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A Complete Population Survey of Epilepsy in Tuberous Sclerosis Complex Patients in Northern Ireland
A Complete Population Survey of Epilepsy in Tuberous Sclerosis Complex Patients in Northern Ireland
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
• Completely penetrant
• 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:
TSC2 (n = 58)
1.80%
4.50%
7.21% TSC1 (n = 22)
Genotype not done (n = 16)
14.41% Gene not found (n = 8)
52.25% Data missing (n = 5)
TSC2+PKD1 (n = 2)
19.82%
Epilepsy, brain
imaging &
neurosurgery
TSC & Epilepsy
Around 80% TSC patients have epilepsy
N.I. TS database 89/111 have epilepsy = 80%
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
29%
26% of
patients are
24% taking 3+
AEDs
(= 24 people)
17%
12%
10%
4%
3%
Learning
difficulty is
common in
patients
None
29.55%
Mild with TSC
42.05%
Mild-moderate
Moderate Severity is
Moderate-severe very variable
Severe
11.36%
3.41% 2.27%
11.36%
mTOR inhibitors:
clinical trials as
treatment for
various aspects of
TS
mTOR inhibitors & TSC
mTOR inhibitors, e.g. Everolimus, provide tumour suppressor activity
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
• Population: TSC & treatment-resistant seizures, 2-65 years (mean age was 10), 25 countries, 366 patients
• 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: