Original Article

Review of Tuberous Sclerosis Complex: A Single Center Experience

10.4274/jpr.galenos.2020.47750

  • Ayşe Tosun
  • Beste Kıpçak Yüzbaşı
  • Ali Akyol

Received Date: 01.12.2019 Accepted Date: 02.03.2020 J Pediatr Res 2021;8(1):75-81

Aim:

The aim of this study is to review the clinical features and treatment of tuberous sclerosis complex patients followed up in our hospital and to compare our findings with the literature.

Materials and Methods:

The clinical-laboratory findings and treatment of 15 tuberous sclerosis patients who presented at a child neurology policlinic between 2007-2017 were retrospectively reviewed.

Results:

Fifteen patients aged between 8 months and 17 years were included in the study. The female/male ratio was 47%/53%. Thirteen patients (86%) were referred with convulsions, 1 (7%) with skin hypo-pigmented macule and 1 (7%) with the detection of a renal cyst in ultrasonography. At the time of diagnosis, skin findings were present in 93% of the patients. There were infantile spasms in 23%, focal seizures in 54%, generalized tonic-clonic in 15% and atonic seizures in 8% of those patients who referred with seizures. In addition to the known antiepileptics in treatment, mTOR inhibitors were used in two patients. Forty percent were diagnosed with resistant epilepsy. Seven of the patients (46%) had various levels of mental retardation. There were cardiac findings in 33%, ocular findings in 33%, and renal involvement in 27% of the patients. The most common (87%) neuroradiologic finding was subependymal nodule.

Conclusion:

It was observed that the signs and symptoms of our patients were compatible with the literature. In childhood, refractory epilepsy and mental retardation were the most important clinical findings. The age of onset of seizures in patients with resistant epilepsy was under one year of age. These patients had infantile spasms and a larger number of cortical tubers in cranial magnetic resonance imaging findings. It was observed that everolimus treatment had no marked effect on seizure frequency. However, patients with tuberous sclerosis should be closely monitored for the development of malignancies in the long term and this monitoring should be continued in adulthood.

Keywords: Childhood, tuberous sclerosis complex, clinical-laboratory findings-treatments

Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited genetic disease in which multiple organ involvement is characterized by common hamartomas in many organs especially including the brain, skin, heart, eye, kidney, lung and liver. TSC is due to programmed hyperplasia of ectodermal and mesodermal cells, which is characterized by epilepsy, adenoma sebaceum and mental retardation. It has a variable age of onset and variable clinical severity. About 2/3 of these cases are formed via spontaneous mutation. Due to mutations in the TSC1 (9q34) and TSC2 (16p13.3) genes respectively, the functions of the hamartin and tuberin proteins encoded by these genes are impaired. The mammalian target of hamartin-tuberin proteins is to inhibit (mTOR) the signal pathway of rapamycin and thereby control cell growth and proliferation. Clinical findings occur with the impaired inhibitor function of these proteins. Its diagnostic criteria were restructured at the International Tuberous Sclerosis Consensus Conference in 2012. (Table I) (1).

The aim of this study is to review retrospectively the clinical features and treatments of TSC patients who had been referred to our hospital and to compare our findings with the literature.


Materials and Methods

Fifteen patients diagnosed with tuberous sclerosis who presented at the Pediatric Neurology Policlinic of Aydın Adnan Menderes University Faculty of Medicine between 2007 and 2017 were included in this study. The age, gender, neurological and systemic examinations, the age of onset of convulsions, seizure types, interictal electroencephalography (EEG), cranial magnetic resonance imaging (MRI), abdominal ultrasonography (USG), echocardiography (ECHO) and ocular findings of these patients were evaluated. The seizure classification was carried out according to family testimony, observed seizure activity and classification of the International League Against Epilepsy.


Statistical Analysis

The SPSS 17.0 package program was used in the statistical analyses. Descriptive statistics was utilized, categorical variables were expressed as frequency and percentage. This is a retrospective file scanning study, so informed consent forms were not obtained from the patients. This study was approved by the Aydın Adnan Menderes University Medical Faculty Ethics Committee (date: 10.05.2018, approval number: 2018/1396).


