1. Epilepsy in Down’s Syndrome Dr Sameer Zuberi Paediatric Neurologist Fraser of Allander Neurosciences Unit Royal Hospital for Sick Children Glasgow

2. What is epilepsy ? An epileptic seizure is the behavioural manifestation of an abnormal hypersynchronous electrical discharge from cortical neurons Epilepsy is recurrent epileptic seizures not provoked by everyday stimuli Almost every condition affecting the cerebral cortex can result in epilepsy

3. Chromosome disorders & Epilepsy 6% of (172) patients with learning difficulties and epilepsy have a chromosome abnormality (Ieshima A et al 1998) Rises to 50% in patients with seizures and >3 dysmorphic features > 400 chromosomal disorders are associated with epilepsy and many (≈ 40) have epilepsy as a common feature. Smaller number have epilepsy as a consistent feature Chromosome studies rarely ordered when faced with a child who develops cognitive problems after the onset of epilepsy

4. Chromosomal disorders strongly associated with epilepsy Wolf-Hirschhorn Syndrome (4p-) Miller-Dieker Syndrome (del 17p13.3) Angelman Syndrome Inversion duplication 15 Syndrome Terminal deletion chromosome 1q Terminal deletion chromosome 1p Ring 14 syndrome Ring 20 syndrome Duplication syndromes –additional segment of material Deletion syndromes –Segment genetic material missing Breakpoint disruptions –Only one or very few genes affected ?Phenotype related to gene dosage- haploinsufficiency or “triplo-excess”

5. How common is epilepsy in Down’s syndrome? Figures depend on size of series, definition of epilepsy, age of cases, source of population Prevalence figures vary from 1 to 9%, compares to <0.5% in general population Are some seizure types such as febrile seizures (0.9%) less common in Down’s Syndrome?

6. Postal Survey of 1000 families with a child with Down’s Syndrome Mary King and John Stephenson (Fits & Faints 1990) Most children do not have epileptic or non- epileptic seizures Infantile spasms occurred in 2% Syncope appeared to be common including reflex anoxic seizures and convulsive syncope

7. Goldberg-Stern et al. Brain Dev 2001; 23:375-8 350 children & adolescents 8% had epilepsy (prevalence) 47% partial seizures 32% infantile spasms 21% generalised tonic clonic seizures

8. Epilepsy Phenotypes in Down Syndrome Infantile spasms Focal epileptic seizures secondary to acquired brain lesions Reflex / startle epilepsy Late onset myoclonic epilepsy in Down’s Syndrome (LOMEDS) A bi-modal distribution

9. Infantile spasms 8-10 x more common than in general population 2 groups –Those symptomatic of perinatal hypoxic brain injury who have a poor prognosis –No acquired brain injury. A relatively good prognosis

10. Infantile Spasms West Syndrome An electroclinical triad of: spasms, hypsarrythmia, and regression or stagnation of mental abilities West Syndrome is not synonymous with Infantile spasms Classified as symptomatic or cryptogenic(15%)

11. Video of behaviour pre-treatment

12. EEG prior to treatment

13. EEG during spasm

14. Treatment options Hormonal treatments Steroids – 2mg/kg of prednisolone for 2 weeks –ACTH Vigabatrin Pyridoxine Sodium valproate Important to repeat the EEG

15. Behaviour post treatment in EEG department

16. EEG post treatment

17. Eisermann et al. Infantile Spasms in Down Syndrome – effects of delayed anticonvulsive treatment. Epilepsy Research 2003; 55:21-7 18 patients with spasms Correlation between treatment lag –cessation spasms – developmental quotient – autistic features

18. Video of Sleep Start

19. EEG during sleep start

20. Non-epileptic Paroxysmal Disorders in Down Syndrome Syncope – Associated with congenital heart disease – Reflex anoxic seizures / reflex asystolic syncope Sleep starts Tics / Tourette Syndrome

21. Focal epileptic seizures Can have benign focal epilepsies such as rolandic epilepsy More common are lesional focal epilepsies –Cyanotic heart disease and abscess –Stroke related to cardiac disease or to cardiac surgery

22. Startle Epileptic Seizures Guerrini R, Genton P, Bureau M, Dravet C, Roger J Reflex seizures are frequent in patients with Down syndrome and epilepsy. Epilepsia. 1990 Jul-Aug;31(4):406-17. Seizures with variety of aetiologies but triggered by sound and touch. Is there reduced cortical inhibition in Down’s Syndrome?

23. Late onset myoclonic epilepsy Incidence of epilepsy in Alzheimer’s disease without Down’s Syndrome is 10% Incidence of epilepsy in Down’s Syndrome with Alzheimer’s like dementia is 75%

24. Late onset progressive myoclonus Most common after age 50 Associated with dementia May respond to valproate or levetiracetam Occasional generalised generalised tonic clonic seizures Also called senile myoclonic epilepsy