This presentation was given by Dr. Scott Demarest during the 2nd Rett Clinic Family Symposium at the Children's Hospital Colorado. It talks about Anxiety and Depression with focus on Rett syndrome. The Rett Clinic is funded by the Rocky Mountain Rett Association.
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Epilepsy in rett and rrd Dr. Scott Demarest
1. Seizure Types and Treatment in
Rett Syndrome and Rett-
related Disorders
Scott Demarest MD
Assistant Professor, Departments of Pediatrics and
Neurology
University of Colorado School of Medicine
Children's Hospital Colorado
2. Disclosures
This Research is supported by:
• The International Foundation for CDKL5 Research
(IFCR)
• NIH funding for the Rett Natural History Study
• Rocky Mountain Rett Association
• My epilepsy genetics research is supported by NIH
funding through a K12 mechanism.
No conflicts of interest.
3. Rett and Rett-related Disorders
• Rett Syndrome – Deletion or dysfunction of MeCP2
• MeCP2 Duplication syndrome
• CDKL5 related Epileptic Encephalopathy
• FOXG1 Deletion or Duplication
• Others genetic syndromes are sometime said to be
“Rett-like”
4. Agenda
1. What are some of the Seizure types we see in these
disorders?
2. How are these disorders different in terms of
Epilepsy?
3. What treatments are best in each condition?
5. What is Epilepsy?
Recurrent (>2) unprovoked (not due to infection in the
brain or trauma) seizures.
This implies an individual is at high risk to have another
seizure (particularly if not treated).
6. Seizure Types
Generalized
• Generalized
Tonic-clonic
• Generalized
Tonic
• Myoclonic
• Absence
• Atonic
Focal
• Can look many different
ways
• Usually something
asymmetric about the
seizure
• May become generalized
Other
Epileptic Spasms
7. How do we read the squiggles
Left Temporal
Right Central
10. Is Epilepsy the Same in Rett and
Rett-related Disorders?
Short answer – NO
It is often not the same from one patient to another
with the same disorder…
So what are some of the general characteristics of
Epilepsy in these disorders?
11. Epilepsy in Rett Syndrome
• ~60-80% of patients with Rett syndrome have
epilepsy
• Age of onset usually between 3-5 years
• 60% have well-controlled seizures
• 30% have uncontrolled seizures
So what determines this?
12. Factors Contributing to Severity of
Epilepsy in Rett Syndrome
Mutations associated with higher risk of having
uncontrolled epilepsy and percentage uncontrolled
Epilepsia, 56(4):569–576, 2015 doi: 10.1111/epi.12941
44%
41%
50%
13. Factors Contributing to Severity
of Epilepsy in Rett Syndrome
Epilepsia, 56(4):569–576, 2015 doi: 10.1111/epi.12941
• Earlier age of onset is
associated with more severe
epilepsy particularly less
than a year
• Type of Rett phenotype
(Classic, Preserved speech,
Congenital) is not associated
with epilepsy severity
• But having epilepsy
correlates with worse
speech, walking, breathing
disorder and regression
scores
Age of onset of epilepsy in patients who developed epilepsy
80%
92.5%
14. Seizure Types in Rett Syndrome
46%
27%
14%
12%
9%
4%
26%
4%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Generalized tonic-
clonic
Focal Absence Myoclonic Tonic Atonic Two seizure types More than 2 seizure
types
Types of Seizures in Rett Syndrome
Epilepsia, 56(4):569–576, 2015 doi: 10.1111/epi.12941
15. Electrographic Status Epilepticus in Sleep (ESES)
Present in 10-15% of patients with Rett syndrome and if occurring
during regression is associated with a worse developmental outcome
Epilepsia, 51(7):1252–1258, 2010 doi: 10.1111/j.1528-1167.2010.02597.x
16. “Rett Spells” vs Seizures
• ~70% of pateints with Rett have “Rett spells”
• Additionally, many symptoms of Rett can mimic
seizures but are not including:
• Hand Steotypies
• Breath-holding, cyanosis, hyperventilation
• Staring and behavior arrest
• Unusual eye movements
• Funny facial movements
• Unwarranted bouts of laughing or screaming
• Motor abnormalities (tremor, dystonia, jerking, spasticity, sudden
loss of tone)
A sudden combination of some of these symptoms that
occur together are typical of a “Rett spell”