Results

Fifteen patients (8 male/53%) were included in the study, ranging in age from 8 months to 17 years. The age of the patients at diagnosis was between 2 months and 9 years, consistent with the age at which they were referred to the clinic. Six of the patients (40%) were diagnosed before one year of age, 3 patients (20%) between 1 and 5 years, and 6 patients (40%) at 5 years of age or over. The most common reason for referring to the clinic was convulsion for 13 patients (86%) as well as skin lesions for 1 patient (7%) and renal cyst for 1 patient (7%).

There were skin findings of TSC in 14 patients (93%) at the time of diagnosis. Hypopigmented skin lesions were found in all 14 of these patients, adenoma sebaceum in 5 patients (33%) and ungual fibroma in 2 patients (13%).

Infantile spasms were detected in 3 (23%) of 13 the patients with seizures. The average age of those patients with infantile spasms was 8 months. The first preferred antiepileptic was vigabatrin for those patients with infantile spasms. Seizure control with vigabatrin was achieved in only one patient. There were no seizures in 2 patients treated with ACTH, for 1 month and 7 months respectively. One of these patients was seizure-free for one year with a ketogenic diet, but later focal seizures which were controlled with vigabatrin and topiramate developed. There were 7 patients with focal seizures (54%). Three patients were treated with phenobarbital, 1 patient with vigabatrin, 1 patient with carbamazepine, 1 with levetiracetam and 1 patient with valproate as the first antiepileptic treatment. The patient who received carbamazepine treatment was followed up without medication for 1.5 years and the 13-year-old patient who received valproate treatment was followed-up without medication for 10 years. Two patients had generalized tonic-clonic seizure (15%) and one patient had atonic seizure (8%). In 7 patients, seizure control was provided with polytherapy and 5 patients were followed with drug resistant epilepsy. The best response to anti-epileptic treatment in those patients with drug resistant epilepsy was achieved with vigabatrin and clobazam dual therapy. No response to therapy was observed in the two patients with drug resistant epilepsy who received everolimus (0.1 mg/kg/day max. 10 mg/day) (Table II).

Seven of the patients (46%) had mental retardation. Obsessive compulsive disorder was detected in one patient and two patients had autism.

Rhabdomyoma was detected in 5 (33%) of the patients by ECHO. The earliest age for the diagnosis of rhabdomyoma was 2 months and latest age was 11 years.

Findings of ocular involvement of TSC were detected in 5 of the patients (33%). Two of them (13%) had retinal hamartoma, one had retinoblastoma, astrocytoma and a hypo-pigmented area in the retina.

In the renal USG, Angiomyolipomas was determined in 4 (27%) patients and two of them were bilateral.

Cortical/subcortical tubers and/or subependymal nodules were detected in all patients. The most common finding in cranial MRI was subependymal nodules (87%). Subependymal giant cell astrocytoma (SEGA) developed in one of the cases (Table II).


Discussion

TSC, which affects many systems including the brain, skin, kidney, eye and heart, was first described by Bourneville in 1880 (2,3). Its incidence is estimated to be 1 in 5.800 (4). The most common neurological complication is convulsion, which occurs in about 90% of patients and begins in the first year of life in 1/3 of patients (5,6). Consistent with the literature, epilepsy was present in 87% of our cases and seizures started in the first year of life in 46%. Infantile spasms, which are seen in 30-60% of TSC, were the first referral cause in 23% of our cases (6-8).

Skin manifestations are common in TSC. The most common skin findings are hypopigmented macules. Usually lesions are seen from birth, while they become more apparent in the first years of life (9,10). Adenoma sebaceum is usually observed in the adolescence period (8,11,12). Hypopigmented skin lesions were present in 93% of our patients and adenoma sebaceum in 33%, skin lesions were not detected in only one 8-year-old patient.

The most common cardiac finding in TSC is rhabdomyoma, one of the tumours with a good prognosis found in 60-80% of cases (13-15). Cardiac rhabdomyomas are detected during the antenatal period or infancy and then stabilization or spontaneous regression is observed with age. The development of a new cardiac rhabdomyoma after infancy is very rare. In one study, a patient at the age of 2 years with rhabdomyoma was presented requiring a new resection after a rhabdomyoma resection as a new-born (16). Rhabdomyomas are usually asymptomatic but may cause atrial or ventricular arrhythmias, sinus node dysfunction and heart block. Even if these cases are asymptomatic, it is necessary to observe new rhabdomyomas and cardiac conduction defects that may develop in follow-up (17,18). There was rhabdomyoma in 33% (5 patients) of the patients in our study. Regression was observed in 3 patients and there was no change in size in 2 patients.

