1. MB Callaghan, DE Donnelly, PJ Morrison
A Complete Population Survey of Epilepsy in Tuberous Sclerosis Complex Patients in Northern Ireland
MB Callaghan, DE Donnelly, PJ Morrison
Northern Ireland Regional Clinical Genetic Centre
Belfast City Hospital
BCH Postgraduate Lecture Theatre
Friday 30th June 2017

2. Tuberous Sclerosis Complex (TSC)
Genetic condition that affects many body systems
Autosomal dominant inheritance with variable expressivity
Completely penetrant
Around 50% of cases are the result of sporadic mutations

3. TSC Genetics TSC1 tumour suppressor gene located on Chr. 9q34
codes for protein hamartin
TSC2 tumour suppressor gene located on Chr. 16p13.3
codes for protein tuberin
Hamartin & tuberin together suppress activation of mTOR signalling & act as a “brake” on processes that drive cell growth & cell division
Mutations in TSC1 & TSC2 result is uncontrolled cell growth & division

4. TSC: A Multi-organ Disease

5. Diagnostic criteria for TS
B. Clinical criteria:
Diagnostic criteria for TS
Genetic criteria: “The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definitive diagnosis of tuberous sclerosis complex.”
Northrup H, Krueger DA. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference .
Northrup H, Krueger DA. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

6. Neurological consequences of TSC
Seizures
Learning difficulties
Developmental delay
autism
Behavioural problems OCD
ADHD
Common CNS radiological findings in TSC:
Giant cell astrocytomas
Cortical & subcortical tubers
Subependymal nodules
White matter cystic lesions

7. TSC Prevalence Population prevalence of TSC is ~ 1:20,000
Population of Northern Ireland is ~ million
Expected size of the TSC population in N.I. - 91
Actual size of TSC population in N.I
Age range years
Maybe doctors have a lower threshold for referring patients with seizures & skin signs to Clinical Genetics?
Maybe being a small island population that has remained relatively stable from the genetic point of view has played a part?

8. Study Methods
Retrospective study of TSC patients using TSC database & ECR
Descriptive statistics used to record:
Genotype
Proportion with epilepsy
Brain imaging
Neurosurgery
Number of anti-epileptic drugs used – poorly controlled if ≥3
Learning difficulties

9. Genotype

10. At least 55 mutations found & no common mutation, 74% had mutation found, Number of pedigrees in NI TS population = 72

11. Epilepsy, brain imaging & neurosurgery

12. TSC & Epilepsy
Around 80% TSC patients have epilepsy
N.I. TS database 89/111 have epilepsy = 80%
80% with epilepsy (71/89) on anti-epileptic drugs
Many of our TS patients with epilepsy have had brain imaging performed
MRI done
No. of pts
% of pts
Yes
48/89
54% No
39/89
44%
Unknown
2/89 2%
Of the patients who had MRI brain performed, 100% had abnormalities associated with TSC
7/48 required neurosurgery

13. Anti-epileptic Drugs

14. 26% of patients are taking 3+ AEDs
(= 24 people)

