Tuberous sclerosis complex (TSC) is a multisystem disease caused by the mutation in one of the two tumour suppressor genes TSC1 and TSC2.1 It affects about 1 in 6000 newborns, and although it can affect multiple organs and systems (brain, skin, heart, kidneys, lungs, liver, eyes), neurological involvement is the cause of the major mortality and morbidity, above all in the paediatric age.2 From a neuropathological point of view, patients with TSC might present with cortical/subcortical tubers, subependymal nodules, subependymal giant cell astrocytomas and white matter migration lines.2
From a clinical point of view, neurological manifestations include epilepsy and its comorbidities, including cognitive disability, autism spectrum disorders, attention deficit hyperactivity disorder and other neuropsychiatric disorders.2 Epilepsy is a very common manifestation, affecting up to 85% of subjects, and presenting in the first years of life in two thirds of subjects.3 Early onset epilepsy can be in the form of infantile spasms or focal seizures, which can coexist or evolve into infantile spasms. The latter represent a significant risk factor for later refractory epilepsy because approximately 75% of patients with a history of infantile spasms will present with refractory seizures up to severe epileptic encephalopathies, including focal refractory seizures and a Lennox-Gastaut phenotype.3
Epileptogenesis in TSC is a very long process, starting far before birth. Indeed, the mutation of TSC1/2 genes determines an overactivity of the mTOR (mammalian target of rapamycin) pathway, which is already evident during foetal life.4 This early mTOR overactivation determines alterations of migration and orientation of neural cells, thus leading to abnormal cortical lamination and dendritic arborisation.5 Abnormalities in this crucial pathway also include the disruption of GABAergic interneuron development as well as the regulation of glutamatergic function, thus meaning an imbalance between excitation and inhibition, which is a clear predisposing factor to epileptic seizures.6
The early dysregulation of the mTOR pathway, causing altered migration and cell morphology, causes the formation of tubers. These are the hallmark of the pathology and can be already visible during prenatal life with foetal magnetic resonance imaging, and include different abnormal cells, such as dysplastic neurons and giant cells.5 Tubers are dynamic lesions, and their continuous changes, both in pre- and postnatal life, can contribute to the establishment of extensive epileptogenic networks.7
Tubers represent focal malformations of cortical development and are characterised by loss of the hexalaminar cortical architecture, presence of an excessive number of astrocytes, and by dysmorphic neurons and giant cells.7 However, although tubers are the most clear lesions, and for which there is a documented link with epilepsy, many other structural and microstructural lesions are evident in TSC brains. In particular, mTOR alteration leads to focal dyslamination and isolated giant, cells even in the absence of major structural abnormalities, resulting in global and focal network alterations that might play a role in both epileptogenicity and abnormal neurodevelopment.
White matter also appears to be extensively involved, with white matter migration lines detectable on conventional brain MRI as a result of abnormal migration.2 However, normal appearing white matter can also be involved by microstructural changes, which are evident when diffusion tensor imaging is performed, and can be linked to epileptogenesis.8 Furthermore, white matter abnormalities appear to be more evident in children with early onset and refractory epilepsy, with persistent seizures seeming to determine extensive connectivity alterations in brain areas crucial for language, social development and global cognitive functioning.9
Management of tuberous sclerosis-related seizures
Table 1 summarises treatment options for TSC-related seizures.
Anti-epileptic drug treatment
The treatment of epilepsy associated with TSC still represents a great challenge for clinicians, due to the high rate of refractoriness, which is evident in up to 67% of cases.3 Early onset seizures should be promptly treated with vigabatrin, which has been shown to be able to stop infantile spasms in up to 95–99% of cases.10 Although its efficacy in focal seizures might be lower, treatment should not be delayed because it has been shown that a shorter gap from seizure onset and treatment initiation guarantees a better long-term outcome, both in terms of seizure refractoriness and neuropsychological evolution.11,12
This kind of disease-specific efficacy of vigabatrin seems to be related both to its ability of increasing GABA concentrations in the synaptic cleft, as well as to a partial action on mTOR inhibition.13 Vigabatrin can be associated with visual field constriction, but the benefit–risk ratio is strongly in favour of this treatment option.14 Unfortunately, there are no other drugs showing such specificity; therefore vigabatrin is the only anti-epileptic drug recommended. However, other drugs enhancing GABAergic transmission, such as topiramate and carbamazepine, could be used.14 If polytherapy is necessary, anti-epileptic drugs showing synergism should be considered, and drugs with multiple mechanisms of action should be preferred in order to cover more seizure types.14
If the first two appropriately chosen anti-epileptic drugs fail to control seizures, a pre-surgical evaluation should be promptly started to assess the possibility of a surgical resection of the epileptic focus. Although data are not homogeneous, seizure freedom is achieved in a mean of 63% (range 25% to 90%) of surgically treated patients, with better results if the epileptogenic zone is accurately localised and the surgery is performed promptly.15
Vagus nerve stimulation
In patients not responding to anti-epileptic treatment and for whom surgery is not an option, vagus nerve stimulation should be considered. Although data are limited, seizure freedom is quite rare after vagus nerve stimulation implantation; however, a clinically significant response with a seizure frequency reduction higher than 50% in about 70% of treated patients.16
In patients with refractory seizures who are not candidates for surgery, a ketogenic diet should also be considered. There are very limited but promising data for this non-pharmacological option, which seems to act with a partial inhibition of mTOR complex.17 In the few available studies, more than 50% seizure reduction has been reported in 90% of cases.18 mTOR inhibition The identification of a specific molecular pathway underlying epilepsy in TSC paved the way for evaluating the efficacy and safety of available mTOR inhibitors (rapamycin and its analogue everolimus) in TSC-related epilepsy.
