Journal of the Formosan Medical Association (2015) 114, 849e854
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
ORIGINAL ARTICLE
The relationship of neuroimaging findings and neuropsychiatric comorbidities in children with tuberous sclerosis complex Cheng-Hsien Huang a, Steven Shinn-Forng Peng b, Wen-Chin Weng c, Yi-Ning Su d, Wang-Tso Lee c,e,*, National Taiwan University Hospital Tuberous Sclerosis Complex (NTUH TSC) Study Group a
Department of Pediatrics, Taipei City Hospital, Yang Ming Branch, Taipei, Taiwan Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan c Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan d Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan e Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan b
Received 4 October 2013; received in revised form 20 December 2013; accepted 23 February 2014
KEYWORDS attention-deficit ehyperactivity disorder; autism spectrum disorder; seizure; tuberous sclerosis complex
Background/Purpose: To clarify the relationship between neuroimaging findings, neuropsychiatric comorbidities, and epilepsy in patients with tuberous sclerosis complex (TSC) in Taiwan. Methods: Medical records from 32 patients with TSC were retrospectively reviewed, including mutational analysis, neuroimaging findings, electroencephalogram findings, and neuropsychiatric comorbidities. Results: Of these patients, six (18.75%) were diagnosed to have autism spectrum disorders (ASD), and 10 (31.25%) were diagnosed to have attention-deficitehyperactivity disorder. In the latter patients, there were no differences in the regional distribution of tuber burden. In addition to a high prevalence of cystic-like tubers, tubers in insular and temporal areas were associated with ASD. Nonsense mutations in the TSC2 gene group had a correlation with autistic behavior. In 26 (81.25%) patients with a history of epilepsy, infantile spasms and partial seizures were the predominant type of epilepsy. Most of them developed seizures prior to age 1 year.
Conflicts of interest: The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. * Corresponding author. Department of Pediatrics, National Taiwan University Hospital, Number 8 Chung-Shan South Road, Taipei 100, Taiwan. E-mail address:
[email protected] (W.-T. Lee). http://dx.doi.org/10.1016/j.jfma.2014.02.008 0929-6646/Copyright ª 2014, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
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C.-H. Huang et al. Conclusion: ASD is a common comorbidity in TSC. Cortical tubers in the temporal lobe and insular area were associated with ASD. The presence of cystic-like tubers on magnetic resonance imaging may also offer a structural marker for ASD in TSC. Copyright ª 2014, Elsevier Taiwan LLC & Formosan Medical Association. All rights reserved.
Introduction
Methods
Tuberous sclerosis complex (TSC) is a multisystem disorder that is inherited as an autosomal dominant trait and occurs in 1 in 6000e10,000 live births.1 However, two-thirds of patients with TSC have sporadic mutations.1 Two genes, TSC1 on 9q34 and TSC2 on 16p13.3, coding for the proteins hamartin and tuberin, respectively, have been found to be related to TSC. Their mutations in humans may cause abnormal tissue growth and differentiation affecting multiple organs in patients, including the brain, eyes, heart, lung, kidneys, and skin.1 Clinical manifestations in patients with TSC may have variable age-related changes. Some presentations may occur at an earlier age, such as renal angiomyolipomas, which appear after age 1 year,1,2 and some may appear at a later stage, such as ungual fibroma, which mostly appears after age 15 years.1 Cardiac rhabdomyomas in children with TSC may appear in the fetus and almost always regress spontaneously in infancy.3 Pulmonary involvement mostly occurs in women and the onset of pulmonary symptoms is in adulthood.4 The major findings of TSC in the central nervous system consist of cortical tubers, subependymal nodules, and subependymal giant-cell astrocytomas (SEGA).5 Epilepsy is found in about 90% of all TSC patients and tubers are believed to be epileptogenic. Seizures usually start in early childhood in most of the cases. Of these, complex partial seizures and infantile spasms are the most common seizure types.1,6 In the past decade, there has been a dramatic increase on research concerned with neuropsychiatric comorbidities in patients with TSC.7e12 Autism spectrum disorders (ASD) have been shown to be more frequent in patients with TSC than in the normal population.13 Several studies have noted the relationship between tubers in temporal lobe and the development of autism in TSC.7,9Although tubers in the temporal lobe are considered to be associated with autism, there are some other risk factors, such as total tuber counts,10 temporal lobe epileptiform discharge7 and earlier age of seizure onset.14 Another common neuropsychiatric problem, attention-deficitehyperactivity disorder (ADHD), is also very common in patients with TSC. About 30e60% of patients with TSC have symptoms related to ADHD.11 Although the exact pathogenetic mechanisms of these comorbidities are still unknown, the commonly accepted hypothesis is that the damage resulting from tubers cause cognitive and emotional impairment in these patients.15 However, there has been little research focused on the relationship between cystic-like tubers and neuropsychiatric comorbidities.7,16 Therefore, in this study, we reviewed 32 TSC patients, followed up in our hospital, to determine the relationship among neuropsychiatric comorbidities, seizures, TSC gene mutations, and tuber characters.
