Slides from the 2018 Cerebral Creatine Deficiency Syndrome (CCDS) Family & Physician Symposium. Dr. Denise Morita, MD presents an overview of seizures, how they relate to CCDS and what families can do to improve the knowledge available regarding CCDS Seizures.

1. CCDS and Seizures
Cerebral Creatine Deficiency Syndromes
Scientific + Patient Symposium
Austin, Texas
July 27, 2018
Denise Morita, MD
Pediatric Neurology
Riverton, Utah

2. Outline
Overview of Seizures and Epilepsy
 Seizures in CCDS
Anticonvulsants & Other Treatments for Seizures
 Anticonvulsants in CCDS
On the Horizon….
 Pharmacogenetics
 How you can help!

3. Classification of Seizures
Focal Seizures (complex partial seizures)
• Brain location: frontal, temporal parietal or occipital lobe
• Semiology/symptoms: motor, alteration of consciousness,
aura, autonomic dysfunction
• Stereotyped
• Usually not provoked
Generalized Seizures
• Generalized tonic clonic
• Atonic or ‘Drop’ – sudden loss of tone
• Tonic - stiffening
• Myoclonic – brief, lightening like jerk
• Absence
• Infantile spasms
EpilepsyDiagnosis.org/Seizure Classification

4. Why is seizure type useful to know?
May suggest where in the brain
the seizure starts
May predict which anticonvulsant
would be helpful
Facilitate communication with you
and your neurologist

5. EEGs
Can confirm the seizure type –
focal or generalized
EEG findings and seizure type
together can define an epilepsy
syndrome
Ambulatory EEG can capture
episodes to determine whether
they are seizures

6. Epilepsy
General
About 1 % of children have 1 seizure during childhood
‘Epilepsy’ is 2 or more unprovoked seizures, or 1 seizure
with a high chance (>60%) of having another seizure
The first anticonvulsant ‘works’ in 60-80% of cases
Drug-resistant epilepsy = refractory epilepsy
2 or more anticonvulsants have not worked
~30% people with epilepsy
Sudden Unexpected Death in Epilepsy
Person with epilepsy unexpectedly dies, no cause found
30% of deaths in people with epilepsy are related to
seizures; 70% are related to ‘natural causes’
Rates: 1/1000 adults with epilepsy per year
0.2/1000 children with epilepsy per year
Risk factors in adults: frequent generalized tonic clonic
seizures.
Risk factors in children: Dravet syndrome, SCN8A,
isodicentric chromosome 15 syndrome

7. Seizures in CCDS
GAMT deficiency
• 80% have seizures
• Onset is usually 10 months –
3 years
• Seizure types: generalized
tonic clonic, atonic, absence
• Infantile spasms are unusual
• 45% drug resistant
Creatine Transporter
Deficiency
• 50% have seizures
• Onset is usually 16 months – 12 years
• Seizure types: myoclonic, generalized
tonic clonic, status epileptics, focal
seizures
AGAT Deficiency
• 9% have seizures
• Seizure type: febrile seizure

8. Many unanswered questions about
seizures in CCDS
Over time, do seizures get better? or worse?
How common is SUDEP in CCDS?
What anticonvulsants work best? Or worst?
etc.….

9. Anticonvulsants
Pick one based on the kind of seizure and possible side
effects (weight gain, weight loss, effect on mood etc.)
Taper up until
1. Seizures stop or decrease ‘enough’
2. Excessive side effects
3. Maximum therapeutic dose
If needed, add another anticonvulsant
Try to taper off ineffective anticonvulsants

10. Anticonvulsants in
GAMT deficiency
Goal is all CCDS is to increase brain creatine
In GAMT deficiency, another goal is to limit accumulation of
GAA
• Decrease glycine (sodium benzoate, phenylbutyrate)
• Limit conversion of glycine to GAA (decrease arginine,
increase ornithine)
 Valproate increases CSF glycine – consider avoiding
Glycine
Guanidinoacetate
(GAA)
Creatine
Arginine
Ornithine
AGAT
GAMT
Creatine
Transporter
S-adenylmethionine
S-adenylhomocysteine

11. CBD oil for epilepsy
Cannibidiol extracted from the marijuana plant – no THC
(tetrahydrocannabinol)
Best studied in children with Dravet Syndrome or Lennox-
Gastaut syndrome
• 37% had 50% seizure reduction over 3 months
• Side effects: sleepiness, decreased appetite, diarrhea;
2 cases of SUDEP
May increase liver enzymes, especially if taking valproate
Interaction with clobazam (Onfi) – may need to decrease
the dose of clobazam (Onfi)

12. Non-pharmacologic Treatment for Seizures
Vagal Nerve Stimulator
• 20-50% of pediatric patients
have 50% decrease in
seizures, may take up to 2
years to see this
• Magnet can be used to stop a
long seizure
• Cannot have an MRI of the
thorax
Ketogenic Diet
• High lipid, moderate protein,
low carbohydrate diet
• 60% of pediatric patients have
50% decrease in seizures,
30% have >90% reduction,
after 6 months
• 20% can stop other
anticonvulsants
• 5% have worsened seizures
Epilepsy Surgery
• Lobectomy
• Hemispherectomy
• Corpus callosotomy
• 70-100% seizure freedom at 1
year, but declines over time

13. On the Horizon….
• Pharmacogenetics
• How you can help!

14. Pharmacogenomics
How genes affect a person’s response to medications
• Fast metabolizer or slow metabolizer
• Likelihood of an allergic reaction
Currently, for anticonvulsants, the only validated test is for
Asian people (China, Malaysia, Thailand) before starting
carbamazepine

15. How You Can Help
Participate in research!
clinicaltrials,gov
Network with other Families
Share your observations with your doctors
Innovation through Collaboration

16. Summary
EpilepsyDiagnosis.org/Seizure Classification
ClinicalTrials.gov
Austin, Texas

18. Focal seizure
Awake but not acting normally
Face, arm or leg twitching
Automatisms (lip smacking,
fumbling etc)
Tired after
Back to Classification of Seizures

19. Convulsive seizure
Stiffening of whole body, then
rhythmic twitching
Can have drooling, cyanosis
(turning blue)
Lasts seconds to minutes,
sometimes 10-20 minutes
Gradual offset
Tired after
Back to Classification of Seizures

20. Absence seizure
Sudden behavioral arrest
Can have automatisms (eye
fluttering, mouth smacking)
Lasts 5-10 seconds
Back to normal right after
Triggered by hyperventilation
EEG shows 3 herz spike wave
discharges during absence seizure
Back to Classification of Seizures

21. Infantile spasm
3-12 months old
Head ducks, arms extend
Few seconds, repeats in clusters
Often on waking up or falling asleep
Crying after
Back to Classification of Seizures