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Advanced Neurology mTOR inhibition in epilepsy

that sirolimus treatment not only lightened facial capillary sites as an open-label trial, investigated 94 infants with
malformations but also resulted in seizure freedom for all tuberous sclerosis complex. This study similarly found
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patients throughout the follow-up period, with a median that the preventive vigabatrin group had significantly
follow-up duration. On the other hand, a prospective study fewer patients with clinical seizures, refractory epilepsy,
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by Sebold et al. reported no significant changes in seizure and infantile spasms. However, the authors observed
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after 6 months of sirolimus. However, the study did note no significant difference in neurodevelopmental delay
significant improvements in individual processing scores between the preventive and conventional groups. 101
from neuropsychological tests, quality-of-life subscales Most recently, Bebin et al. published their observations
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related to anger, depression, and cognitive function, as well from the PREVENT trial, a phase 2b, multicenter,
as a shortened recovery time from stroke-like episodes.
randomized, double-blinded, placebo-controlled trial
7. Other seizure treatments with mTOR (n=84) comparing the use of vigabatrin at the first
signaling modulation epileptiform electroencephalogram and seizure onset
in tuberous sclerosis complex infants. Contradictorily,
7.1. Ketogenic diet the study found that preventive vigabatrin only reduced
The ketogenic diet is a well-established treatment modality the incidence of infantile spasms at 24 months, without
for refractory epilepsy. There are many hypotheses about its significantly impacting other seizure types or drug-
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mechanism of action, with modulation of the insulin/Akt/ resistant epilepsy, unlike the EPISTOPS trial. It also did
mTORC1 pathway thought to be one of the complex synergic not improve neurocognitive outcomes at 24 months. The
mechanistic interplays that occur following the initiation authors concluded that while prophylactic vigabatrin use
of the ketogenic diet. Kossoff et al. demonstrated that could prevent infantile spasms, it was insufficient to prevent
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92% of children with tuberous sclerosis complex-related long-term negative neurocognitive outcomes. We
refractory epilepsy experienced a >50% reduction in postulate that this observation could be due to insufficient
seizures, and 67% had a >90% reduction in seizures after mTOR modulation by vigabatrin to address the underlying
6 months on the ketogenic diet. In 2018, the International ongoing epileptogenesis in the tuberous sclerosis complex.
Ketogenic Diet Study Group included tuberous sclerosis At present, a phase 2 randomized, double-blind, placebo-
complex as one of the epilepsy syndromes or conditions controlled multicenter study (TSC-STEPS) is underway
that consistently benefit from the ketogenic diet. 97 to evaluate the efficacy of preventive sirolimus use in
infants with tuberous sclerosis complex (ClinicalTrials.
7.2. Vigabatrin gov: NCT05104983). In addition, another two-arm,
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Vigabatrin is primarily known as an irreversible randomized, double-blind, double-dummy, placebo-
GABA transaminase inhibitor. However, Zhang et al. controlled phase 2/3 study (ViRap trial) is comparing the
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demonstrated that vigabatrin not only increases brain efficacy, tolerability, and safety of prophylactic sirolimus
GABA levels but also reduces mTOR downstream S6 versus vigabatrin in infants with tuberous sclerosis
phosphorylation activity in a TSC1-knockout mouse complex (ClinicalTrials.gov: NCT04987463). 104
model. It is particularly effective against tuberous sclerosis 7.3. Metformin
complex-related epileptic spasms in early childhood. 99
There is growing evidence supporting the use of metformin
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In 2011, findings by Jóźwiak et al. sparked significant in oncological conditions. Metformin is also thought
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interest in the concept of preventive treatment for tuberous to influence the mTOR signaling pathway. It has been
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sclerosis complex. Their prospective, open-label trial postulated to inhibit mTORC1 activities through several
involved 45 infants with an early diagnosis of tuberous mechanisms, including the activation of the AMPK pathway,
sclerosis complex before seizure onset. In the conventional reduction in IGF1 and insulin signaling, upregulation of
treatment group, vigabatrin was started within a week after p53 and DICER1 gene expression, and downregulation of
seizure onset, whereas in the preventive group, vigabatrin c-MYC and HIF-1a expression. Amin et al. conducted
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was initiated before seizure onset, within a week after the first randomized, double-blind, placebo-controlled
the appearance of epileptiform activity. The authors trial (MiTS trial) to investigate the safety and efficacy of
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observed that the preventive group had significantly lower metformin in 55 patients with tuberous sclerosis complex
rates of mental retardation, more seizure-free patients, and aged 10 – 65 years. After 12 months of therapy, metformin
a lower incidence of refractory epilepsy at 24 months of age was found to significantly reduce SEGA volume by 20.8%
compared to the conventional treatment group. 100 (vs. 3.0% in the placebo group; P = 0.03) and reduce
Another prospective study, EPISTOP, conducted seizure frequency by 43.7% (vs. 3.1% in the placebo group;
across six sites as a randomized controlled trial and four P = 0.03), with 25% of the patients becoming seizure-free

Volume 3 Issue 3 (2024) 15 doi: 10.36922/an.3568