The most common renal lesions are Angiomyolipomas and renal cysts. Renal angiomyolipomas occur in about 50% of the patients (19). While the frequency of angiomyolipomas increases with age, there is no such relationship in renal cysts (20). Renal involvement was detected in 27% of our patients, lower than the rate reported in the literature. This was related to the young age of our patients.

Ocular findings of patients with TSC include retinal and non-retinal lesions. Retinal hamartomas remain stable for many years and rarely affect vision. Non-retinal lesions consist of depigmentation in the iris, choroid coloboma, and eyelid angiofibromas. Eye findings were reported at different rates in the literature. Retinal hamartoma was found in 44%,10.2% and 25% in different studies (21,12,22). In a cohort study in the United States, they were seen in approximately 50% of patients (23). There were findings of ocular involvement in 33% of our patients.

Cranial lesions in TSC are developmental anomalies such as cortical tubers, subependymal nodules, heterotopic grey and white matter abnormalities, and SEGA. It has been reported that cortical tubers are seen at a rate of 82-100%, and subependymal nodules at a rate of 50-100% (7,24). When the cranial MRI findings of our cases were examined, the incidence of the cortical tuber (93%) and subependymal nodule (86%) was consistent with the literature. Giant cell astrocytomas are seen in 10-15% of patients with TSC and frequently in the first 20 years. In one study, the mean age of diagnosis of SEGA was 13.3 years (25). Therefore, yearly MRI scans up to 21 years of age are recommended (25-27). In one of our patients, SEGA was detected at the age of 11 years.

In TSC, mental retardation is reported at a rate of about 50% (5,28). There was a significant relationship between the average number of cortical tubers of more than 7-10, the presence of these tubers in the occipital lobe, the presence of infantile spasm in the history and the learning disability (29,30). Various levels of mental retardation were detected in 46% of our patients. The cortical tuber number was between 9 and 14 in cranial MRI in our patients with infantile spasm and learning disability. These cortical tubers were mostly located in the occipital region. The cortical tuber numbers in patients without learning disabilities were between 1 and 5.

The association of autism with TSC has been reported at a rate of 25-50% (31,32). Early-onset of seizures is also associated with severe cognitive impairment and autism-like behavior (6,33). In our cases, obsessive compulsive disorder was detected in one patient and two patients had autism. The fact that it was detected less than the literature may be associated with the low number of patients in our study.

Epilepsy is the most common neurological finding in patients with TSC (6). The most common types of seizures are infantile spasm or focal seizures, but most of them also have other types of seizures, such as tonic, clonic, tonic-clonic, myoclonic, atonic, and atypical absences (34). Infantile spasms can also turn into epileptic spasms (6,35). Focal seizures were mostly commonly observed in our patients (40%). The earliest seizure onset age was 1 month and the average age was 16 months. The presence of epileptic activity in EEG was found to be 76% (28.5% focal, 9.5% generalized, 38% hypsarrhythmia) in one study (7). Epileptic activity was detected in 80% of our patients (47% focal, 13% generalized, 20% hypsarrhythmia). The presence of early onset seizures in children with TSC increases the risk of developing resistant epilepsy and/or epileptic encephalopathy. It was shown that 42% of children who were diagnosed with TSC before the age of 2 years developed drug resistant seizures (6). In a meta-analysis, vigabatrin was found to be effective in 95% of cases with infantile spasms (36). However, visual field defects (incidence 30-40%) limits the usage of the drug (37,38). Valproate and topiramate have similar efficacy for infantile spasm. Vigabatrin can be used as a single agent in infantile spasm and add-on therapy can be applied when drug resistance develops (38,39). Benzodiazepines such as nitrazepam and clonazepam are rarely efficient as a single agent for infantile spasm and are often used as adjunctive therapy or rescue medication. Antiepileptic drugs such as topiramate, lamotrigine, levetiracetam, zonisamide, and carbamazepine were found effective in preventing seizures or reducing seizure frequency in other seizure types in TSC (40,41). Felbamate is a useful for individuals with partial-onset refractory partial seizures, especially together with vigabatrin (42). It has also been shown that clobazam is a potential beneficial agent in TSC (43). More than 20% of patients with TSC can develop drug resistance epilepsy. For these patients, ketogenic diets, vagal nerve stimulation and resective epilepsy surgery are increasingly used (44). An over 50% reduction in seizures was observed in 11 of 12 refractory epilepsy patients who received ketogenic diet (45). In a study on epilepsy surgery, 37 out of 70 patients (53%) were seizure free and a further 8 (11%) had a significant decrease in seizure frequency (46).

