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
 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

TSC Genetics
• TSC1tumour suppressor gene located on Chr. 9q34
• codes for protein hamartin

• TSC2tumour 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
TSC: A Multi-organ Disease
 B. Clinical criteria:

Diagnostic criteria for TS

A. 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
 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
TSC Prevalence
• Population prevalence of TSC is ~ 1:20,000

• Population of Northern Ireland is ~ 1.811 million

• Expected size of the TSC population in N.I. - 91

• Actual size of TSC population in N.I. - 111

• Age range 1 - 81 years

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
Genotype
Location of Gene Mutations in the Northern Ireland TS Population

TSC2 (n = 58)
5% 2%
7% TSC1 (n = 22)

Genotype not done (n = 16)

14%
Gene not found (n = 8)
52%
Data missing (n = 5)

TSC2+PKD1 (n = 2)
20%
Epilepsy, brain imaging
& neurosurgery
 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

Anti-epileptic Drugs
 % TS patients with epilepsy on given number of AEDs

29%
26% of
patients are
24%
taking 3+
AEDs
(= 24 people)
17%

12%
10%

4%
3%

0 AEDs 1 AED 2 AEDs 3 AEDs 4 AEDs 5 AEDs No. not known

Learning difficulty in TS
patients with epilepsy
 LD in TS patients with seizures

Learning
difficulty is
common in
patients
30% None with TSC
Mild
42%
Mild-moderate Severity is
Moderate very variable
Moderate-severe
11% Severe

4% 2%
11%
mTOR inhibitors: clinical
trials as treatment for
various aspects of TS
 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
(2008-2012) subependymal giant cell astrocytomas (SEGAs) in TS patients

EXIST-2 Trial to determine whether Everolimus might be able to reduce the size of
(2008-2013) angiomyolipomas (AMLs) in TS patients

EXIST-3 Trial to determine whether Everolimus might be able to reduce seizure

(2012-2016) frequency in TS patients
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
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)

 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
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.

Conclusion
• 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
 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: 2153-63.

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. 2013 October ;
49(4): 243–254.