: Now stands for Genetic Epilepsy w/ Febrile Seizures +: wide semiology, FS persist >6 yrs of age, then develop absence, myoclonic, atonic, and myoclonic-astatic epilepsy (Doose syndrome) missense mutations that alter channel activity Family members with the SAME mutation, often have variable seizure types and severity Mouse models demonstrate the primary effect of mutations is to decrease activity of GABAergic inhibitory neurons
GEFS+ Spectrum Severe myoclonic epilepsy of infancy SCN1A SCN1B GEFS+ SCN2A Childhood absence and FS GABRG2 Benign familial neonatal-infantile seizures Ottman, 2002
CLINICALLY: • Genetic epilepsy with febrile seizures plus (GEFS+) • Febrile seizures first, then unprovoked generalized seizures • Often do not respond to medication • Development usually intact • Family history variable • 50-60% penetrance • “complex monogenic” inheritance versus autosomal dominant Genetics: -4 different alpha subunits of Na channel - Dots represent GEFS+ Mutations - 85% mutations result in Dravet Syndrome, Aut D, inactivate the protein, typically by truncation early in the SCN1A sequence, most are de novo - 10% mutations GEFS+ alter the function of proteins in the receptor
Early diagnosis and treatment can change course of disease ! 65- 75% of pts on ketogenic diet had >75% seizure reduction Kang et al, 2005: Caraballo, 2011, Nabbout et al, 2011
Dravet’s Syndrome Treatment: Response to treatment improves cognitive and developmental course Disease specific AEDs: Clobazam Stiripentol Avoid Na channel AEDs Consider early introduction of Ketogenic diet or other dietary treatments Role of Cannibidiol?
Current need and initiation of double-blind randomized control trials
Current need and initiation of double-blind randomized control trials -8 pts had EEGs before and after treatment, and showed no effect -Response of pts who had MOVED to CO, 2x that of pts who resided in state
Current Cannibidoil Trials 1. ‘Availability” trial: 137 pts treated, mean reduction in seizure number, 54% of pts had a 50% reduction in seizures 2. Effect of Cannibidoil on Neuropsychological profile for patients with refractory Epilepsy: RESULTS AVAILABLE SOON 3. Randomized “Placebo” clinical trial in pts with Dravet syndrome: RESULTS AVAILABLE SOON 4. Randomized “Placebo” clinical trial in pts with Lennox-Gastaut syndrome: RESULTS AVAILABLE SOON 5. Smaller trials in specific patient populations
Current Cannibidoil Trials • NEREG TRIAL: • High CBD/low THC concentration MMJ • Open label trial • Various age categories • Variable seizure types, but all Medically refractory epilepsy • Following: • Seizure frequency • Effect of Anti-epileptic medications • Measuring Patient Questionnaires on: • -Sleep • Behavioral Health, especially Anxiety, Mood
Exciting: Dravet Trial at NEREG • Fenfluramine: amphetamine-like drug • Pilot study of the effect on seizures of pts with Dravet syndrome showed significant promise • Follow-up study: randomized, placebo trial for patient with Dravet’s syndrome • Follow up open label trial • Careful, cardiac monitoring with echocardiograms during study • ENROLLING NOW!
Tuberous Sclerosis Incidence: 1 in 6,000 live births; more than 1 million worldwide • TSC1 and TSC2 • 1/3 dominant inheritance • 2/3 spontaneous mutation • Diagnosable at birth • Hypopigmented macules • CT / MRI • Conditions: • Cognitive impairment/Autism • Severe, refractory epilepsy/Epileptic spasms/Lennox-Gastaut Syndrome 36 weeks 22 week
Tuberous Sclerosis • TSC2 gene was identified in 1993 at 16p13 which encodes the protein tuberin, • TSC1 identified in 1997 at 9q34 which encodes the protein hamartin. • In 2002 tuberin-hamartin complex found to inhibit mTOR (mammalian target of rapamycin) via the GTPase-activating protein.
