Epilepsy & Behavior 77 (2017) 13–18

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Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Epilepsy may be the major risk factor of mental retardation in children

with tuberous sclerosis: A retrospective cohort study
Yang-Yang Wang a, Ling-Yu Pang a, Shu-Fang Ma a, Meng-Na Zhang a, Li-Ying Liu a, Li-Ping Zou a,b,⁎
a
Department of Paediatrics, Chinese PLA General Hospital, Beijing 100853, China
b
Centre of Epilepsy, Beijing Institute for Brain Disorders, Beijing 100069, China

a r t i c l e i n f o a b s t r a c t

Article history: Mental retardation (MR) is one of the most common cognitive comorbidities in children with tuberous sclerosis,
Received 13 July 2017 and there are enormous studies about its risk factors. The genetic difference and the severity of epilepsy are the
Revised 17 September 2017 two main factors, but their weight in the occurrence of MR is still unclear. Two hundred twenty-three patients
Accepted 18 September 2017
with tuberous sclerosis who received intelligence assessment, genetic mutation analysis, and the epilepsy
Available online xxxx
severity assessment were included in our study. Genotype–neurocognitive phenotype correlations and
Keywords:
epilepsy–neurocognitive phenotype correlations were analyzed by binary logistic regression analysis. No
Tuberous sclerosis statistical significant result was found on genotype–neurocognitive phenotype correlations, which contrasted
Mental retardation the previous report. The prevalence of MR was 50.0% for the patients with tuberous sclerosis complex-1
Epilepsy (TSC1) mutation, 54.5% for TSC2 (p = 0.561), 54.7% for patients with protein-truncating (PT) and 50.0% for
Genotype patients with nontruncating (NT) (p = 0.791), and 54.3% for patients with family history and 53.7% for patients
without family history (p = 0.748). Statistical significant results were found on epilepsy–neurocognitive pheno-
type correlations, both on E-chess score (p = 0.01) and the occurrence of infantile spasms (p = 0.014), which
was consistent to the previous study. For children with tuberous sclerosis, instead of genetic factors, epilepsy
may play the main role for the presence of mental retardation. Patients with mental retardation tend to have
earlier seizure attack, take more AEDs, have more seizure types, and have higher seizure frequency. Among the
four cognitive functions in Denver II, social ability and language ability are more vulnerable to be influenced
than fine and gross motor ability.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic
disorder. As a birth defect, its clinical manifestations are complex and
diverse, including a series of neuropsychiatric disorders in behavioural,
cognitive, and psychological aspects [1]. At present, these aspects of
abnormalities have been listed as a separate complication, known as tu-
berous sclerosis associated with neuropsychiatric disorders (TAND)
[1–3]. Among them, mental retardation is one of the most common
neuropsychiatric disorders, affecting 44%–70% patients [4–10], and its
impact on quality of life can be lasting and detrimental. Previous studies
on risk factors for mental retardation in tuberous sclerosis have proved
that it mainly associated with genotype [11,12], cortical tubers [13,14],
and epilepsy [15]. Among them, the impact of cortical tubers on cogni-
tive function has been widely studied. (18)F-fluordesoxyglucose posi-
tron emission tomography/magnetic resonance imaging ((18)F-FDG
PET/MRI) and diffusion tensor imaging (DTI) have been used as further
aid in predicting the likelihood of epilepsy in tubers of different lesion
⁎ Corresponding author at: Department of Paediatrics, Chinese PLA General Hospital, 28
Fuxing Road, Beijing 100853, China.
E-mail address: zouliping21@sina.com (L.-P. Zou).
types [13], and patients with cystic tubers whose mutation region
is in TSC2 are more likely to present mental retardation [16]. Besides,
present study shows that early intervention can improve the
prognosis of neuropsychiatric development [17]. However, the first
peak of mental development was infancy [18], but the tubers
develop gradually as children grow, and during infancy, they are
not fully developed [19]. Therefore, despite their relationship, it
may only be a signal of mental retardation but not the cause. There-
fore, the cause of MR falls to the other two factors and we planned to
analyze their correlations and then try to give some indicators for the
early intervention.
