Rodent models of infantile spasms and the hunt for new ... - … · Rodent models of infantile...
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Rodent models of infantile spasms and the hunt for new
treatments
Morris H. Scantlebury M.D. Assistant Professor, Departments of
Pediatrics and Clinical Neurosciences, University of Calgary, Canada.
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Treatments
• Vigabatrin- effective 20-30% of the time. Much higher in patients with TS.
• ACTH/prednisolone- Effective 60-70% of the time
• Treatments are refractory 30-50% of the time
Both treatments associated
with considerable toxic
side-effects!
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• Persistent psychomotor disabilities despite treatment
• Emergence of other seizure types
• High mortality of ~ 30% (50% are disease-related )
Outcome Infantile Spasms
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• WE NEED SAFER AND BETTER TREATMENTS FOR INFANTILE SPASMS
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ANIMAL MODELS OF INFANTILE SPASMS
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Animal models of epilepsy: What are the considerations to model?
• There are many, many experimental models of epilepsy involving both in-vivo and in-vitro preparations
• There are several things to consider when evaluating or developing a model of epilepsy– Species – Syndrome– Developmental specificity– Sex differences– Etiology– Methods of induction– Anatomical targets (Where to direct the inciting insult, where should be the
damage– Genetic background– Predisposing factors– Reason for using the model (high throughput for screening drugs or to study
mechanisms)– Comorbidities (depression, autism, learning and memory deficits)– COST!!!!!!!
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SPECIES DIFFERENCES
DeFelipe J, Frontier in neuroanatomy 2011
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HUMAN MOUSE
DeFelipe J, Frontier in neuroanatomy 2011
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DeFelipe J, Frontier in Neuroanatomy 2011
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Which epilepsy syndrome to model?
Blumke et al, Epilepsia 2011
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*****
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Lee et al, Epilepsia 2008
Chronic TTX Infusion (right hippocampus)Model of Infantile SpasmsModel of sodium channel dysfunction
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HFO increase at time of seizure
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Vigabatrin suppresses spasms and late HFO of ictal onset
Interictal HFOs were also suppressed
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• ECOG, 636 spasms in 11patients
• 104-148 contacts
– Placement guided by EEG, MRI, PET
• Recorded HFO correlated with EMG with spasms
• Augmentation of HFO preceded the onset of spasms seen mainly in Rolandic cortex
• Post-surgical outcomes better if maximal HFO resected
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Down’s syndrome based model of IS• Model of infantile spasms created by exposing
Down’s mice to a GABA B agonist such as baclofen or GHB. Note these mice overexpress (g-coupled inward rectifying potassium channels) specifically GIRK 2 channels
• GIRK 2 KO Down’s mice are resistant to GIRK channel agonist-induced spasms- thus there is a specific molecular target for developing treatments of IS
Cortez MA et al 2009, Joshi K et al 2016
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Cortez MA et al 2009, Joshi K et al 2016
WT
Ts65Dn
Ts65Dn + GBL- interictal
Ts65Dn + GBL- ictal
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Ultra slow oscillations common around
time of spasms
The USO are due to GIRK channel
over activity
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NMDA-Induced Motor Seizures Following Prenatal Betamethasone
Velisek et al, Ann Neurol 2007
Baseline
After NMDA
After NMDA
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Effects of ACTH on Latency to NMDA-evoked Events
Velisek et al, Ann Neurol 2007
Naïve Rats
Prenatal Exposureto Betamethasone
