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Corresponding authors at: Department of Pediatrics, Hokkaido University Hospital, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan (Hideaki Shiraishi) and Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan (Mitsuhiro Kato).
Hokkaido University Hospital Clinical Research and Medical Innovation Center, Research and Development Division, Hokkaido 060-8648, JapanUniversity of Toyama Hospital, Center for Clinical Research, Toyama 930-0194, Japan
Corresponding authors at: Department of Pediatrics, Hokkaido University Hospital, North 15, West 7, Kita-ku, Sapporo, Hokkaido 060-8638, Japan (Hideaki Shiraishi) and Department of Pediatrics, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan (Mitsuhiro Kato).
The efficacy of the mechanistic target of rapamycin inhibitor, sirolimus, was recently reported for patients more than 6 years of age by Kato et al. We evaluated the efficacy and safety of sirolimus in a 2-year-old patient with recurrent focal seizures with impaired consciousness after focal cortical dysplasia (FCD) type IIa resection.
Methods
The patient was a 2-year-old girl who had recurrent seizures after undergoing FCD resection at 4 months of age. The initial dose of sirolimus was 0.5 mg/day and was gradually increased using the trough blood concentration before oral administration as an index, and evaluation was performed at 92 weeks.
Results
The trough blood level of sirolimus was increased to 6.1 ng/mL and maintenance therapy was started at 40 weeks. Focal seizures with impairment of consciousness with tonic extension of the limbs decreased. No critically serious adverse events occurred.
Conclusion
Sirolimus was effective against epileptic seizures from FCD type II even for a child under 5 years of age. There were no critically serious adverse events and administration could be continued.
Focal cortical dysplasia (FCD) is one of the most obvious lesions in which the core symptom is an intractable epileptic seizure that develops in infancy. In one study, somatic mosaic mutations in the mechanistic target of rapamycin (MTOR) gene were identified in six of 13 patients (46%) with FCD type II with dysmorphic neurons on pathological diagnosis, especially type IIb with balloon cells [
]. Our current study is the feasibility study of sirolimus administration for patients under 5 years of age with FCD type II.
2. Case presentation
2.1 Case report
Our patient was a 2-year-old girl. From 3 days of age, seizures appeared, with left rotation of the neck and leftward deviation of both eyes, which lasted for 1–2 min. At 14 days of age, the seizures began to swarm about 20 times a day, and phenobarbital was started. After starting phenobarbital, the number of seizures decreased temporarily, but started to increase again from about one month, and in addition to the above-mentioned seizures, motionless stare and mouth-muffled seizures began to appear. Seizures during the sleep-onset period were particularly common, and as a result of frequent seizures a day, sleep time was shortened.
MRI and functional imaging demonstrated FCD in the right occipital lobe (Fig. 1A-D). Right occipital lobe resection was performed at 4 months of age and the postoperative pathology showed FCD type IIa (Fig. 1E, F). The surgery was performed without chronic invasive EEG monitoring, and electrocorticography was performed only during the surgery. Her seizures were suppressed temporarily just after the surgery, but recurred at 1 year and 10 months of age. During awakening and sleeping, the eyes were deviated to the left, awareness was impaired, and the limbs were extended with tonic posturing more than 40 times a day which was confirmed by long-term video-EEG monitoring at the age of 3 years.
Fig. 1MRI and functional images. (A) The boundary between white matter and gray matter was unclear in the right occipital lobe. (B) Lobectomy was conducted at the right occipital lobe. (C) Interictal 99mTc-ethyl-cysteinate dimer single photon emission computed tomography (ECD SPECT) showed hypoperfusion and ictal SPECT demonstrated hyperperfusion in the right occipital lobe. (D) 18F-fluorodeoxyglucose positron emission tomography (FDG PET) showed hypometabolism in the right occipital lobe. (E) Histopathology (hematoxylin-eosin stain) demonstrated dysmorphic neurons in the operative specimen. (F) Magnified histopathology did not demonstrate balloon cells. Rt, right; T2WI, T2-weighted image.
She took the following antiepileptic drugs: phenobarbital (5.3 mg/kg/day), levetiracetam (20 mg/kg/day), carbamazepine (8 mg/kg/day), and zonisamide (20 mg/kg/day). These doses were not changed during the study. Seizure frequency was noted in a diary kept by the parents. At the age of 2 years and 4 months, her developmental quotient by the Enjoji-type intelligence development test was 123.
According to the assigned protocol as shown in Fig. 2, she was administered sirolimus [
A single-arm open-label clinical trial on the efficacy and safety of sirolimus for epileptic seizures associated with focal cortical dysplasia type II: A study protocol.
