Treating Epilepsy in Tuberous Sclerosis With Everolimus: Getting Closer

Commentary

Everolimus Treatment of Refractory Epilepsy in Tuberous Sclerosis Complex.

Krueger DA, Wilfong AA, Holland-Bouley K, Anderson AE, Agricola K, Tudor C, Mays M, Lopez CM, Kim MO, Franz DN. Ann Neurol 2013;74:679–687

OBJECTIVE: Epilepsy is a major manifestation of tuberous sclerosis complex (TSC). Everolimus is a mammalian target of rapamycin complex 1 inhibitor with demonstrated benefit in several aspects of TSC. We report the first prospective human clinical trial to directly assess whether everolimus will also benefit epilepsy in TSC patients. METHODS: The effect of everolimus on seizure control was assessed using a prospective, multicenter, open-label, phase I/II clinical trial. Patients ≥2 years of age with confirmed diagnosis of TSC and medically refractory epilepsy were treated for a total of 12 weeks. The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency over a 4-week period before and after treatment. Secondary endpoints assessed impact on electroencephalography (EEG), behavior, and quality of life. RESULTS: Twenty-three patients were enrolled, and 20 patients were treated with everolimus. Seizure frequency was reduced by ≥50% in 12 of 20 subjects. Overall, seizures were reduced in 17 of the 20 by a median reduction of 73% (p < 0.001). Seizure frequency was also reduced during 23-hour EEG monitoring (p = 0.007). Significant reductions in seizure duration and improvement in parent-reported behavior and quality of life were also observed. There were 83 reported adverse events that were thought to be treatment-related, all of which were mild or moderate in severity. INTERPRETATION: Seizure control improved in the majority of TSC patients with medically refractory epilepsy following treatment with everolimus. Everolimus demonstrated additional benefits on behavior and quality of life. Treatment was safe and well tolerated. Everolimus may be a therapeutic option for refractory epilepsy in this population.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by hamartomas in any organ system, especially the brain, retina, heart, skin, kidney, lung, and liver. Neurological manifestations are responsible for most disability, and include cognitive impairment and subependymal giant cell astrocytomas (SEGAs), but epilepsy is the most common problem, occurring in about 90 percent of individuals with TSC. The epilepsy typically begins early in life and is often intractable. Most TSC cases arise from new inactivating mutations in the TSC1 (encoding hamartin) or TSC2 (encoding tuberin) tumor suppressing genes.

The molecular mechanism of TSC is hyperactivity of the “mammalian target of rapamycin” (mTOR) pathway, which is felt to be responsible for both the hamartomas and epilepsy (1). mTOR is a protein kinase that regulates cell growth, proliferation, and survival, as well as expression of neurotransmitter receptors, synaptic plasticity, and axonal and dendritic morphology. Hamartin and tuberin form a complex that activates a GTPase (guansosine triphosphate hydrolase) that inactivates the RHEB (RAS protein homologue enriched in brain)-signaling protein, leading to inhibition of the mTOR pathway; mutations of TSC1 or TSC2 therefore release inhibition of this pathway.

Rapamycin, initially developed as an antifungal agent, was the first agent determined to inhibit the mTOR system (2). It was shown to cause regression of SEGAs in humans with TSC (3). In addition, early treatment with rapamycin was shown to prevent premature death and development of epilepsy in experimental models of TSC such as the TSC1^GFAP conditional knockout mouse (4), leading to investigation of mTOR inhibitors as therapy for human TSC.

Most clinical investigations have been done with everolimus, a rapamycin analog that was originally FDA approved for immunosuppression to prevent organ rejection following renal and cardiac transplantation, and as treatment for meta-static renal cell carcinoma. Marked regression of SEGAs within 3 months of treatment was demonstrated in an open study (5), and then confirmed in a large, international, multicenter, double-blind, placebo-controlled phase III trial (6). The FDA and the European Medicines Agency now approve everolimus for treatment of SEGAs that cannot be cured by neurosurgery. The patients in the open trial have now been followed for approximately 3 years with an observed sustained response (7). The most common adverse effects of this agent were upper respiratory infections, stomatitis, sinusitis, otitis media, and amenorrhea (7). Serious adverse effects requiring hospitalization were uncommon, but included bronchitis, pneumonia, vomiting, and convulsions (6). Subsequently, a randomized, double-blind, placebo-controlled study has also demonstrated regression of angiomyolipomas with everolimus (8).

The possibility that everolimus might treat seizures arises not only from animal models (4) but also from the clinical trials for SEGAs, which showed some reduction in seizures from baseline on 24-hour video EEG monitoring (5, 6). Limitations of these trials include the facts that many patients with infrequent seizures were enrolled, and that changes in antiepileptic drugs (AEDs) occurred during the trial. A subsequent open trial of everolimus in seven patients with TSC and intractable epilepsy with fixed AED doses found some seizure reduction in four patients, and a greater than 50% reduction in two patients over 36 weeks of everolimus treatment as measured by seizure diaries (9).

The current study selected TSC patients with severe drug resistant epilepsy, requiring at least eight seizures in the 30 days before enrollment. Seizures were tracked by seizure diaries, and by comparison of 24-hour video EEG recording performed at the beginning and end of the 16-week exposure to everolimus. This was the first study with the correct patient population in adequate numbers to test the efficacy of this agent for treating seizures. The magnitude of the seizure reduction was impressive, but a randomized, double-blind, placebo-controlled trial, level I evidence, is needed to confirm this antiseizure effect.

This work is ground-breaking, because this drug is intended to treat the underlying cause of the epilepsy, and not just suppress the seizures. The myriad downstream results of modulation of the mTOR pathway imply that the exact mechanisms of seizure prevention are uncertain, although they certainly must differ from those of current AEDs. These actions could include long-term depression and potentiation, and neuronal plasticity, but might also involve more mundane changes in synaptic excitability. It has been suggested that these complex actions of mTOR inhibitors on experimental models and human epilepsy amount to a genuine antiepileptic effect (10). The TSC patients in the current study already had advanced drug resistant epilepsy, but the proposal has been made that rapamycin and everolimus act by interrupting a progressive, ongoing process of epileptogenesis (10). The fact that seizure frequency progressively decreased during exposure to everolimus in the current study could be interpreted as supporting this idea. However, this concept of antiepileptogenic action of mTOR inhibitors would only be meaningful if the improved seizure control persisted after withdrawal of the agent, which has not yet been demonstrated. Even the shrinkage of SEGAs from everolimus therapy reverses when this drug is withdrawn (5).

Studies in experimental rodent models of acquired epilepsy, including the kainate model of epilepsy and the controlled cortical impact injury of posttraumatic epilepsy, provide evidence of disease modification by mTOR inhibition (10). In addition, altered mTOR pathway signaling is found in human focal cortical dysplasia, hemimegalencephaly, and ganglio-glioma brain tissue specimens. It has therefore been proposed that mTOR dysregulation might be a factor in epileptogenesis in many forms of acquired epilepsy. Nonetheless, there is currently no evidence for antiseizure effects for rapamycin or everolimus in human epilepsy of any etiology other than TSC.

Everolimus therapy is a unique new approach to treating epilepsy in TSC, and is full of promise. Even so, this is an immunosuppressant agent that needs to be used with care. It cannot be introduced widely into clinical practice as an AED for TSC until a randomized, double-blind, placebo-controlled trial demonstrates its safety and efficacy. May this come soon.