We collected the data of 639 children from 0 to 14 years old diag-
nosed with tuberous sclerosis in the Paediatric Department of Chinese
PLA General Hospital from 2011/9 to 2016/9. According to the inclusion
and exclusion criteria, a total of 223 patients were enrolled, all undergo-
ing gene test, the assessment of mental development and severity of ep-
ilepsy. We used early childhood epilepsy severity scale (E-chess) [20],
which was designed by Cambridge University, to analyze the severity
of epilepsy in the children with tuberous sclerosis. We further assessed
the impact of an epileptic syndrome, infantile spasms, which was not in-
cluded in E-chess score, on children's cognitive development. Through
this study, we also planned to help better identifying the potential

https://doi.org/10.1016/j.yebeh.2017.09.017
1525-5050/© 2017 Elsevier Inc. All rights reserved.
14 Y.-Y. Wang et al. / Epilepsy & Behavior 77 (2017) 13–18
mechanisms of mental retardation and to provide more evidences for
further intervention.
2. Methods
We collected the data of 639 patients with tuberous sclerosis at the
Paediatric Department of Chinese PLA General Hospital from 2011/9
to 2016/9. Fig. 1 shows the flowchart of patient screening, and Table 2
shows the inclusion and exclusion criteria. For all the included patients,
it would be 2–3 years from the first onset of epilepsy to the epilepsy
severity assessment date. Basic assessments included a structured
clinical history detailing gender, age of onset, family history, frequency
of seizures, seizure patterns, time period over which seizures occurred,
number of seizure types, number of AEDs used, and the effect of the
AEDs. In addition, standardized and validated psychological measures
were used to assess mental development level, Raven's Standard
Progress Matrices (SPM) for children equal to or older than 6 years
old, and Denver Development Screening Test II (Denver II) for children
below 6 years old. Because of their younger age and the difference of
scale, we classified the patients' cognitive development into mental
retardation positive and negative according to the score. For children
below 6 years old, if the Denver II result was normal on development
and intelligibility, we then would record it as mental retardation nega-
tive; otherwise positive. For children equal to or older than 6 years of
age, if the score of SPM was more than 70, we then would record it as
mental retardation negative, otherwise positive. All the diagnosis of
mental retardation was done by the senior experts.
All children and their parents were genotyped on TSC1/TSC2 point
mutation, TSC2 large fragment deletion and rearrangement mutation.
Fig. 1. The flowchart of patient screening.
Genetic testing was performed after obtaining informed consent from
the respective guardians of patients. It was carried out at the Molecular
Pathology Centre of Affiliated Hospital of the Air Force Institute or
Beijing Genomics Institute using venous blood samples. High through-
put sequencing results were validated on Sanger sequencing, wherever
necessary. All of the detected mutations would require pathogenicity
assessment. First, the reported mutations would be screened by
accessing Leiden Open Variation Databases (LOVD) (http://chromium.
lovd.nl/LOVD2/TSC/home.php). If the mutation was not detected in
one genetic testing center, we would do it in another center. The
patients who were not found to have mutations or whose mutations
had been identified as genetic polymorphisms would be excluded
from our study, because according to the current study, their mutations
may be mosaic on TSC1/TSC2, and including these patients may lead to
biases [21]. Patients with more than 1 mutation would be excluded
because it was not clear which sites caused the disease. Some of the
nonreported missense mutations were evaluated using the PolyPhen
Website (http://genetics.bwh.harvard.edu/pph2/) to predict pathoge-
nicity. Mutation type, mutant exons and nucleotides were also
recorded. To further study the effect of specific mutation domains on
neuropsychology, the mutation domains were described in our study,
including TSC1: Rho activating domain, tuberin interaction domain
(TID), coil-coil domain (CCD), and ezrin-radixin-moesin (ERM); TSC2:
hematin interaction domain (HID), alternative splice sites, transcription
activating domain (TAD), GTPase-activating protein (GAP), and
calmodulin-bind domain (CaMD). As for family history, it would be
confirmed by both clinical data and their genotype. Mutations were
additionally classified into protein-truncating (PT, nonsense, frame-
shift, splice site, and large deletions of at least one exon) and
nontruncating (NT, missense, and small in-frame deletions and inser-
tions) mutations.