]. The dose of sirolimus was gradually increased to reach the maximum dose of 4 mg/day at 80 weeks (Fig. 3B). The trough blood level of sirolimus increased to 6.1 ng/mL at 40 weeks, and maintenance therapy was started. The maximum blood concentration of sirolimus reached 6.8 ng/mL at 48 weeks (Fig. 3B). During the 4-week pre-observation period, focal impaired awareness seizures (FIAS) with head rotation and tonic extension of the limbs appeared 43 times mainly during the daytime. The FIAS began to decrease 48 weeks after the start of sirolimus and decreased to 2 times/4 weeks at 92 weeks (Fig. 3A). Her intellectual abilities were well-developed for her age. Her IQ was 114, based on the Tanaka-Binet test performed at 92 weeks after the start of the study.
Fig. 2Study protocol. Administration of sirolimus was adjusted by the trough serum concentration: 5–15 ng/mL during the variable administration period. A blood sample was collected 4 weeks after a change was made in the administered dose of sirolimus. The maximum dose of sirolimus was 4 mg/day.
Fig. 3Change in seizures and dose of sirolimus and trough concentrations. (A) The blue line shows the number of focal impaired awareness seizures (FIAS) with tonic extension of the limbs. (B) The blue bars show the dose of sirolimus (mg/day), and the red dots show the trough concentration of sirolimus (ng/mL).
Her EEG showed focal or rhythmic spikes in the T6, O2, F3 and F4 electrodes interictally, and the rhythmic spikes in O1 and T5 before sirolimus treatment evolved to slow waves in the bilateral frontal area and Fp2, F8 and T4 after sirolimus treatment. Therefore, the rhythmic spike activity, which is closely related to ictogenesis, disappeared and was replaced by a slow wave component with sirolimus administration.
2.2 Adverse events
There were no abnormal blood findings, i.e., hypercholesterolemia or elevated transaminases, before or after sirolimus administration. Mild stomatitis was observed, but it disappeared without worsening. There were 10 adverse events, of which three were serious adverse events, but not critical. The patient developed bronchopneumonia. All events were considered as unpredictable serious adverse events.
3. Discussion
Kato et al. reported the efficacy of sirolimus in patients with FCD type II over 6 years of age in a protocol using an initial dose of 1 mg/day and titration by 1 mg/day under sirolimus concentration evaluation [
]. Our protocol of titrating at an initial dose of 0.5 mg/day and 0.5 mg/day in a 2-year-old child showed almost similar sirolimus concentration trends. We therefore confirmed that our protocol was reasonable for our child patients.
Our current study suggests a long-term effect on epileptic seizures caused by sirolimus and that seizure symptoms might be reduced even in children under 5 years of age using our protocol. Initially, as everolimus has a tumor-reducing effect in tuberous sclerosis, we speculated that sirolimus modifies the microtissue structure in FCD and suppresses seizure symptoms. We expected that there would be a time lag in the onset of the effect. However, FIAS were immediately suppressed, and the suppressing effect was maintained until at least the end of the continuation period.
Therefore, sirolimus is considered to have an immediate antiseizure effect, which is different from its tumor suppressive effect [
]. The antiseizure effect can be considered as an immediate effect of, for example, adrenocorticotropic hormone on the spasm accompanied by tuberous sclerosis; namely a mechanism in which anti-inflammatory action acts immediately on seizure suppression [
]. But it is not clear why the effect was relatively rapid in this case. In the FCDS-01 study by Kato et al., some patients, varying in age from 12 to 57 years, also showed a rapid response to sirolimus (Patients 3, 10, 11, and 16) [
]. It is still unknown why patients with FCD type II show a variable response to sirolimus. One reason may be the frequency of variant alleles at the lesion, but as few patients have genetic analysis of their brain tissue, this is yet to be determined.
Zhong et al. recently reported that GABAergic interneuron and synapse transmission are mTOR-dependently disturbed in an experimental mouse model of FCD. They suggested that postsynaptic mechanisms independent of interneuron reduction or altered expression of GABA synapse genes might account for the impaired GABAergic neurotransmission in FCD type II, as well as other mTOR-related epilepsies [
In conclusion, sirolimus was effective in suppressing seizures in a young child, demonstrating the potential effectiveness of sirolimus in FCD type II cases.
4. Consent for publication
We have obtained consent from the patient's parent or guardian to publish this case report as it includes a detailed medical history of the patient that may identify an individual.
Author Contributions.
HS and MK were responsible for the organization and coordination of the study. YU, KE and HS treated patients as attending physicians and obtained clinical data. TT, SY, JT, NS and AM developed the trial design.
All authors contributed to the writing of the final manuscript. All members of the study team contributed to the management or administration of the trial.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was supported by a grant from the Japan Agency for Medical Research and Development for projects promoting clinical trials for development of new drugs (18lk0201069h0002). Nobelpharma Co., Ltd. provided the sirolimus.
Ethical publication statement
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. This study was conducted with permission from the Hokkaido University Hospital Accredited Clinical Research Review Committee (jRCTs031190157).
References
Nakashima M.
Saitsu H.
Takei N.
Tohyama J.
Kato M.
Kitaura H.
et al.
Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb.
A single-arm open-label clinical trial on the efficacy and safety of sirolimus for epileptic seizures associated with focal cortical dysplasia type II: A study protocol.
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