Seizure Types and Treatment in Rett Syndrome and Rett-related Disorders

Scott Demarest MDAssistant Professor, Departments of Pediatrics and NeurologyUniversity of Colorado School of MedicineChildren's Hospital Colorado

Disclosures

This Research is supported by:

• The International Foundation for CDKL5 Research (IFCR)

• NIH funding for the Rett Natural History Study

My epilepsy genetics research is supported by NIH funding through a K12 mechanism.

No conflicts of interest.

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”

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?

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).

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

Is Epilepsy the Same in Rett andRett-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?

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?

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%

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%

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 seizuretypes

Types of Seizures in Rett Syndrome

Epilepsia, 56(4):569–576, 2015 doi: 10.1111/epi.12941

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

“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”

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

Epilepsy in MeCP2 Duplication

Less common so we know less…• Almost all have epilepsy• Epilepsy is generally harder 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

CDKL5 Syndrome

Has been called:

• The “early-onset seizure” variant of Rett Syndrome

• EIEE2 - Early Infantile Epileptic Encephalopathy type-2

• Atypical Rett Syndrome

• CDKL5-related Epileptic Encephalopathy

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

What is our involvement with CDKL5?

Dr. Benke established the multidisciplinary Rett Clinic here in December 2011 with the help of the Rocky Mountain RettAssociation.

We see patients with both Classic and atypical Rett Syndrome

Thus far have seen 35 patients with CDKL5 Syndrome.This is more than any other single center in the US (possibly the world)

Most reports in the literature have less than 20 patients

We are members of the CDKL5 Centers of Excellence

This is helping us learn more about this rare disease.

Clinical Spectrum

There is actually a wide spectrum:

1/6 of our patients have a more “mild” formThey 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 (no “Hotspots”)

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

• 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

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

Epilepsy in FOXG1 Related Disorders

Deletion/ mutation:• Epilepsy onset is later and can have a variety of seizure types• Seizure are harder 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

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 EEGMeCP2 Duplication• More often have epilepsy and can be hard to treatCDKL5• Always have epilepsy, almost always severe and usually life but can be

manageableFOXG1• Deletions (later and harder to treat) vs Duplications (Infantile Spasms)

Special Thanks

Tim Benke

Tristen Dinkel

Rett Clinic Team

Our patients and families with Rett and Rett-related disorders

Rocky Mountain RettInternational Foundation for CDKL5 Research

CDKL5 Centers of Excellence