The severity of the epilepsy was measured by the E-chess on general
[20]. Early childhood epilepsy severity scale was designed by the
University of Cambridge in 2008, and it can reflect the severity of
epilepsy in patients with tuberous sclerosis more systematically. It
includes five parts, frequency of seizures, time period over which
seizure occurred, number of seizure types, number of anticonvulsants
used, and the effect of the AEDs. Additionally, considering the dramatic
impairment of infantile spasms (IS), we particularly compared the level
of cognitive developments of patients with and without IS.
There were 223 patients who met all the criteria above. Data analysis
was performed using SPSS 24. Genotype–neurocognitive phenotype
correlations and epilepsy–neurocognitive phenotype correlations were
analyzed by binary logistic regression analysis. In the study, the two-
tailed test for p b 0.05 was considered statistically significant. GraphPad
Prism 7 and Photoshop CS6 were used to draw the figures.
All methods were carried out in accordance with relevant guidelines
and regulations.
All experimental protocols were approved by the PLA General
Hospital.
Consent was obtained from all the patients in our study including
the use of all their clinical data and genetic testing reports.
3. Results
Basic information of the patients was listed in Table 1. There were
120 in 223 patients (53.8%) presenting mental retardation,
consistent with previous studies of 44–70% [4–10]. Among them,
70 (58.3%) were male and 50 (41.7%) were female. The age between
patients with and without mental retardation showed no statistical
difference.
3.1. Genotype–neurocognitive phenotype correlations
Patients with different genotypes presented no difference in
cognitive development. Accounting for 13.5% of the included patients,
 Y.-Y. Wang et al. / Epilepsy & Behavior 77 (2017) 13–18 15

Table 1 4. Discussion
Characteristics of the study sample with and without mental retardation.

MR+ MR− Unlike previous studies [4], our study demonstrated that for children
Basic information
with tuberous sclerosis, the difference in their genotype was not the
Age (month) 40.8 (2.73) 42.7 (1.34) leading cause of mental retardation. This was also different from our ini-
Gender tiative. In previous studies, patients with mutations in TSC2 are less
Male 70 49 mentally developed than those in TSC1 [4,11], but these findings have
Female 50 54
not been found in our study. We also analyzed the influence of mutation
Genotype
TSC1 15 15 types and family history, and the results were also negative, contrary to
TSC2 105 88 the previous reports that patients with truncated mutations or a family
Family history history were less well-developed [11].
Familial 25 21 We further analyzed the reasons and proposed that for patients less
Sporadic 95 82
Mutation type
than 2 years old, epilepsy may be the leading cause of their mental
PT 98 81 retardation. All patients included in our study were children, and
NT 22 22 differences in genotype may not determine the mental development
E-chess⁎ 11.32 10.44 of different patients from birth. Instead, it cumulatively and gradually
Infantile spasms⁎ 81 32
affects patients. Studies have shown that the differences in genetic
IS+ 62 30
IS− 58 73 background will affect the distribution of tubers [22], which will affect
intellectual development differently. Besides, functional neuroimaging
⁎ Stands for statistical significance.