In our patients, the best response to anti-epileptic treatment in patients with resistant epilepsy were achieved with vigabatrin and clobazam dual therapy. At a rate of 40%, seizures resistant to treatment continue. The age of onset of seizures in patients with resistant epilepsy is under 1 year of age and prevalent for those who have a large number of cortical tubers in their cranial MRI findings. Increasing evidence suggested that mTOR inhibitors may be useful in the treatment of epilepsy in TSC. mTOR is a serine/threonine kinase belonging to the phosphotidylinositide 3-kinase (PI3K)-related protein kinase family. It plays an important role in the regulation of a number of cellular functions, including particularly cell growth, metabolism and proliferation and in the maintenance of cellular homeostasis. Glutamate, an excitatory neurotransmitter and subclinical epileptiform discharges increase mTOR activity. mTOR regulates long-term synaptic potency, depression and epileptogenesis learning and memory formation (47,48).

Many investigators have found an improvement in learning disability, seizure frequency, survival and motor development for TSC-related mice, following treatment with everolimus or rapamycin (mTOR inhibitors) (47,49). In non-TSC animal models, rapamycin inhibits epileptogenesis in post-traumatic epilepsy (50). Significant reduction in seizure frequency was observed in treatment with rapamycin in patients with TSC (51). In one study, 5 out of 7 patients with resistant epilepsy treated with rapamycin were seizure-free after 6 months of treatment (52). In a multicentre study, everolimus as an adjunctive therapy for treatment-resistant focal onset seizures was compared with a placebo. A significant decrease in seizure frequency was found (53). Another randomized controlled study showed that sirolimus treatment resulted in a 41% reduction in seizure frequency (54). In our study, two refractory epilepsy patients received everolimus but no marked change in seizure frequency was achieved.


Study Limitations

This study has small number of patients with TSC and the lack of a longer follow-up term, including into adulthood are considered to be the limitations of our study.


Conclusion

We found that the clinical features, organ involvement, and treatment resistance of our patients were not different from the literature. The onset age of seizures in patients with resistant epilepsy was under 1 year of age and they had a larger number of cortical tubers in their cranial MRI findings. Patients with tuberous sclerosis should be closely monitored for the development of malignancies due to defective tumor suppressor genes. The need for this observation should be continued in adulthood especially in terms of giant cell astrocytoma in patients with subependymal nodules, cardiac conduction defects in patients with rhabdomyoma, and for the development of  "lymphangioleiomyomatosis" in women.


Ethics

Ethics Committee Approval: This study was approved by the Aydın Adnan Menderes University Faculty of Medicine Ethics Committee (date: 10.05.2018, approval number: 2018/1396).

Informed Consent: This is a retrospective file scanning study, so informed consent forms were not obtained from the patients.

Peer-review: Internally peer-reviewed.

Authorship Contributions

Concept: A.T., A.A., Design: A.T., Data Collection or Processing: B.K.Y., Supervision: A.A., Writing: A.T., B.K.Y.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