15. Learning difficulty in TS patients with epilepsy

16. Learning difficulty is common in patients with TSC
Severity is very variable
% of patients with learning difficulty: 63/89 = 70%
10/63 mild; 2/63 mild-moderate; 10/63 moderate; 3/63 moderate-severe; 37/63 severe
Of those with severe LD, 18/37 are prescribed 3 or more AEDs. One of those has had neurosurgery. One has had neurosurgery and is currently prescribed Everolimus.
Of those with moderate-severe LD, 1 in prescribed 3 AEDs, 1 is currently on Everolimus, one is neither. None have undergone neurosurgery.
Of those with moderate LD, 1 was prescribed 5 AEDs, 2 had undergone neurosurgery, one had been prescribed Everolimus for a non-seizure related indication but had been switched to Sutent, and one was currently on Everolimus.
Of those with mild-moderate LD, both were prescribed 1 AED and both were prescribed Everolimus for a non-epilepsy related indication. It is noteworthy that they belong to the same pedigree.
Of those with mild LD, none were prescribed 3 or more AEDs, one had undergone neurosurgery.
If Everolimus offered to those who have required neurosurgery for seizure control: 7-2 already on the drug:
5 patients x £36,135 per patient per year.
= £180,675
If Everolimus offered to those with severe LD on 3 or more AEDs (excluding the one patient that is already prescribed the drug):
17 patients x £36,135 per patient per year.
= £614,295 to fund Everolimus for this patient group for a year.
If Everolimus offered to those prescribed 3 or more AEDs = 24-1 patient already prescribed the drug:
23 patients x £36,135 per patient per year.
= £831,105 to fund Everolimus for this patient group for a year.
Votubia brand 10 mg od = £36,135 per patient per year.

17. mTOR inhibitors: clinical trials as treatment for various aspects of TS

18. mTOR inhibitors & TSC
mTOR inhibitors, e.g. Everolimus, provide tumour suppressor activity
3 clinical trials of Everolimus have been carried out:
EXIST-1 Trial to determine whether Everolimus might be able to reduce the size of ( ) subependymal giant cell astrocytomas (SEGAs) in TS patients
EXIST-2 Trial to determine whether Everolimus might be able to reduce the size of ( ) angiomyolipomas (AMLs) in TS patients
EXIST-3 Trial to determine whether Everolimus might be able to reduce seizure
( ) frequency in TS patients

19. EXIST-3 trial: association between Everolimus & reduction in seizure frequency1
Type of study: Phase 3 double-blind placebo-controlled RCT
Population: TSC & treatment-resistant seizures, 2-65 years (mean age was 10), 25 countries, 366 patients
Intervention: Everolimus given as an adjunct to current AEDs
Comparison: placebo
3 arms of study:
High-exposure Everolimus (defined by plasma trough concentration of 9-15 ng/ml)
Low-exposure Everolimus (defined by plasma trough concentration of 3-7 ng/ml)
Placebo

20. Outcomes Reduction in seizure frequency was:
40% in high-exposure arm (95% CI 31·5–49·0; 52 patients; p<0·0001)
28% in low-exposure arm (95% CI 20·3–37·3; 33 patients; p=0·0077)
5% in placebo arm. (95% CI 9·2–22·8; 18 patients)

21. What % of N.I. T.S.C. patients might benefit from Everolimus for seizures?
Proposed group: those with poorly-controlled epilepsy.
Q – How to best define poorly-controlled epilepsy?
A – One possible definition is those on 3 or more AEDs plus those who have required neurosurgery.
24 (26%) patients in N.I. on 3 or more AEDs
7 patients with neurosurgery (6 frontal lobe, 1 corpus callosum):
1 on Everolimus for renal AMLs + 3 AEDs
1 on Everolimus for renal AMLs & < 3 AEDs
1 on 3 AEDs (therefore already included in group above)
4 eligible patients from the neurosurgery group

22. Cost of Everolimus versus potential cost of not prescribing it
If not prescribed, potentially…
Greater number of seizures 
added cost of hospital admissions,
additional outpatient clinic appointments,
prescription of additional AEDs
Cost of time missed from school/work by patients.
Cost of time missed from work by parents of affected children.

23. Conclusion Intended clinical outcome is:
Everolimus may be of benefit for some of Northern Ireland’s TSC patients who experience seizures
Intended clinical outcome is:
Reduced seizure frequency
Likely secondary clinical outcomes:
Reduce the size of AMLs
Reduce the size of subependymal giant cell astrocytomas
Intended benefits for the patients:
Improvement in quality of life
Delayed progression of disease

24. References
1. French JA, Lawson JA et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2015; 388:
2. Northrup H, Krueger DA. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Published in: Pediatr Neurol October ; 49(4): 243–254.