We reviewed medical records of patients with TSC followed up at the National Taiwan University Hospital, Taipei, Taiwan. The data analyzed included: neuroimaging findings; electroencephalogram findings; TSC1 and TSC2 mutations; mentality; neuropsychiatric comorbidities (such as ASD and ADHD); seizure history; and other neuropsychological assessments. Neuropsychological tests, including the Child Behavior Checklist, Leiter’s parent rating scale, Wechsler intelligence scale for children, Wechsler adult intelligence scale, and Bayley Scales of Infant and Toddler Development II, were performed to evaluate the cognitive conditions of patients. The Institutional Ethical Committee of the National Taiwan University Hospital approved this cross-sectional study. The patients were classified into three groups according to the results of neuropsychiatric tests: normal development, borderline development, and intellectual disability. Categories were chosen based on: (1) normal development for intelligent quotient > 80 on the Wechsler intelligence scales for children and adults; (2) borderline development for scores 70e80; and (3) intellectual disability for scores < 70. The TSC1 and TSC2 gene mutations were analyzed using denaturing high-performance liquid chromatography, followed by direct sequencing if any abnormalities were found. The mutations of TSC1 and TSC2 genes were divided into four categories: missense, nonsense, frameshift, and large deletion. Brain magnetic resonance imaging (MRI) studies were reviewed by one pediatric neuroradiologist (S.S.F.P.) without knowing the results of neuropsychological assessments and electroencephalogram findings. MRI studies consisted of pre- and post-contrast T1-weighted, T2-weighted, and fluid-attenuated inversion recovery sequences. The following features were analyzed: the presence of cystic-like tubers; numbers and sites of tubers (frontal, parietal, temporal, mesiotemporal, insular, occipital, and cerebellar); and SEGA by using fluidattenuated inversion recovery sequences with sections of 4e5 mm thickness and 1-mm gap covering whole brain. SPSS software version 18 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The associations between the presence of cystic-like tubers, TSC gene mutations, and ASD were also analyzed with the Fisher exact test. Analysis of the number and locations of tubers and neuropsychiatric comorbidities was performed using the ManneWhitney U test. KruskaleWallis test was applied for the analysis of statistic difference in mentality category and age of seizure onset. A p value < 0.05 was considered to be significant.
Neuroimaging findings in tuberous sclerosis
Results Demographic data In total, 67 patients were diagnosed to have TSC. Of these, only 32 cases aged from 1 month to 45 years had complete results of TSC gene mutations and MRI examination in our hospital, and were enrolled in the study. Sixteen patients were female and 16 male (Table 1). There were two families in our study.
Numbers and locations of tubers and other findings in MRI The total number of tubers in our patients ranged from 0 to 85. Two patients did not have tubers although they did have mutation in TSC1 and TSC2. The individual with TSC2 mutation had normal intelligence, but the other with TSC1 mutation had impaired mentality. For those tuber-positive patients (15 male and 15 female), cortical tubers were found predominantly within the frontal and parietal lobes. The mean standard deviation (SD) numbers of tubers in different regions in descending order were: frontal, 12.86 9.58; parietal, 6.5 5.58; occipital, 4.16 4.49; temporal, 4.03 4.16; mesiotemporal, 0.8 1.65; insular, 0.43 0.73; and cerebellum, 0.23 0.68. Twelve patients (38%) had cystic-like tubers on brain MRI, and the number ranged from 1 to 26. Most cystic-like tubers were located in parietal and frontal lobes. The mean SD numbers of cystic-like tubers in different regions in descending order were: parietal, 2.17 2.98; frontal, 2.0 4.2; temporal, 0.42 1; occipital, 0.25 0.62; and cerebellum, 0.08 0.29. There were no cystic-like tubers found within the mesiotemporal, insula, or brainstem area. Twenty-two patients (68.75%) had SEGA in our study. The mean SD age of these patients was 7.3 7.8 years, ranging from 1 year to 30 years.
