The management of epilepsy in people with an intellectual disability

1. The management of epilepsy in people with an intellectual disability Professor Mike Kerr WALES Cardiff University, Wales

2. Aim • To explore key research evidence relevant to the management of people with an intellectual disability who have epilepsy • To describe some key clinical skills relevant to the management of people with an intellectual disability who have epilepsy

3. Structure • Special issue: Epidemiology/Specific syndromes/ Clinical issues associated with aetiology of ID • Impact of epilepsy: the decision to treat? • Treatment impact • Key skills in treatment implementation: assessing behavioural change • Conclusion

4. Definitions • Intellectual disability is a composite of • 1. IQ < 70 • 2. Acquiring problem during the developmental period <18 • 3. Associated problems with adaptive functioning

5. Epidemiology Population: prevalence / relative risk Individual: specific syndrome

6. Prevalence • Wide range depending on sample, e.g., institution or community • A key factor is severity of intellectual disability • Minimum 16% of population with intellectual disability Morgan CL, et al. Am J Ment Retard 2003;108(suppl 5):293-300

7. Male Female Relative risk by age for people with intellectual disability and epilepsy 40 30 Relative risk 20 10 0 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85+ Age Morgan CL, et al. Am J Ment Retard 2003;108(suppl 5):293-300

8. Issues in individual patients Common epilepsy syndromes? Seizure features associated with aetiology of developmental disorder Clinical challenges caused by genetic aetiologies

9. Common seizure syndromes associated with intellectual disability Severe myoclonic epilepsy of infancy Lennox-Gastaut syndrome Westsyndrome Landau-Kleffner syndrome

10. Seizure issues associated with aetiology of developmental disorder Angelmansyndrome • 90% seizures • usually generalized Tuberous sclerosis • 80% seizures • infantile spasms common • 5-10% seizures • in late adulthood • often myoclonic • related to Alzheimer's disease Down syndrome Rettsyndrome • Seizures common • major differential diagnosis • with autonomic breathing disorders

11. Clinical challenges associated with genetic aetiologies • Diagnosis Rett Other

12. Rett syndromedifferential diagnosis

13. Please review patient - • Previous assessment Neurology • Now on carbamazepine • Failed lamotrigine • “Has chronic epilepsy can you improve his condition please?” • Story – inconclusive • In clinic significant jerking/tics • FH brother older no seizures and has mild ID • NOT EPILEPSY

14. ARX associated syndromes ARX: homeodomain, C-terminal aristaless domain, N-terminal octapeptide domain, 4 polypeptide tracts; 24bp dup most frequent mutation NB: maternal somatic and germline mosaicism

15. Decision to treat: the impact of epilepsy Chronicity Mortality Mental/Behavioural health Cognitive deterioration Injury hospitilisation Social inclusion

16. Idiopathic(n = 68) Cryptogenic(n = 54) Remotesymptomatic(n = 123) Chronicity: Cumulative probability of 5-year remission without AEDs 1.0 0.8 0.6 Proportion in remission 0.4 0.2 0 5 10 15 20 25 30 35 40 45 Years after onset of epilepsy Sillanpää M, et al. N Engl J Med 1998;338:1715-22

17. Mental/behavioural ill health • Strong association with increased pathologies • Little evidence of aetiological process different to underlying problems associated with ID

18. Challenging behaviourPopulation norm* • Recent estimates (Lowe et al 2007) suggest that 4.5 (range 2.5-7.5) per 10000 population are rated as having severe challenging behaviour; accounting for about 10% (5.5-16.8%) of the population with an intellectual disability. There is a strong male preponderance (63%), 21% have a diagnosis of autism and about one third are believed to have a co-existent psychiatric diagnosis *Lowe et al, 2007

19. Mental health problems in children with epilepsy Davies et al. Dev Med & Child Neurol 2003, 45: 292-295

20. How can we explain?

21. Significant associationsno surprises here!

22. Significant associationsno surprises here!

23. Adults

24. Group Mean age(SD) % Male Residence (%) Mean ABS1 score(SD) Mean ABC2 score(SD) Triad of Social Impairments3(%) Indication of Mental Illness4(%) Indep-endent Family home Staffed home Epilepsy(n=58) 39.6(13.3) 52 3 50 47 132.45(71.1) 29.96(22.3) 537 52 No Epilepsy(n=260) 41.9(15.3) 42 12 44 44 179.75(67.9) 21.26(22.5) 297 45 Characteristics of those with epilepsy (n=58) and those without epilepsy (n=260) 1 ABS=Adaptive Behavior Scale (Nihira et al. 1993) 2 ABC=Aberrant Behavior Checklist (Aman & Singh, 1986) 3 The triad of social impairments are characteristic of autism spectrum disorder (Wing & Gould, 1979) 4 Meeting threshold levels on the Psychopathology Instrument for Mentally Retarded Adults (Matson, 1988) 5 Significant difference Mann-Whitney U=4,640, p=.000 6 Significant difference Mann-Whitney U=5,383, p=.001 7 Significant difference c2=13.4, df=1, p=.000

25. Total scores for the epilepsy and non-epilepsy groups did not differ for: 1.PIMRA did not differ significantly (mean = 11.3 compared to 10.7) or for threshold level indicating possible mental illness (54.5% compared to 44.4%, c2 = 1.11, p=.292). 2. ABC scores for the epilepsy and non-epilepsy groups did not differ significantly (mean = 30.8 compared to 26.1). Neither did the proportion of participants with an ABC score above 45, used to define individuals as having challenging behaviour (23.6% compared to 20.0% 3. No difference in the proportion of participants with the triad of social impairments (52.7% compared to 38.2%, c2 = 2.35, p=.126).