has demonstrated that multiple brain areas including the dysplastic
tissues are engaged in any given cognitive task [23]. Therefore, we
TSC1 mutations were found in 30 patients; TSC2 mutations were found never doubted the differences in genetic background on clinical
in 193 patients, accounting for 86.5% of the total included patients. No symptoms, especially on cognitive development. However, the impact
statistical significant result was found on genotype–neurocognitive is not achieved overnight, and its superimposing effect might be seen
phenotype correlations, which contrasted the previous reports [4,11]. after several years. The impact of mutations of TSC1 or TSC2 on the m-
The prevalence of MR was 50.0% for the patients with TSC1 mutation, TOR signaling pathway is gradually accumulated, as the disease
54.5% for TSC2 (p = 0.561), 54.7% for patients with protein-truncating spectrum reflected: as the age changes, different symptoms will
(PT) and 50.0% for patients with nontruncating (NT) (p = 0.791), sequentially emerge, and even without seizure, some patients' cognitive
54.3% for patients with family history, and 53.7% for patients without level will still be impaired during preschool years and thereafter [19].
family history (p = 0.748). This may partly explain the reasons for the differences in the results of
As shown in Fig. 2, we further analyzed whether there were our research and what has been reported.
differences between different functional domains, but still found no Unlike genetic factors, the influence of epilepsy on cognitive
statistical difference. development can be catastrophic. The definition of the International
League against Epilepsy incorporates cognitive problems as part of the
definition: “Epilepsy is a disease characterized by an enduring predispo-
3.2. Epilepsy–neurocognitive phenotype correlations sition to generate epileptic seizures and by the neurobiological,
cognitive, psychological, and social consequences of this condition”
In terms of the severity of epilepsy, statistical differences were found [24]. With respect to the epilepsy severity, we compared the score of
on epilepsy–neurocognitive phenotype correlations, both on E-chess E-chess and analyzed the influence of infantile spasms. We then
score (p = 0.01) and the occurrence of infantile spasms (p = 0.014), received unanimous results: from whichever aspect, epilepsy would
which was consistent to the previous study. The mean score of E- influence the cognitive development. Firstly, the overall prognosis of
chess score was 10.91 (SD = 1.97). The mean score of E-chess in patients with infantile spasms is poor. As we have shown, 67.39% of in-
patients with MR was 11.32 (SD = 1.65), and that of patients without fants with IS developed mental retardation and, as for the long-term
MR was 10.44 (SD = 2.20). For patients with IS, the percentage of MR prognosis, it may be higher if control is poor. Previous studies have
was 67.39%, and for patients without IS, the percentage of MR was shown that early onset disrupts critical periods of development and
only 44.27%. leads to poor cognitive outcomes [4]. Early onset, whether epilepsy
In Fig. 3, the four different aspects of cognitive function in patients syndrome or not, can seriously affect the cognitive development.
with mental retardation, the age of the first seizure onset in patients Infantile spasms, as a catastrophic epilepsy syndrome, have the long-
with epilepsy, the number of AEDs the patients took, the frequency of term and undesirable prognosis. In addition to tuberous sclerosis,
seizure in patients with or without MR, and the distribution of seizure other genetic metabolic diseases or acquired infection, trauma may
types in patients with or without MR have been listed. also lead to its occurrence [25]. The prognosis of different causes of
In the 639 patients, 9 had no seizures before, and only 1 in them infantile spasms is different [26]. Despite the immature treatment of
presented MR. The genotype of this patient was the same as that of infantile spasms, ACTH, vigabatrin are found to be effective [25,27,28].