Images

  1. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatr Neurol 2013; 49:243-54.
  2. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. N Engl J Med 2006; 355:1345-56.
  3. Curatolo P, Bombardieri R, JozwiakS. Tuberoussclerosis. Lancet 2008; 372:657-68.
  4. O’Callaghan F, Shiell A, Osborne J, Martyn C. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 1998; 352:318-9.
  5. Webb DW, Fryer AE, Osborne JP. Morbidity associated with tuberous sclerosis: a population study. Dev Med Child Neurol 1996; 38:146-55.
  6. Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 2010; 51:1236-41.
  7. Saltık S, Karatoprak EY, Taşel B. Epilepsy in patients with tuberous sclerosis, Türk Ped Arş 2013; 48:123-30.
  8. Pampiglione G, Moynahan EJ. The tuberous sclerosis syndrome: clinical and EEG studies in 100 children. J Neurol Neurosurg. Psychiatry 1976; 39:666-73.
  9. Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci 1991; 615:125-27.
  10. Fitzpatrick TB. History and significance of white macules, earliest visible sign of tuberous sclerosis. Ann NY Acad Sci 1991; 615:26.
  11. Reed WB, Nickel WR, Campion G. Internal manifestations of tuberous sclerosis. Arch Dermatol 1963; 87:715.
  12. İncecik F, Hergüner Ö, Özcan K, Altunbaşak Ş. Retrospective evaluation of 19 cases with tuberous sclerosis. Türk Pediatri Arş 2006; 41:156-60.
  13. Baron Y, Barkovich J. MR. Imaging of tuberous sclerosis in neonates and young infants. Am J Neuroradiol 1999; 20:907-16.
  14. Quek SC, Yip W, Quek ST, Chang SK, Wong ML, Low PS. Cardiac manifestation in tuberous sclerosis: a 10-year review. J Pediatr Child Health 1998; 34:283-7.
  15. Benyounes N, Fohlen M, Devys JM, Delalande O, Moures JM, Cohen A. Cardiac rhabdomyomas in tuberous sclerosis patients: a patient report and review of the literature. Arch Cardiovasc Dis 2012; 105:442-5.
  16. Thatte NM, Guleserian KJ. New-onset cardiac rhabdomyoma beyond infancy in a patient with tuberous sclerosis complex. Cardiol Young 2016; 26:396-9.
  17. Freedom RM, Lee KJ, MacDonald C, Taylor G. Selected aspects of cardiac tumours in infancy and childhood. Pediatr Cardiol 2000; 21:299-316.
  18. Sciacca P, Giacchi V, Mattia C. Rhabdomyomas and tuberous sclerosis complex: our experience in 33 patients. BMC Cardiovasc Disord 2014; 14:66.
  19. Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES. Renal lesion growth in children with tuberous sclerosis complex. J Urol 1998; 160:141-5.
  20. Narla LD, Slovis TL, Watts FB, Nigro M. The renal lesions of tuberous sclerosis (cyst and angiomyolipoma) screening with sonography and computerized tomography. Pediatr Radiol 1998; 18:205-9.
  21. Rowley SA, O’Callaghan FJ, Osborne JP. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br J Ophthalmol 2001; 85:420-3.
  22. Erol İ, Savaş T, Şekerci S. Tuberous sclerosis complex; one centre experience. Turk Ped Ars 2015; 50:51-60.
  23. Hodgson N, Kinori M, Goldbaum MH. Ophtalmic manifestations of tuberous sclerosis: a review. Clin Experiment Ophthalmol 2017; 45:81-6.
  24. Ridler K, Suckling J, Higgins N, Bolton P, Bullmore E. Standardized whole brain mapping of tubers and subependymal nodules in tuberous sclerosis complex. J Child Neurol 2004; 19:658-65.
  25. O’Callaghan FJ, Martyn CN, Renowden S, Noakes M, Presdee D, Osborne JP. Subependymal nodules, giant cell astrocytomas and the tuberous sclerosis complex: a population-based study. Arch Dis Child 2008; 93:751-4.
  26. Nishio S, Morioka T, Suzuki S, Kira R, Mihara F, Fukui M. Subependymal giant cell astrocytoma: clinical and neuroimaging features of four cases. J Clin Neurosci 2001; 8:31-4.
  27. Goh S, Butler W, Thiele EA. Subependymal giant cell tumours in tuberous sclerosis complex. Neurology 2004; 63:1457-61.
  28. Webb DW, Fryer AE, Osborne JP. On the incidence of fits and mental retardation in tuberous sclerosis. J Med Genet 1991; 28:395-7.