Previously available treatment options for epilepsy in TSC only provided a symptomatic treatment for seizures, whereas these drugs act on TSC pathogenesis, even presenting the potential of representing a disease-modifying systemic therapy. A first prospective, multicentre Phase I/II study enrolled 20 patients, and 72% of the 18 individuals completing the 48 months observation showed a ≥50% reduction in seizure frequency.19,20 In a German clinical series, 57% of enrolled children showed 25–100% of seizure frequency reduction with adjunctive everolimus.21 In another small study focusing on children and adolescents, 71% of subjects treated with everolimus showed a reduction in seizure frequency ≥50%.22
Furthermore, a recent open-label, single centre study enrolled 15 patients under the age of 18 years and found a responder rate of 80% (12/15), with 58% of patients (7/12) seizure-free.23 Positive results have also been obtained in a randomised controlled trial evaluating efficacy of everolimus in 23 children, with 75% of them showing a ≥50% reduction in seizure frequency.24
A Phase III, double-blind, placebo-controlled study (Examining Everolimus in a Study of Tuberous Sclerosis Complex; EXIST-3), compared the efficacy and safety of two dosing regimens of add-on everolimus versus placebo in patients with TSC and refractory focal epilepsy.25 This study included an initial 8-week baseline phase, followed by an 18-week core phase and a 48-week extension phase. During the core phase with 366 patients enrolled, a greater reduction in seizure frequency was obtained with the two targeted exposure ranges of everolimus (3–7ng/ml and 9–15ng/ml) in comparison with placebo. The response rate, defined as a seizure frequency reduction ≥50%, was 15.1% in the placebo group, 28.2% in the low-exposure everolimus group, and 40.0% in the high-exposure everolimus group. Everolimus-related adverse events were quite common but based on the positive results of this trial, the European Commission approved everolimus as an adjunctive treatment for patients with refractory partial-onset seizures associated with TSC over the age of two years.
Despite all the recent progress and the introduction of new anti-epileptic drugs, the management of TSC-related epilepsy still represents a real challenge for clinicians, with about two-thirds of patients presenting refractory seizures.3 Neuropsychiatric comorbidity also represents a significant burden; therefore timing of treatment is crucial. Also considering that TSC can be increasingly diagnosed before or soon after birth, before any neurological symptoms appear, a preventive anti-epileptic treatment before the onset of seizures has been proposed.
This was aimed to try to minimise the impact of early onset seizures;26 however, actual evidence is still insufficient to recommend this treatment approach. Two trials are undergoing to try to solve this issue: EPISTOP (Long-term, prospective study evaluating clinical and molecular biomarkers of EPIleptogenesiS in a genetic model of epilepsy – Tuberous sclerOsis complex); and PREVeNT (Preventing Epilepsy Using Vigabatrin In Infants With Tuberous Sclerosis Complex). The EPISTOP trial – a long-term, prospective, randomised, parallel-group, triple-masked (participant, care provider, and investigator) multicentre European study tracking epileptogenesis, epilepsy and neurodevelopment in infants with TSC – has as a primary objective the identification of the clinical and molecular biomarkers of epileptogenesis in patients with TSC.
The secondary objective is to compare the effects of administration of standard antiepileptic treatment after presentation with clinical seizures versus preventive treatment after recorded epileptiform EEG discharges without seizures. The PREVeNT trial is a randomised, triple-blind (participant, care provider, and investigator), placebo-controlled study of infants with TSC having the developmental impact of early versus delayed treatment with vigabatrin as primary outcome. Hopefully the results of these studies will provide some practical tips to suggest the best time to initiate treatment to guarantee an optimal treatment approach for all infants with a pre-symptomatic diagnosis of TSC.
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