another patient with MR, TSC1, EXON15, c.1888-1891delAAAG, and p. However, for the patient's lifespan, whether these are effective or not
Lys630GlnfsX22. That patient took three kinds of antiepileptic drugs is unclear. Nevertheless, there is still a correlation between clinicians
daily but the effect was not satisfying, and his E-chess score was 11. intervening as early as possible and the seizure control [29]. Secondly,
it is advisable to measure the severity of epilepsy, but by the E-chess,
Table 2 the difference of the measures between different groups was not
Inclusion and exclusion criteria. obvious. We initially prepared to use the E-chess to assess the degree
Inclusion criteria Exclusion criteria of epilepsy in patients, and we intended to use this indicator alone or
in combination with other criteria such as genetic background, epi-
1. Clear diagnosis of TSC by both genetic and 1. Pathogenic mutations are
clinical manifestation not clear lepsy syndrome to assist the prediction of the patient's likelihood
2. Age:0–14 years 2. Irregular taking of AEDs of developing mental retardation. However, the results showed
3. Complete clinical data and regular follow-up 3. Previous surgery treatment that the use of E-chess alone was not feasible. Although the differ-
records ence of E-chess in patients with and without mental retardation
4. At least 2 years from the first onset of epilepsy
was statistically significant, the peak of both was between 10 and
16 Y.-Y. Wang et al. / Epilepsy & Behavior 77 (2017) 13–18

Fig. 2. The distribution of mutation of TSC1 and TSC2. The upper figure shows all the detected mutation in TSC1, the lower TSC2, and the functional domains were marked by the
quadrilateral contours with different colours. As it can be seen, the mutations are scattered, and there is no difference in the presence of mental retardation in different functional
domains. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

13, and it was difficult to find the significant watershed. Therefore,
we believe that although E-chess is effective in measuring the sever-
ity of epilepsy in patients with TSC, it cannot be used as an indicator
with a strong guiding significance. Nevertheless, we still found that
patients with mental retardation tent to have earlier seizure attack,
take more AEDs, have more seizure types, and have higher seizure
frequency. Among the four cognitive functions in Denver II, social
ability and language ability are more vulnerable to be influenced
than fine and gross motor ability. We did not include EEG in our
study. Possibly, EEG and more detailed assessment of epilepsy are
necessary, and we are working on it now.
There has been increasing concern regarding the cumulative
neurobiological burden associated with chronic epilepsy and the risk
of progressive cognitive impairment. More broadly, the implications of
even static cognitive impairments in childhood may have lifespan
implications [30]. It has been demonstrated in general population re-
search that intelligence level in childhood is associated with cognitive
outcomes decades later, the higher childhood intelligence, the better
cognitive outcomes and vice versa [27]. At present, for patients with tu-
berous sclerosis, there are two hypotheses on the mechanism of epilep-
sy-associated mental retardation: “chronic accumulation model” and
the “second hit model” [3,22]. But in practical clinical work, these two
may present mutual effect, and in the whole process, age may play a
vital role. From our study, for younger age groups, the effect of the dif-
ference in genetic background has not yet fully presented, so the main
factors leading to mental retardation fall to epilepsy and for the gene-
caused vulnerable brain, epilepsy, as a second hit, has an enormous
impact.
Patients with tuberous sclerosis are not born with cortical tubers
[19], but patients have been born with genetic abnormalities; but
these abnormalities at this time may not necessarily present with visible
intracranial lesions. Nonetheless, it is undeniable that in the process of
embryonic development, the destruction caused by the mutations has
never stopped, so many patients are born with hypomelanotic macules
and/or cardiac rhabdomyoma [19]. Intracranial lesions at this time may
be minimal, and the onset of epilepsy is not dependent on the tubers.
Epileptiform discharges can occur in areas without tubers, and some
patients with TSC with epilepsy do not have tubers detectable by
magnetic resonance imaging (MRI) [3]. Therefore, despite differences
in genes leading to differences in the distribution of tuber, differences
in the distribution of tuber leading to different seizure types, different
seizure types affecting cognition differently, and making syllogism-
style inference like genes can affect cognition are certainly not
convincible, especially for patients with younger age. Whether the effect
of gene differences on cognition is independent of the onset of epilepsy
is currently inconclusive. Genetic backgrounds which are different from
 Y.-Y. Wang et al. / Epilepsy & Behavior 77 (2017) 13–18 17

Fig. 3. A. The four different aspects of cognitive function level in patients with mental retardation. All these were evaluated according to Denver II. The average age of patients when doing
the test was 32.2 months. Their average age of social ability, fine motor, language, and gross motor were only 20.4, 22.2, 17.1, and 22.7 months. B. The age of the first seizure onset in
patients with epilepsy. The patients whose first onset age was in 2 years are more vulnerable to mental retardation. C. The number of AEDs patients took. The peak number of AEDs
patients with MR took was 2, and many patients even have taken no less than 5 kinds of AEDs. The peak number of AEDs patients without MR took was 1, and only 3 patients took 5
kinds of drugs, and no one took more than this number. D. The frequency of seizure in patients with or without MR. Patients without MR tent to have seizure onset no more than once
a week, whereas patients with MR are more likely to have seizure onset daily or even more. E. The distribution of seizure types in patients with or without MR. Patients with seizure
types of epileptic spasms or tonic–clonic are more likely to be impaired on their cognitive function compared with those with other seizure types.