18. Treatment of Epilepsy in Rett Syndrome
There is no single drug that is best for treating epilepsy
in Rett Syndrome
• Most common – Depakote, Carbamazepine,
Phenobarbital, Lamotrigine
• Mixture of other seizure meds were nearly as good
• If medications are not working:
• Ketogenic diet may be helpful
• VNS seems to work well
19. Epilepsy in MeCP2 Duplication
Less common so we know less…
• Almost all have epilepsy
• Epilepsy is generally hard to treat
• Usually starts in childhood (4-8 years-old)
• Can have any seizure type but EEG and seizure types
often are consistent with Lennox-Gastaut syndrome
(LGS)
• There is no data about what medication is best
• VNS, Ketogenic diet and Corpus Callosotomy may be
helpful
20. CDKL5 Syndrome
Has been called:
• The “early-onset seizure” variant of Rett Syndrome
• EIEE2 (Early Infantile Epileptic Encephalopathy type
2)
• Atypical Rett Syndrome
• CDKL5 Epileptic Encephalopathy
21. CDKL5 Syndrome
Phenotype:
• Early seizure onset (first few weeks to month of life)
• Typically no significant regressions but abnormal
development throughout
• Many patients are not able to walk and have
severely limited language
22. What is our involvement with CDKL5?
Dr. Benke established the multidisciplinary Rett Clinic here
in December 2011 with the help of the Rocky Mountain
Rett Association.
We see patients with both Classic and atypical Rett
Syndrome
Thus far have seen 44 patients with CDKL5 Syndrome.
This is more than any other single center in the US (possibly the world)
We are members of the CDKL5 Centers of Excellence
This is helping us learn more about this rare disease.
23. Clinical Spectrum
There is actually a wide spectrum:
1/6 of our patients have a more “mild” form
They are able to walk, talk and use their hands well enough to feed
themselves.
All but one still had severe epilepsy starting in the first 2 months of life
Only one is currently seizure free
These patients had many different types of gene
changes (Not Hotspots)
24. Epilepsy in CDKL5
Epilepsy onset 88% in the first 8 weeks of life, Median age of onset 4
weeks and 1/3 of patients had onset in the first 2 weeks.
80% of patients develop infantile spasms
• But only 30-50% have hypsarrhythmia
• (our unpublished data)
Others have described a hypermotor tonic spasms sequence as a specific
and unique seizure type.
• We are seeing this as probably not unique to CDKL5 but certainly
characteristic, but as a combination of tonic, epileptic spasms,
hypermotor or other focal seizures that cluster together
25. Age of onset of Epilepsy by Mutation Type
PMID: 27770071
29. Treatment of Epilepsy in CDKL5
• Epilepsy is very hard to treat and almost always life-
long
• Focus is on addressing the most bothersome seizure
types while avoiding medication side effects
• There is no single treatment that is best but most
patients seem to be helped by something
• Keep trying new treatments but patiently and
systematically
30. Epilepsy in FOXG1 Related Disorders
Deletion/ mutation:
• Epilepsy onset is later and can have a variety of seizure types
• Seizure are hard to treat and often require multiple
medications
• Patients have more difficulty with ambulation and hand use
Duplications:
• Nearly always get infantile spasms
• This is usually can be treated successfully with ACTH
• Patients usually do not have ongoing seizures as they get
older
Both groups have severe language difficulty and poor
socialization
31. Conclusions
Rett Syndrome
• Epilepsy is common but only 1/3 of those with epilepsy will if be
refractory
• If meds don’t work Ketogenic diet or VNS might
• Rett spells vs Seizures…if you aren’t sure get an EEG
MeCP2 Duplication
• More often have epilepsy and can be hard to treat
CDKL5
• Always have epilepsy, almost always severe and usually life but can
be manageable
FOXG1
• Deletions (later and harder to treat) vs Duplications (Infantile
Spasms)
32. Special Thanks
Tim Benke
Tristen Dinkel
Rett Clinic Team
Our patients and
families with Rett and
Rett-related disorders
Rocky Mountain Rett
International Foundation for CDKL5 Research
CDKL5 Centers of Excellence