Gene mutation analysis and comorbidities Six patients had TSC1 mutations, and 26 had TSC2 mutations. In the TSC1 gene, there were four frameshift mutations, and two missense mutations. For those with mutations in the TSC2 gene, nine were insertions/deletions, which caused frameshift mutations, eight were nonsense mutations with early termination codons, eight were missense mutations, and one was a large deletion. Only nonsense mutations in TSC2 gene group were significantly associated with autism (p Z 0.02). In patients with TSC2 gene mutations and autism (n Z 5), mutations involving the hamartin interaction domain were noted in two cases (nonsense mutation at exon 3 and deletion at exons 2e8, respectively). Another two mutations were involved in the alternative splicing domain (nonsense mutations at exons 26 and 29). Cystic-like tubers showed a higher correlation with TSC2 mutation than TSC1 mutation although this was not statistically significant (p Z 0.06; Tables 1 and 2).
851 Table 1 Patient characteristics.
demographics
and
TSC1 n (%) TSC2 n (%) Total number 6 Male 2 (33.3) Female 4 Seizure 4 (66.6) 2 seizure types 2 Infantile spasms 0 Complex partial seizure 1 Simple partial seizure 2 Generalized 2 Clonic 1 Tonic 0 Myoclonic 0 ADHD 2 (33.3) ASD 1 (16.6) Mentality 4 Normal 1 (25) Borderline 1 (25) Intellectual disability 2 (50) Mutation type Missense 1 Nonsense 1 Frameshift 4 Large deletion 0 Tuber number Cystic tuber 0 Tuber counts in location, Mean standard deviation Frontal 5.5 4.6 Parietal 1.7 1.8 Temporal 1.2 1.3 Mesiotemporal 0 Occipital 0.3 0.8 Insular 0.3 0.5 Cerebellum 0.3 0.5 Brainstem 0
26 14 (53.8) 12 22 (84.6) 7 7 3 2 5 1 1 1 8 (30.7) 5 (19.2) 23 7 (30.4) 4 (17.3) 12 (52.1)
clinical p
NS NS
NS NS NS
8 8 9 1 12
0.06
13.6 10.1 7.1 5.7 4.4 4.4 0.7 1.2 4.7 4.6 0.4 0.8 0.2 0.7 0
0.04a < 0.01a 0.06a NS < 0.01a NS NS NS
ADHD Z attention-deficitehyperactivity disorder; ASD Z autism spectrum disorder; TSC Z tuberous sclerosis complex. a ManneWhitney U test.
Table 2 The relationship between tuberous sclerosis complex (TSC) mutation type and autistic spectrum disorder (ASD).
Mutation type Missense Frameshift Nonsense Large deletion Total
TSC2 mutation with ASD n
TSC2 mutation without ASD n
p
0 0 4 1 5
8 9 4 0 21
NS NS 0.02 NS
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C.-H. Huang et al.
Neuropsychological assessments
Analysis of distribution of tubers and risk factors
Eight patients had normal mentality, 14 had intellectual disability, five had borderline intelligence, and there was no available information about cognition for five patients. No significant association between presence of cystic-like tuber, total tuber counts, tuber location, and cognitive outcome was noted. Of the 32 patients, six (18.75%) had autistic disorders, and 10 (31.25%) had a history of ADHD. For the patients with autistic disorders, five had TSC2 gene mutations and one patient had a TSC1 gene mutation. In addition, four cases in this group had cystic-like tubers (Table 1). Although it was not statistically significant, the prevalence of cystic-like tubers was higher in patients with autistic disorders. Twenty-six (81.25%) patients had a history of epilepsy. No significant correlation was found between the tuber location, presence of cystic tubers, total tuber count, and epilepsy. Age of seizure onset was known for 23 cases. Seizure onset occurred by age 6 months in 12 cases (52.17%), and by age 1 year in 20 patients (86.95%). Of these 26 patients with a history of epilepsy, seizure type was documented for 16 patients, seven of whom (43.75%) had a history of infantile spasms; all of them had TSC2 mutations. The cognitive outcome was correlated with the age of seizure onset (p Z 0.04) and seizure type (p < 0.01). For 11 patients with seizures prior to age 6 months, seven (64%) had intellectual disability. All of the patients with infantile spasms had impaired mentality (Table 3). Excluding infantile spasms, more than one seizure type was noted in nine of these 16 patients (56.25%), and simple partial seizures or complex partial seizures were documented in eight cases (50%). Freedom from seizures for at least 6 months was seen in six of these 26 patients (23%) under antiepileptic drug treatment. All these six patients had TSC2 gene mutations. However, they were not related to the location or number of tubers.
