American Journal of Clinical Medicine Research, 2019, Vol. 7, No. 2, 57-59
Available online at http://pubs.sciepub.com/ajcmr/7/2/5
Published by Science and Education Publishing
DOI:10.12691/ajcmr-7-2-5

The Association between Epileptiform Activity andAutistic Symptoms in Three Cases
with Tuberous Sclerosis
Kunio Yui1,*, George Imataka2, Hitomi Sasaki1, Ryoichi Shiroki1
1

Department of Urology, Fujita Health University School of Medicine, Aichi, Toyoake, 470-1192, Japan2
Department of Pediatrics, Dokkyo Medical University, Mibu 321-0293, Tochigi,Mibu, Japan*Corresponding author: yui16@bell.ocn.ne.jp

Received September 10, 2019; Revised October 24, 2019; Accepted October 30, 2019

Abstract This case study examined the association between epileptic activity such as epileptiform discharges andautistic symptoms; and to examine the effect of mTOR inhibitor everolimus on seizures and epileptiform discharges
in three cases with TSC and autistic symptoms. The everolimus treatment improved autistic symptoms in all fourcases, however, epileptiform discharges did not disappear in all four cases with everolimus treatment. Thus,epileptiform activity and autistic symptoms may be two end-results of separate brain dysfunction. The evrolimus
treatment disappeared a seizure in only one case, suggesting partial overlap between mTOR hyperactivity and aseizure in small subset of cases with TSC. This study for firstly revealed that the everolimus treatment wasinefficient for epileptiform discharges. Antiepileptic therapy at early stage of brain development might be effective
for epileptic activity.

Keywords: tuberous sclerosis complex, seizure control, Epileptiform discharges, autistic symptoms, mTOR
inhibitor

Cite This Article: Kunio Yui, George Imataka, Hitomi Sasaki, and Ryoichi Shiroki, “The Association
between Epileptiform Activity and Autistic Symptoms in Three Cases with Tuberous Sclerosis.” American
Journal of Clinical Medicine Research, vol. 7, no. 2 (2019): 57-59. doi: 10.12691/ajcmr-7-2-5.

1. Introduction

2. Case Reports

Most children suffering from TSC with ASD
experienced early onset of epilepsy including infantile
spasms, West syndrome or focal seizures with impaired
awareness [1]. Epileptic activity such as epileptiformdischarges (referred to as spikes) in these seizures may
contribute to the brain dysfunction as called epileptic
encephalopathy,1 which may sometimes induce autistic
symptoms such as impaired communication andrepetitive behavior [1]. However, the contribution of
epileptiform activity to the development of autistic
symptoms remains open to debate [1].
TSC is caused by mutations in the TSC1 or TSC2 genes,
and induce mTOR hyperactivation, inducing neuropsychiatricimpairments and epileptogenesis [2]. mTOR inhibitors(everolimus and rapamycin) improve TSC-associatedseizures and ASD, and epileptiform activity such as
epileptiform discharge [3]. However, there is few data on
potential anti-epileptogenic action of mTOR inhibitors [4].
This study attempted to untangle the association
between epileptiform discharges and autistic symptoms;
and to examine the effect of everolimus on epileptiformdischarges in four cases with TSC. This study may shedlight on a new aspect of the neurobiological bases of ASD.

Case 1 was 10 years old male with TSC accompaniedwith the autistic social impairment and verbal stereotypy.
A subpendymal nodule located at the left frontal area andAML were detected, meeting the TSC diagnostic criteria.
At age 5 months, the patient experienced a severe epilepsy
syndrome of the triad of focal epileptic spasms (Westsyndrome), characterized by clusters of epileptic spasms,
psychomotor delay, and a specific interictal EEG
pattern known as hypsarrhythmia. He continued to takeanticonvulsants, however his seizures persisted. Thus, hereceived focal resection of a subpendymal nodule, and hisseizure disappeared following this resection at age 2 years.
However, epileptiform discharges were still detected.
At age 10 years, his EEG was highly disorganized withlow voltage irregular slow waves intermixed withmultifocal spikes. At age 6 years, his ASD symptoms graduallydeveloped. To improve his autistic symptoms and EEG
abnormalities, he was treated with everolimus (3.6 mg/dayfor 24 weeks). The everolimus treatment disappeared
autistic symptoms. However, epileptiform discharges
persisted.
Case 2 was 9 years old girl with TSC accompaniedwith the autistic social impairment. At age 7 years, a58