Model of NMDA induced spasms in the stressed
brain sensitive to ACTH
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Upregulation of MC4 receptors in the hypothalamus in rats with spasms- if blocked
pharmacologically then ACTH is no longer effective
Immunohistochemistry Western blot
Inching closer to
knowing the exact
mechanism and site
of action of ACTH
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Development of the triple-hit model of infantile spasms based on
our best understanding of the mechanisms
• Hypothesized that spasms occur in patients with both abnormal cortical and brainstem function and/or abnormal communication between the two structures as can occur due to white matter injury
• Abnormal serotonerigic mechanisms would potentiate the spasms
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Age : P9, Flexion spasm Age : P9, Extension spasm
DOXORUBICIN: TO INDUCE CORTICAL AND BRAINSTEM INJURY
LIPOPOLYSACCHARIDE: TO INDUCE INFLAMMATORY CASCADES
AND WHITE MATTER INJURY
PCPA: TO REDUCE SEROTONIN LEVELS
Scantlebury MH et al: Neurobiol Dis 2010
Multiple-hit model: Robust model that allows
for the rapid screening of drugs for IS
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Scantlebury MH et al: Neurobiol Dis 2010
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Scantlebury MH et al: Neurobiol Dis 2010
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Autistic features and learning deficits
Scantlebury MH et al: Neurobiol Dis 2010
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Scantlebury MH, et al: Neurobiol Dis 2010
Spasms refractory to ACTH – Paritaly Responsive to Vigabatrin
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Ono et al 2010
Carisbamate, but not phenytoin, suppresses spasms acutely
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Rapamycin suppresses spasms and improves cognitive outcome
Raffo et al 2010
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Briggs et al Epilepsia 2014
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Surface Righting
Postnatal age
P5 P6 P7 P9 P10 P11 P12
La
tency (
sec)
0
20
40
60
80
100Saline/ND
Saline/KD
Treatment/ND
Treatment/KD
Age: p=0.001; Treatment x Age: p=0.01
Open Field
Postnatal age
P5 P6 P7 P9 P10 P11 P12
La
ten
cy (
se
c)
0
20
40
60
80
100Treatment: p=0.006; Age: p<0.001; Treatment x Age: p=0.001
Negative Geotaxis
Postnatal age
P5 P6 P7 P9 P10 P11 P12
La
ten
cy (
se
c)
0
20
40
60
80
100Treatment: p=0.006; Age: p<0.001; Treatment x Age: p<0.001
Postnatal age
P4 P5 P6 P7 P8 P9 P10 P11 P12
Bo
dy w
eig
ht (g
)
8
10
12
14
16
18
20
22
24 ND/Saline
KD/Saline
ND/Treatment
KD/Treatment
Treatment: p<0.001Age: p<0.001Treatment vs Age: p<0.001
* *
#
* *
*
#
#
*
#
*
*,#: significant differences from ND/Saline
Scantlebury lab 2017 unpublished
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Pedro R. Olivetti et al., Sci Transl Med 2014; Chachua T et al, Epilepsia 2016
• E2 treatment
prevent spasms
and long-term
seizures, restores
GABAergic INs
• Not observed in
model of NMDA –
induced spasms
• Arrested decent
of the testes and
changes in sex-
specific behaviors
a side effect
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MODLES Method Age Seizure type Ictal EEG Inter Ictal EEG Treatments
Acquired
CRH** i.c.v. injections of CRH P5-16 Limbic like
seizures(
Chewing)
Swimming, Leg
clonus,
Tonic limb
posturing
Semi rhythmic sharp wave and
increased beta activity
- Effective: Phenytoin, alpha
helical CRH
Ineffective: ACTH
NMDA** i.p. injections of NMDA P12-18 Tail twisting,
spasms
Suppression of activity or
“serrated waves” which is runs
of slow waves with
superimposed fast activity
- Effective: Vigabatrin (P12), VPA
(P18), B6, (P12 and P18)
Ineffective: VPA (P12), ACTH
Betamethasone-
NMDA**
i.p. injections of NMDA in
pups prenatally exposed to
betamethasone
P15 Tail twisting,
spasms
Suppression of activity or
“serrated waves” which is runs
of slow waves with
superimposed fast activity
- Effective:ACTH
TTX** Infusion of TTX into cortex
and hippocampus
P21-adults spasms High amplitude slow wave
transient followed by attenuation
with superimposed fast activity