the normal population may make patients with TSC more susceptible to
epilepsy, but the genetic background differences between these affected
individuals may need a longer period before the accumulative effect on
pathway leads to mental retardation.
In addition, it is noteworthy that in 9 excluded patients without
epileptic seizures, only 1 presented mental retardation, and the
genotype of this patient was the same as another patient with epilepsy,
both located in EXON 15 in TSC1, c.1888-1891delAAAG, and p.
Lys630GlnfsX22. However, the other patient suffered from refractory ep-
ilepsy, taking 3 kinds of AEDs for more than 2 years so far, but the effect
was still poor. In fact, this situation is not uncommon in our study and
clinical work. Some patients' parents have the same genotype with
them, but they show few symptoms, and before the diagnosis of their
children, they even did not realize their disease. This may be due to the
difference in other sites of the signaling pathway. Although the overall
neurodevelopment of patients without epilepsy is much better than
those with epilepsy, it is difficult to explain it through this single factor.
Regardless of the lack of mature management for patients with
tuberous sclerosis, using rapamycin as a targeted therapy has achieved
very significant therapeutic effect [27]. Analysis in animal experiments
has now shown that a brief treatment with the mTOR inhibitor
rapamycin in adult mice rescued not only the synaptic plasticity, but
also the behavioural deficits in this animal model of tuberous sclerosis
[31]. This revealed a biological basis for the therapeutic effect in some
of the cognitive deficits in patients with tuberous sclerosis. However,
for many of them, only after the onset of seizures will they have the
desire to seek for medical help, but this time the second hit has already
presented. For older patients, the role of cumulative effect has been
evident and in some way, irreversible, so this is when the intervention
has already been delayed.
Our patients are all children, so on one hand, we still need a long-
term study to identify the role of genetic factors, and on the other
hand, through our intervention, we hope to be able to reverse the im-
pairment of tuberous sclerosis on their cognitive development.
Acknowledgments
This study was supported by grants from the Major State Basic Re-
search Development Program (973) (No. 2012CB517903), the National
Natural Science Foundation of China (No. 81671279, 81471329, and
81211140048), the Beijing Municipal Natural Science Foundation (No.
7142150, 7081002, and 7042024).
Author contributor statement
Y.W. was in charge of the analysis and interpretation of data and
manuscript writing.
L.P., S.M., M.Z., and L.L. were in charge of the acquisition of data and
follow-up.
L.Z. came up with the study concept and was in charge of the
designing, critical revision of manuscript for intellectual content, and
the diagnosis of TSC and mental retardation.
Data availability statement
All data used for this project are publicly available and accessible
online and more detailed data can be given on request.
Competing financial interests
The authors declare no competing financial interests.
References
[1] Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tu-
berous sclerosis complex. Lancet Neurol Jul 2015;14(7):733–45 [PubMed PMID:
26067126].
[2] de Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D, Ess KC, et al. Tuberous
sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist.
Pediatr Neurol Jan 2015;52(1):25–35 [PubMed PMID: 25532776. Pubmed Central
PMCID: PMC4427347].
18 Y.-Y. Wang et al. / Epilepsy & Behavior 77 (2017) 13–18
[3] Sahin M, Henske EP, Manning BD, Ess KC, Bissler JJ, Klann E, et al. Advances and
future directions for tuberous sclerosis complex research: recommendations from
the 2015 strategic planning conference. Pediatr Neurol Jul 2016;60:1–12 [PubMed
PMID: 27267556. Pubmed Central PMCID: PMC4921275].