  29. Goodman M, Lamm SH, Engel A, Shepherd CW, Houser OW, Gomez MR. Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J Child Neurol 1997; 12:85-90.
  30. O’Callaghan FJ, Harris T, Joinson C, et al. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child 2004; 89:530-3.
  31. Wiznitzer M. Autism and tuberous sclerosis. J Child Neurol 2004; 19:675-79.
  32. Jeste SS, Sahin M, Bolton P, Ploubidis GB, Humphrey A. Characterization of autism in young children with tuberous sclerosis complex. J Child Neurol 2008; 23:520-5.
  33. Talos DM, Sun H, Zhou X, et al. The interaction between early life epilepsy and autistic-like behavioural consequences: a role for the mammalian target of rapamycin (mTOR) pathway. PLoS One 2012; 7:e35885.
  34. Thiele EA. Managing epilepsy in tuberous sclerosis complex. J Child Neurol 2004; 19:680-6.
  35. Cusmai R, Chiron C, Curatolo P, Dulac O, Tran-Dinh S. Topographic comparative study of magnetic resonance imaging and electroencephalography in 34 children with tuberous sclerosis. Epilepsia 1990; 31:747-55.
  36. Hancock E, Osborne J. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J Child Neurol 1999; 14:71-4.
  37. Lawden MC, Eke T, Degg C, Harding GFA, Wild JM. Visual field defects associated with vigabatrin therapy. J Neurol Neurosurg Psychiatry 1999; 67:716-22.
  38. Manuchehri K, Goodman S, Siviter L, Nightingale S. A controlled study of vigabatrin and visual abnormalities. Br J Ophthalmol 2000; 84:499-505.
  39. Buoni S, Zannolli R, Strambi M, Fois A. Combined treatment with vigabatrin and topiramate in West syndrome. J Child Neurol 2004; 19:385-6.
  40. Franz D, Tudor C, Leonard J. Topiramate as therapy for tuberous sclerosis complex-associated seizures. Epilepsia 2000; 41(Suppl 7):87.
  41. Collins JJ, Tudor C, Leonard JM, Chuck G, Franz DN. Levetiracetam as adjunctive antiepileptic therapy for patients with tuberous sclerosis complex: a retrospective open-label trial. J Child Neurol 2006; 21:53-7.
  42. Franz DN, Tudor C, Leonard J, et al. Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia 2001; 42:935-40.
  43. Pellock JM, Faught E, Leppik IE, Shinnar S, Zupanc ML. Felbamate: consensus of current clinical experience. Epilepsy Res 2006; 71:89-101.
  44. Jennesson M, van Eeghen AM, Caruso PA, Paolini JL, Thiele EA. Clobazam therapy of refractory epilepsy in tuberoussclerosis complex. Epilepsy Res 2013; 104:269-74.
  45. Kossoff EH, Thiele EA, Pfeifer HH, Mc Grogan JR, Freeman JM. Tuberous sclerosis complex and the ketogenic diet. Epilepsia 2005; 46:1684-6.
  46. Coppola G, Klepper J, Ammendola E et al. The effects of the ketogenic diet in refractory partial seizures with reference to tuberoussclerosis. Eur J Paediatr Neurol 2006; 10:148-51.
  47. Madhavan D, Schaffer S, Yankovsky A, et al. Surgical outcome in tuberous sclerosis complex: A multicentre survey. Epilepsia 2007; 48:1625-8.
  48. Meikle L, Polizzi K, Egnor A, et al. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signalling lead to improved survival and function. J Neurosci 2008; 28:5422-32.
  49. Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies. Epilepsia 2009; 51:27-36.
  50. Zeng LH, Rensing NR, Wong M. Developing Antiepileptogenic Drugs for Acquired Epilepsy: Targeting the Mammalian Target of Rapamycin (mTOR) Pathway. Mol Cell Pharmacol 2009; 1:124-9.
  51. Muncy J, Butler IJ, Koenig MK. Rapamycin reduces seizure frequency in tuberous sclerosis complex. J Child Neurol 2009; 24:477.
  52. Canpolat M, Per H, Gumus H, et al. Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86. Childs Nerv Syst 2014; 30:227-40.
  53. French JA, Lawson JA, Yapici Z 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 2016; 388:2153-63.
  54. Overwater IE, Rietman AB, Bindels-de Heus K et al. Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial. Neurology 2016; 87:1011-18.