26. Treatment impact Evidence-based prescribing?

27. What trials are there? • Pharmacological & Non-pharmacological • Data from 2 Cochrane reviews: • Beavis J, Kerr M, Marson AG (2007) Pharmacological interventions for epilepsy in people with intellectual disabilities (Review). The Cochrane Library3, 1-15. • Beavis J, Kerr M, Marson AG (2007) Non-Pharmacological interventions for epilepsy in people with intellectual disabilities (Review). The Cochrane LibraryIn press.

28. This gave a total of 13 studies to be evaluated for inclusion in this review with a total of 829 participants comparing 9 different pharmacological agents: Lamotrigine, carbamazepine, gabapentin, topiramate, vigabatrin, felbamate, clobazam, cinromide and flunarizine. Four of these trials were cross-over trials (Battaglia, Erikkson, Kaski, Siegel), Six were parallel studies (Crumrine, Kerr, Motte, Ritter, Sachdeo, Yamatogi), One was an open label parallel study (Crawford) In two studies the design was unclear (Luna, Schlumberger). Description of studies

29. Key studies

30. Key studies – seizure freedom

31. Key studies – seizure frequency/responder rate

32. Key studies – adverse events

33. Non pharmacological studies =

34. Real-world trials:Usually open and non-controlled Topiramate Levetiracetam

35. Topiramate – Finland Percentage of sample Seizure reduction Arvio and Silanpää. J Intellect Disability Res 2005;49:183-9

36. Levetiracetam – Wales Percentage of sample Seizure reduction Hanson and Kerr. Unpublished audit.

37. RCT vs open studies: seizure effect Wishful thinking Open 50-70% seizurereduction RCT 20-30% seizurereduction Placebo effect / natural history Skill

38. Managing treatment change Assessing a “behaviour” presentation

39. Behavioural presentations in epilepsy – practical issues Diagnostic On treatment change Not connected to treatment change

40. Assessment wish list Clear Video or other Description of behaviour And environment Evidence base for Drug effects on behaviour Knowledge of how Epilepsy Associates with Behaviour change Knowledge of Other Causes of behaviour change

41. Why the environment?

42. Treatment-related AEs Control Related “forced normalisation” Medication prescribed Behavioural outcome Drug related

43. Treatment related evidence base • Very unusual for a trial to actually use a validated measure of behaviour • Leaves us very uninformed • Extremely important as carer often does not match with objective measures • One RCT – Placebo controlled Topiramate (already shown) • One prospective multicentre study non controlled 2 month baseline

44. N=30 for study non controlled 2 month baseline 12 month on drug The ABC comprises 58 behaviours, each relating to one of five subscales: irritability, hyperactivity, lethargy, stereotypy and inappropriate speech. Total ABC scores did not change (baseline median = 18.0, average post-intervention median = 19.3, z = -.15, p = .988). There was also no change on any of the five subscales. In addition, there was no association between the total frequency of seizures and total ABC score at any time point (-.17 ≤ rho ≤ .10, .412 ≤ p ≤ .869). Prospective multicentre add on Levetiracetam* Kerr et al In Preparation

45. Other impacts on behaviour Physical illness

46. Physical health in epilepsy treatment There is very Strong Evidence That PWID Have a Very high Chance of Unrecognised Physical Illness* Reflux Leukaemia UTI Prior to treatment Special concern for Weight loss Symtomatic signs of ill health During treatment Gastric reflux And everything else Hypothyroid Missed grommets Menieres Reflux Anaemia *Baxter H, Lowe K, Houston H, Jones G, Felce D & Kerr M (2005) Previously unidentified morbidity in patients with intellectual disability. British Journal of General Practice56, 93-8.

47. Assessment-best bets with intellectual disability Temporal Association With seizures Ictal disorder Most Likely Longstanding Disability Related Factors* Behavioural Emotional change Forced normalisation Major Seizure frequency reduction Physical illness Psychiatric Illness behaviour Treatment related (unlikely)** Other *Espie et al JNNP 2003 **Beavis J, Kerr M, Marson AG (2007) Pharmacological interventions for epilepsy in people with intellectual disabilities (Review). The Cochrane Library3, 1-15.

48. Conclusion • A person with intellectual disability and epilepsy will be the most rewarding patient of the day: • An intellectual challenge through complex aetiology, severity of epilepsy, paucity of evidence base and the skills of treatment application