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Advanced Neurology mTOR inhibition in epilepsy

mTOR dual kinase inhibitors, not only suppress mTOC1 6.2.2. Focal cortical dysplasia
and mTORC2 but also target additional pathways—either In recent years, there has been growing interest in
vertically along the same pathway by inhibiting PI3K the use of mTOR inhibitors for treating FCD Type II.
activity or horizontally by targeting HDAC or ATR proteins Leitner et al. observed lower ribosomal protein S6
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in different pathways. Despite these advancements, the phosphorylation in the brain tissues of patients with FCD
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clinical use of these drugs is still far from being established.
type II (n=9) and tuberous sclerosis complex (n=5) who
Temsirolimus, an intravenous rapalog, was approved had undergone surgical resection and were treated with
by the U.S. FDA in 2007 for the treatment of advanced everolimus, compared to the control group. These patients
renal cell carcinoma (Table 1). Deforolimus has shown also exhibited higher synaptic transmission and cellular
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promising clinical responses in metastatic soft tissue or respiration, as well as lower levels of neuron ensheathment,
bone sarcoma, but further studies on its safety and efficacy nuclear mRNA catabolism, and organophosphate
are still needed. 58 metabolism (Table 3). Shiraishi et al. reported a case of a
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2-year-old girl who had surgical resection of FCD type II
6.2. mTOR inhibitor used in non-tuberous sclerosis at the age of 4 months. Her seizures recurred at the age
complex-related epilepsy
of 1 year and 10 months and were refractory to various
6.2.1. PMSE and hemimegalencephaly antiseizure medications. Treatment with sirolimus resulted
One of the earliest descriptions of mTOR inhibitor use in non- in a 95% seizure reduction over 92 weeks. 84
tuberous sclerosis complex-related epilepsy was reported in An open-label, multicenter clinical trial involving
2013. Parker et al. demonstrated that fibroblasts from 16 patients with FCD type II initiated oral sirolimus at an
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80
skin biopsies of patients with PMSE had higher mTORC1 initial dose of 1 mg/d for patients with a weight of <40 kg
activity compared to those from the control group and and 2 mg/d for those weighing ≥40 kg, with subsequent
their asymptomatic heterozygous parents. The mTORC1 titration to achieve a blood trough level of 5 – 15 ng/mL.
85
activity level and migration defects in these fibroblasts were The trial reported a response rate of 33%, defined as the
normalized with sirolimus. The authors further described percentage of patients showing a seizure reduction of
the clinical experience of sirolimus use in five patients with ≥50% during the 12-week maintenance period. 85
PMSE. Three patients achieved seizure freedom, whereas
one experienced a 75% reduction in seizures (Table 3). All A recent double-blinded, crossover, randomized
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treated patients were more interactive or socially engaged clinical trial involved 22 patients with FCD type II-related
than untreated historical controls. In this cohort, a seizures, in which a population pharmacokinetic model of
80
3-month-old patient who received prophylactic sirolimus everolimus was developed to explore its optimal dosage
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treatment at 3 months of age remained seizure-free regime. The authors suggested that an initial everolimus
2
throughout the follow-up period, highlighting its potential dose of 7 – 9 mg/m should be used for patients with a
2
2
role as a disease-modifying agent. 80 body surface area of <1 m , and 6 – 7 mg/m for those
with a body surface area between 1 and 2 m , to meet
2
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Xu et al. reported a 6-day-old girl with the target trough concentration of 5 – 15 ng/mL. In
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hemimegalencephaly due to a mosaic MTOR variant a prospective, randomized, double-blinded, placebo-
with 16% mosaicism. Her seizures were initially resistant controlled, crossover, phase 2 trial (ClinicalTrials.gov:
to nine antiseizure medications. While awaiting for NCT03198949), the anti-epileptic efficacy of everolimus
hemispherectomy, sirolimus treatment led to a >50% was evaluated in patients aged 4 – 40 years who had
reduction in seizures within 1 week and improved pathologically confirmed FCD Type II and drug-
neurodevelopment in 2 weeks. 81 resistant epilepsy with at least three seizures per month
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On the other hand, Hadouiri et al. reported a conflicting for 2 months. In the 4-week baseline phase, antiseizure
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case involving a 12-year-old girl with hypomelanosis of Ito, medications were kept constant, and seizure burden was
focal cerebral hypertrophy involving the left hemisphere, monitored. Patients were then randomly assigned in a 1:1
and an MTOR missense variant with 41% mosaicism ratio to either the everolimus-first or placebo-first group
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in her skin-derived DNA. No seizure reduction was for the 12-week core phase 1, followed by a crossover
observed after 5 months of everolimus treatment, and her to the other treatment arm for another 12 weeks of core
clinical condition continued to deteriorate. The authors phase 2. A 29-week unblinded extension phase was offered
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hypothesized that the degree of mutation mosaicism, as to all patients, during which they received everolimus if
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well as the severity of epilepsy, might impact the efficacy of they consented. In the 1 4 weeks (titration period) of
st
mTOR inhibitors, underscoring the challenges in treating both core phases, everolimus was started at a daily dose
this heterogeneous clinical entity of mTORopathies. 82 of 4.5 mg/m and titrated to attain a trough concentration
2
Volume 3 Issue 3 (2024) 12 doi: 10.36922/an.3568