Multi-focal spikes and
sharp wave discharges
None tested
Genetic
Down’s* i.c.v injection of GHB to the
Ts(1716)65Dn mouse
P7 to adults spasms Bursts of epileptiform activity
followed by attenuation
Generalized voltage
attenuation
Effective: ACTH1-24, CGP
354348, ethosuxamide,
valproate, Vigabatrin (partially)
Ineffecttive: ACTH1-39,
Serotonin, baclofen, (latter two
exacerbate the seizures)
ARX* Conditional knock-out Adults spasms spike wave discharge followed
by voltage attenuation on the
EEG
Reduced delta and beta
activity
None tested
ARX(GCG)10+7* Triplet repeat knock in
expansion
P7-11 spasms sharp transient followed by
attenuation of the background
activity
High amplitude spike –
slow wave discharges
Estradiol
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IS lies along a spectrum of the DEEDs
EIEE IS LGS
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Comparison of the clinical feature of the epileptic encephalopathies
Clinical features EIEE EME IS LGS
Age at onset 75% < 1 month 96% < 1 month 90% 3-12 months 1-7 years
Incidence/10,000
live births
Rare (unknown) Rare (unknown) 3-5 2.8
Seizure Types Tonic spasms*
Partial motor
Erratic focal motor
Hemiconvulsions
Generalized tonic
Erratic/fragmentary
myoclonus *
Tonic
Tonic spasms (rare)
Simple focal
Spasms (flexor, extensor, mixed
flexor/extensor) *
Focal
Drop attacks
Tonic (80-90%)*
Atypical absence
Atonic
Drop attacks
Non-convulsive status
Ictal EEG Burst Suppresion
Attenuation
No clear correlate Electrodecremental (attenuation
+/- with overriding fast activity)
Paroxysmal fast
Attenuation
Slow spike wave discharges
Combination
Inter Ictal EEG Burst Suppresion Burst Suppresion Hypsarrhythmia Slow spike wave discharges
Prognosis Poor Poor Etiology dependent Poor
Treatment Non- effective
Zonisamide,
Vigabatrin in
single case
reports
Non-effective. Pyridoxine
in those due to pyridoxine
deficiency
ACTH, Vigabatrin in some
patients
Often intractable. Polytherapy often
applied.
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EIEE
EME IS
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LGS
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Etiologies of the catastrophic epilepsies
Etiology EIEE EME IS
Structural abnormalities,
acquired or genetic
Cerebral dysgenesis
Aicardi syndrome
Hemimegalencephaly
Lissencephaly
Porencephaly
Hydrocephalus
Subacute Diffuse
Encephalopathy
Rare HIE, birth trauma
Stroke, Hemorrhage
Meningitis , encephalitis, congenital
infections
Focal cortical dysplasia
Tuberous sclerosis
Aicardi syndrome
Periventricular nodular heterotopia
Subcortical band heterotopia
Polymicrogyria
Hemimegencephaly
Lissencephaly
Pachygyria
Microdysgenesis
Holoprosencephaly
Inborn errors of metabolism
/mitochondrial disorders
Many genetic causes
emerging
Non-ketotic hyperglycinemia,
Propionic aciduria,
Methyl melonic academia ,
d-Glyceric academia,
Sulphite defficiency
xantnine deficiency
Menke’s disease,
Molybdenum co-factor
deficiency
Zellweger’s syndrome,
Pyridoxine dependency
Tay Sach’s (phenylketonuria)
dihydropteridine reductase deficiency
Histidinemia
Pyridoxine dependency
Urea cycle disorders
Alpers syndrome
Leighs syndrome (cytochrome c oxidase
deficiency)
Other chromosomal
abnormalities
Down’s syndrome (Trisomy 21)
ARX
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….therefore the knowledge gained from
understanding one model may be applicable
across the spectrum of etiologies of the epileptic
encephalopathies….
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Conclusion
• There is major recent advances in the understanding of the epileptic encephalopathies that would lead to new, safe and effective etiology specific treatments which are urgently needed clinically
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Thanks …
• Past and present Lab members:– Dr. Morris Scantlebury
– Dr. Karlene Barrett
– Ms Anamika Choudhary
– Mr Lucas Scott
– Ms Keelin Rivard
• Funding:
– ACHRI start-up funds
– ACHRI postdoctoral fellowship (Karlene)
– ACRI-BDB theme group bridge funding
– CSMREP
– CIHR Project scheme
• Collaborators:– Dr. Richard Wilson
– Dr. Quentin Pittman
– Dr. Arijit Roy