[4] Winterkorn EB, Pulsifer MB, Thiele EA. Cognitive prognosis of patients with tuberous
sclerosis complex. Neurology Jan 02 2007;68(1):62–4 [PubMed PMID: 17200495].
[5] Goodman M, Lamm SH, Engel A, Shepherd CW, Houser OW, Gomez MR. Cortical
tuber count: a biomarker indicating neurologic severity of tuberous sclerosis
complex. J Child Neurol Feb 1997;12(2):85–90 [PubMed PMID: 9075016].
[6] Jansen FE, Vincken KL, Algra A, Anbeek P, Braams O, Nellist M, et al. Cognitive
impairment in tuberous sclerosis complex is a multifactorial condition. Neurology
Mar 18 2008;70(12):916–23 [PubMed PMID: 18032744].
[7] Jansen FE, Braams O, Vincken KL, Algra A, Anbeek P, Jennekens-Schinkel A, et al.
Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2
mutations. Neurology Mar 18 2008;70(12):908–15 [PubMed PMID: 18032745].
[8] Shepherd CW, Houser OW, Gomez MR. MR findings in tuberous sclerosis complex
and correlation with seizure development and mental impairment. AJNR Am J
Neuroradiol Jan 1995;16(1):149–55 [PubMed PMID: 7900584].
[9] O'Callaghan FJ, Harris T, Joinson C, Bolton P, Noakes M, Presdee D, et al. The relation
of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis
Child Jun 2004;89(6):530–3 [PubMed PMID: 15155396. Pubmed Central PMCID:
PMC1719953].
[10] Takanashi J, Sugita K, Fujii K, Niimi H. MR evaluation of tuberous sclerosis: increased
sensitivity with fluid-attenuated inversion recovery and relation to severity of
seizures and mental retardation. AJNR Am J Neuroradiol Oct 1995;16(9):1923–8
[PubMed PMID: 8693996].
[11] van Eeghen AM, Black ME, Pulsifer MB, Kwiatkowski DJ, Thiele EA. Genotype and
cognitive phenotype of patients with tuberous sclerosis complex. Eur J Hum Genet
May 2012;20(5):510–5 [PubMed PMID: 22189265. Pubmed Central PMCID:
PMC3330219].
[12] Wong HT, McCartney DL, Lewis JC, Sampson JR, Howe CJ, de Vries PJ. Intellectual
ability in tuberous sclerosis complex correlates with predicted effects of mutations
on TSC1 and TSC2 proteins. J Med Genet Dec 2015;52(12):815–22 [PubMed PMID:
26408672].
[13] Chandra PS, Salamon N, Huang J, Wu JY, Koh S, Vinters HV, et al. FDG-PET/MRI
coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and
cortex in patients with tuberous sclerosis complex: a preliminary report. Epilepsia
Sep 2006;47(9):1543–9 [PubMed PMID: 16981871].
[14] Ruppe V, Dilsiz P, Reiss CS, Carlson C, Devinsky O, Zagzag D, et al. Developmental
brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of
cortical tubers and perituberal cortex. Epilepsia Apr 2014;55(4):539–50 [PubMed
PMID: 24512506].
[15] Joinson C, O'Callaghan FJ, Osborne JP, Martyn C, Harris T, Bolton PF. Learning
disability and epilepsy in an epidemiological sample of individuals with tuberous
sclerosis complex. Psychol Med Feb 2003;33(2):335–44 [PubMed PMID: 12622312].
[16] Chu-Shore CJ, Major P, Montenegro M, Thiele E. Cyst-like tubers are associated with
TSC2 and epilepsy in tuberous sclerosis complex. Neurology Mar 31 2009;72(13):
1165–9 [PubMed PMID: 19332694].
[17] Davies DM, de Vries PJ, Johnson SR, McCartney DL, Cox JA, Serra AL, et al.
Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic
lymphangioleiomyomatosis: a phase 2 trial. Clin Cancer Res Jun 15 2011;
17(12):4071–81 [PubMed PMID: 21525172].