Special Issues in Patients With Tuberous Sclerosis • Treatment Issues: • Specific gene targeted therapies with mTOR inhibitors: • Afinitor: for Renal tumors ( angiomyolipoma) • For Brain tumors, SEGA • Specific Responsiveness: Vigabatrin for all • seizure types • Dietary Therapy
Special Issues in Patients With Tuberous Sclerosis • Treatment Issues: Exception to the rule: • Targeted surgery for a genetic epilepsy using functional imaging as a guide to epileptic activity
Clinical Protocols • Clobazam and Aggression-Related Adverse Events in Pediatric Patients With Lennox–Gastaut Syndrome • Juliann M. Paolicchi MD, Gail Ross PhD, Deborah Lee MD, PhD, Rebecca Drummond PhD and Jouko Isojarvi MD, PhD • Pediatric Neurology, 2015-10-01, Volume 53, Issue 4, Pages 338-342 • , • Clobazam is equally safe and efficacious for seizures associated with Lennox–Gastaut syndrome across different age groups: Post hoc analyses of short- and long-term clinical trial results • Yu-Tze Ng, Joan Conry, Wendy G. Mitchell, Jeffrey Buchhalter, Jouko Isojarvi, Deborah Lee, Rebecca Drummond, Steve Chung • May 2015(46), 22-25. • Trial of Diazepam Nasal Spray vs Diastat: concluded • Trial of Perampenal ( typically used in partial seizures) in the treatment of Generalized seizures in Children
Conclusion: Advantages of early genetic testing for patients with treatment resistant epilepsy: 1. Initiate targeted treatments to decrease seizure burden/cognitive impact of epilepsy • SCN1A, SCN2A • Avoid Na channel drugs, VGB • Early introduction of the ketogenic diet • Clobazam • Stiripental • UBE3A: long-acting BZs, avoid Na channel drugs • Vigabatrin: STXBP1, other 9q34.11 genes, TSC1, TSC2(TS) • Dietary Treatment: SCL2A1, CDLK5, SCN1A, GEFS+ • Specific translational therapies • Mtor inhibitors for TSC 2. Avoid unnecessary procedures/ ineffective therapy trials
Genetic Associations with Epileptic Encephalopathies • Are there specific genes that we need to look for NOW? • Epileptic Spasms: CDLK5, ARX • Pyrodoxine/Folinic Acid dependent: ALDH7A1, FOLR1 • GEFS+ gene family: SCN1A, 1B. 2A, 8A • Glut Tranporter type 1 def: SLC2A1 • Early infantile EE: ARX, STXBP1, SPTAN1, PCDH19 • Retts: MECP2, MEF2C • Angelman’s: UB3a • Alperts: POLG • TS: TSC1, 2
Conclusion: Advantages of early genetic testing for patients with treatment resistant epilepsy: 1. Initiate targeted treatments to decrease seizure burden/cognitive impact of epilepsy 2. Develop Specific translational therapies • Mtor inhibitors for TSC 3.. Avoid unnecessary procedures/ ineffective therapy trials 4. Cost-effectiveness of early genetic testing: a) J Paolicchi, et al A Health Economic Study of Genetic Testing in Refractory Epilepsy Patients
Diagnostic Yield of Epilepsy Panels in Children With Medication-Refractory EpilepsyPediatric Neurology 6/19Eric Segal, MD, Helio Pedro, MD, Karen Valdez-Gonzalez, MS, Sarah Parisotto, MS, Felicia Gliksman, MD, Stephen Thompson, MD, Jomard Sabri, BA, Evan Fertig, MD
Conclusions: Broader Implications • Single mutations are no longer the whole story: • Diverse expressed clinical presentations • Similar syndromes may be secondary to different mutations • Treatment resistant epilepsy + unremarkable MRI +/- movement disorder = genetic disorder • Classification and Treatment of the epilepsies are already being influenced by genotypic classifications
Advances in the Genetics of Epileptic Encephalopathies:EPGP/HEP Project Juliann M. Paolicchi, MA MD • Racial and ethnic differences in epilepsy classification among probands in the Epilepsy Phenome/Genome Project (EPGP). • Epilepsy Res. 2013 Dec;107(3):306-10. • -Lennox-Gastaut syndrome of unknown cause: phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project. • .Epilepsia. 2013 Nov;54(11):1898-904. • -The epilepsy phenome/genome project. • Clin Trials. 2013 Aug;10(4):568-86. • -Polymicrogyria -associated epilepsy: a multicenter phenotypic study from the Epilepsy Phenome/Genome Project.Epilepsia. 2013 Aug;54(8):1368-75 • -Evidence for a shared genetic susceptibility to migraine and epilepsy. • .Epilepsia. 2013 Feb;54(2):288-95 • -The Epilepsy Phenome/Genome Project ( EPGP) informatics Platform. • Int J Med Inform. 2013 Apr;82(4):248-59.
Perampanel Perampanel is a new and unique seizure medication that blocks the action of glutamate at AMPA receptors in the brain. Glutamate is an excitatory neurotransmittor that spreads the overexcitation characteristic of epileptic spread. Inclusion criteria: Age 4 to less than 12yrs • Epilepsy diagnosis with primary generalized seizures with or without generalization • Currently being treated with stable doses of 1 to a max of 2 approved AEDs. • ( A VNS will be counted as one of the 2 allowed AEDs) Trial type: Double –blind, placebo controlled trial: Highest quality trial: Some patients get medicine, some do not, and no one knows who does until the end. Followed by Open label: If you choose to continue, you do get the medicine, and everyone knows.
Conclusions: • Are there specific genes that we need to look for NOW? • Epileptic Spasms: CDLK5, ARX • Pyrodoxine/Folinic Acid dependent: ALDH7A1, FOLR1 • GEFS+ gene family: SCN1A, 1B. 2A, 8A • Glut Tranporter type 1 def: SLC2A1 • Early infantile EE: ARX, STXBP1, SPTAN1, PCDH19 • Retts: MECP2, MEF2C • Angelman’s: UB3a • Alperts: POLG • TS: TSC1, 2