Transcript Research and advances in epilepsy

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
Major Focus of Pediatric Epilepsy
Research:
1. Identifying Genetic Causes of
Epilepsy
2. Targeting Therapies to Specific
Cause of Epilepsy
3. Focus on Outcome: How do
new therapies work best? How
can we prevent further effects of
epilepsy
Juliann M. Paolicchi, MA MD
Northeastern Regional Epilepsy Group
Clinical Professor, Rutgers University
Medical Center
Financial Disclosures
 NINDS: Epilepsy Phenome-Genome Study
 NINDS: Human Epilepsy Project
 Clinical Investigator:
 Lundbeck Pharmaceuticals
 Zogenix
 Acorda Pharmaceuticals
 Consultant/Speaker:
 Lundbeck Pharmaceuticals
 Cyberonics
 Quest Diagnostics

Treatment of Epilepsy with
Previously Untreated Epilepsy Patients (n=470)
Anti-Epileptic
Medications
Kwan P, Brodie MJ. NEJM
2000; 342:314-319
Epilepsy: Incidence/100,000
200
150
100
50
0
0
20
40
60
Age
Hauser, Epilepsia 33:1992
80
100
Neurobiological spectrum of the epilepsies
polygenic
inheritance
acquired cause
trauma, hypoxia,
vascular etc.
single
gene
Structural/
Metabolic
Genetic
Age
Recent Breakthroughs in the
Genetic Basis of Epilepsy
Syndromes
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Early Childhood Epileptic Encephalopathies:
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Cortical dysgenesis
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Doose Syndrome
Dravet’s syndrome
Childhood Epilepsy Syndromes:
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Neuronal Migration disorders
Zellweger’s syndrome
Walker-Warburg syndrome
Genetic Epilepsy Febrile Seizures +
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Otahara’s Syndrome
Early Myoclonic Epilepsy
Migrating partial epilepsy of infancy
Epileptic (Infantile spasms)
Juvenile Myoclonic Epilepsies
Progressive Myoclonic Epilepsy Syndromes
Known genetic syndromes:
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Angelman’s Syndrome
Tuberous Sclerosis
What causes epileptic encephalopathy in
infancy?
The answer may lie in our genes
K. D. Holland and B. E. Hallinan,
Neurology 75(13) 2010: 1132-1133
Gene
Clinical clues
Locus
Gene product
STXBP1
Early-onset (4 months) tonic
seizures, spasms, or myoclonic
seizures, some with burstsuppression on EEG, severe
mental retardation2,3
9q34.1
Syntaxin binding
protein 1
CDKL5
Seizure onset 6 months,
hypotonia,
deceleration of head
growth, profound mental
retardation, usually females
affected 5,8a
Xp22.3
Cyclin-dependent kinaselike 5
ARX
Early onset of infantile
spasms (6 months), dystonia and
chorea may also be present,
mental retardation, mostly males9
Xp22.13
Aristaless-related homeobox
protein
SCN1A
Prolonged febrile seizures
and hemiconvulsions, subsequent
developmental decline and
afebrile
seizures, onset of seizures
less than 1 year10
2q24
Voltage-gated Na channel
PCDH19
Similar to SCN1A mutation
phenotype,predominately
females11
Xq22.1
Protocadherin 19
a. Patients with FOXG1 mutations can have a similar phenotype except seizures are less common.
Case 1:
A Tale of Two Sisters
 AW:
 KW:
 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: -
 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
CDKL5 mutations cause infantile spasms, early onset
seizures, and severe mental retardation in female
patients
Archer, HL, Evans J, Edwards, S, et al.
J Med Genet 2006; 43(9):729-734
Department of Medical Genetics, Cardiff University, University Hospital of Wales, Cardiff, UK
Abstract
-In a group of 72 patients
referred for genetic testing of
CDKL5:
Pts with mutation:
Objective: 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.
-severe DD and epilepsy <1 yr :
7/42F (17%)
Severe DD
Autistic features and tactile
sensitivity
Only 1 Rett-like features
Normal MRI
Severe epileptic
encephalopathy with ES, and
subsequent myoclonic epilepsy
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
3 ½ yrs
age 2 and 2 ½ years
4 mos
4 yrs
2 ½ yrs
AW and KW: Marked response to ketogenic diet!
Dravet’s
Syndrome
 Severe Myoclonic Epilepsy
of Infancy ( SMEI)
 First described by C 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
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. Goldin
Emory 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
SCN1A
Severe myoclonic
epilepsy of infancy
SCN1B
GEFS+
SCN2A
Childhood absence
and FS
GABRG2
Ottman, 2002
Benign familial
neonatal-infantile
seizures
 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
20
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
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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
22 week
36 weeks
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 GTPaseactivating 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?
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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 MedicationRefractory Epilepsy
Pediatric Neurology 6/19
Eric Segal, MD, Helio Pedro, MD, Karen ValdezGonzalez, 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
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.
Juliann M. Paolicchi, MA MD
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?








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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