American Journal of Clinical Medicine Research

subdendymal nodule on left anterior horn of lateral
ventricle was detected. At age 4 months, she experienced
focal seizures with impaired awareness characterized byclusters of epileptic spasms from right face to left handseizure, following language development delay. She wastreated with anticonvulsants, and her seizure disappeared.
At age 2 years, she experienced re-occurrence offocal seizure with impaired awareness and treated withclonazepam, resulting disappearance of her seizure.

At age 7 years, her EEG indicated high voltage irregularslow waves intermixed with spikes and polyspikes(hypsarhythmia). At age 4 years, her impaired social
interaction gradually developed. Everolimus treatment(2.5 mg/day for 24 weeks) improved social impairment,
however, her seizures and epileptiform discharges did notdisappear. Thus, at age 9 years, she received complete
corpus callosotomy, leading to disappearances of seizuresand epileptiform discharges.

Figure 1. Electroencephalographic recordings of case 2

American Journal of Clinical Medicine Research

Case 3 was age 6 years old girl with TSC accompaniedwith autistic social impairments and stereotyped behaviors.
At age 6 months, SEGA located at the right foramen of
Monro and subpendymal nodules located at both side
interventricular form were detected, meeting thediagnostic criteria for TSC. At age 6 months, she
exhibited infantile spasms. At age 13 months, she
experienced her first episode of focal seizures withimpaired awareness. The patient was treated with various
anticonvulsants, however, her epilepsy gradually
increased in frequency and severity. Her EEG frequently
showed spikes and spike-and-wave complexes at thecentral areas. Since she was 7 months of age, shedeveloped impaired social interaction. She had difficultywith motor coordination. At age six years, everolimus
treatment (3.0 mg/day for 24 weeks) improved autistic
symptoms and disappearance of her seizures, however,
epileptic discharges persisted.

3. Discussion
Epileptic seizures of case 1 disappeared with antiepileptic
therapy before everolimus treatment. Epileptiform discharges
disappeared in all four cases during and after the
everolimus treatment. Several neurological studies
confirmed the relationship of the epileptiform discharges
and autistic symptoms [1]. While, some longitudinal casestudies postulated that autistic symptoms and seizures may
be separate phenotype from a standpoint of mechanisms[1]. Thus, the association between epileptiform discharges
and autistic symptoms remains open to debate. This study
revealed no overlap between the epileptiform discharges
and autistic suymptoms in all cases. The core TSC
pathophysiology, hyperactivation of the mTOR pathway,
induces impaired brain functioning such as abnormalities
in intracellular signaling inducing altered neuronal connections,leading to the autistic symptoms and epilepsy [2]. The
everolimus treatment improved autistic symptoms in allfour cases. Previous studies indicated that mTOR hyperactivity
is critical for epileptiform discharges, suggesting thatmTOR inhibitors may disappear epileptiform discharges[3]. However, epileptiform discharges did not disappeared

59with everolimus treatment in all cases. Our finding,considering together with the previous postulation that noclinical data on anti-epileptogenic activity of everolimus[5], and mTOR inhibitors have only stalling effect forepilepsy progress [4], our above finding may bereasonable.
A previous review article suggested overlap in thepresentation of epileptogenesis and autistic symptoms [1].
In this study, although everolimus treatment improved
autistic symptoms in all four cases, epileptiformdischarges did not disappear in all four cases witheverolimus treatment. Thus, epileptiform activity andautistic symptoms may be two separate terminal-output ofbrain dysfunction. Additionally, the present finding thatthe everolimus treatment disappeared seizure in only case
4 suggested partial overlap between mTOR hyperactivity
and seizures in small subset of cases with TSC.
There are few information on the most optional
treatment for refractory seizures associated with TSC[5].
Although mTOR inhibitors have efficacy in the treatmentof TSC-associated seizures [3], this study for firstly
revealed that everolimus treatment may inefficient for
epileptiform discharges. Antiepileptic therapy at earlystage of brain development might be effective for epilepticactivity.

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Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).