[18] Goswami U. The Wiley-Blackwell handbook of childhood cognitive development,
23; 2011 605–26.
[19] Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet Aug 23 2008;
372(9639):657–68 [PubMed PMID: 18722871].
[20] Humphrey A, Ploubidis GB, Yates JR, Steinberg T, Bolton PF. The early childhood ep-
ilepsy severity scale (E-Chess). Epilepsy Res May 2008;79(2–3):139–45 [PubMed
PMID: 18387786].
[21] Nathan N, Keppler-Noreuil KM, Biesecker LG, Moss J, Darling TN. Mosaic disorders of
the PI3K/PTEN/AKT/TSC/mTORC1 signaling pathway. Dermatol Clin Jan 2017;35(1):
51–60 [PubMed PMID: 27890237. Pubmed Central PMCID: PMC5130114].
[22] Overwater IE, Swenker R, van der Ende EL, Hanemaayer KB, Hoogeveen-Westerveld
M, van Eeghen AM, et al. Genotype and brain pathology phenotype in children with
tuberous sclerosis complex. Eur J Hum Genet Dec 2016;24(12):1688–95 [PubMed
PMID: 27406250. Pubmed Central PMCID: PMC5117934 from Dutch Epilepsy Foun-
dation, and grants and non-financial support from Novartis outside the submitted
work; and the Erasmus MC received honoraria from Novartis for educational lec-
tures presented by the author. The remaining authors declare no conflict of interest].
[23] Korman B, Krsek P, Duchowny M, Maton B, Pacheco-Jacome E, Rey G. Early seizure
onset and dysplastic lesion extent independently disrupt cognitive networks. Neu-
rology Aug 20 2013;81(8):745–51 [PubMed PMID: 23873975].
[24] Beghi E, Berg A, Carpio A, Forsgren L, Hesdorffer DC, Hauser WA, et al. Comment on
epileptic seizures and epilepsy: definitions proposed by the International League
Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia
Oct 2005;46(10):1698–9 [author reply 701-2. PubMed PMID: 16190948].
[25] Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome,
West syndrome and related phenotypes: what we know in 2013. Brain Dev Oct
2014;36(9):739–51 [PubMed PMID: 24268986].
[26] Djuric M, Kravljanac R, Tadic B, Mrljes-Popovic N, Appleton RE. Long-term outcome
in children with infantile spasms treated with vigabatrin: a cohort of 180 patients.
Epilepsia Dec 2014;55(12):1918–25 [PubMed PMID: 25377998].
[27] Jozwiak S, Kotulska K, Domanska-Pakiela D, Lojszczyk B, Syczewska M, Chmielewski
D, et al. Antiepileptic treatment before the onset of seizures reduces epilepsy
severity and risk of mental retardation in infants with tuberous sclerosis complex.
Eur J Paediatr Neurol Sep 2011;15(5):424–31 [PubMed PMID: 21507691].
[28] Go CY, Mackay MT, Weiss SK, Stephens D, Adams-Webber T, Ashwal S, et al.
Evidence-based guideline update: medical treatment of infantile spasms. Report of
the guideline development subcommittee of the american academy of neurology
and the practice committee of the child neurology society. Neurology Jun 12
2012;78(24):1974–80 [PubMed PMID: 22689735. Pubmed Central PMCID:
PMC3369510].
[29] Goh S, Kwiatkowski DJ, Dorer DJ, Thiele EA. Infantile spasms and intellectual out-
comes in children with tuberous sclerosis complex. Neurology Jul 26 2005;65(2):
235–8 [PubMed PMID: 16043792].
[30] Hermann B, Jones J, Sheth R, Dow C, Koehn M, Seidenberg M. Children with new-
onset epilepsy: neuropsychological status and brain structure. Brain Oct 2006;
129(Pt 10):2609–19 [PubMed PMID: 16928696].
[31] Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, et al. Reversal of learn-
ing deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat Med Aug 2008;
14(8):843–8 [PubMed PMID: 18568033. Pubmed Central PMCID: PMC2664098].