No significant correlation was uncovered between distribution of tubers and epilepsy or ADHD behavior. However, the numbers of tubers in the temporal and insular areas had a statistically significant association with patients having ASD (p Z 0.02 and p Z 0.01, respectively; Table 4).
Table 3
Characters of seizure type and mentality.
Cognition
ID (%)
Total number History of seizures 2 seizure types Infantile spasms Complex partial seizure Simple partial seizure Generalized Clonic Tonic Myoclonic Age of seizure onset (total) 6 mo 7e12 mo 12 mo
14 5 13 (93) 4 (80) 4 2 7 0 1 1
8 6 (75) 3 0 2
1
2
1
2 1 1 1 12
2 0 0 0 4
3 1 0 0 7
7 3 2
2 1 1
2 4 1
ID Z intellectual disability.
Borderline Normal p (%) (%)
< 0.01
0.04
Discussion In this study, we found more cystic-like tubers in TSC2mutated patients compared with those in TSC1 mutations. Previous studies have demonstrated an association between cystic-like tubers and TSC2 gene mutation.16 Aside from the association with TSC2 gene mutations, previous reports also revealed the correlation between the presence of cysticlike tubers and ASD,7,16 although the exact mechanism is still unknown. In this study, we have demonstrated the correlation among seizures and neuropsychiatric comorbidities, including ADHD and ASD, in those gene-confirmed patients with TSC. We also found that the cortical tubers in temporal and insular areas play a significant role in TSC patients with ASD. In addition, we found a higher prevalence of cystic-like tubers in patients with TSC and ASD. ASD is characterized by impairments in social communication and interaction, restricted interests and repetitive activities. The higher prevalence of ASD in patients with TSC is an emerging finding in recent reports.8,13 An abnormal brain network plays an important role in many neuropsychiatric disorders, such as ADHD and ASD. The temporal lobe and insular area have been reported to be involved in ASD.7,17e19 The temporal lobe is associated with social perception, language, and “theory-of-mind” abilities. Animal models have also shown that the damage in temporal lobe may cause changes in social function.20 Furthermore, the superior temporal sulcus was believed to play a crucial role in the network of social interaction.21 Lange et al’s18 study also revealed atypical diffusion tensor hemispheric asymmetry in the superior temporal gyrus and temporal system for an individual with autism. The insula is considered an important region involved in interoceptive, affective, and empathic processes. Recent studies have demonstrated abnormal functional connectivity between the insula and the certain brain regions involved in emotional, sensory, and language processing.17,19 Our results may give evidence to support this hypothesis and are the first to demonstrate this association in patients with TSC. Unlike Numis et al’s7 observation of no significant association between ASD and TSC mutation type (missense, nonsense/frameshift, splice site, or deletion), our results showed a clear relationship between ASD and nonsense mutations in the TSC2 gene. This finding may arise from the fact that nonsense mutations producing a shortened protein may function improperly. For example, truncation of FOXP2 gene may result in an impairment of speech and language and may also be involved in the pathogenesis of autism.22 In addition, the interaction of TSC1 and TSC2 genes is complicated. Hamatin and tuberin form a heterodimer and are involved in the mTOR signaling pathway.23 de Vries and Howe24 and de Vries25 have already shown the close
Neuroimaging findings in tuberous sclerosis Table 4
853
The relationship between MRI character and neuropsychiatric comorbidities.
Total cases TSC1 TSC2 Cystic-like tuber SEGA Tuber number in Location
Total count Frontal, Parietal Temporal Mesiotemporal Occipital Insular Cerebellum Cystic frontal Cystic parietal Cystic temporal Cystic occipital Cystic cerebellum
TSC with ASD (mean SD)
TSC without ASD (mean SD)
pa
6 1 5 4 4 41.33 32.53 16.67 15.51 8.33 4.50 6.67 6.47 1.33 1.75 7.17 6.77 1.17 1.17 0.00 0.00 2.83 5.98 1.50 3.21 0.33 0.82 0.17 0.41 0.17 0.41
26 5 21 8 18 23.81 18.61 11.00 8.03 5.58 5.81 3.12 3.24 0.46 0.86 3.15 3.53 0.23 0.43 0.27 0.72 0.27 0.72 0.65 1.77 0.12 0.59 0.08 0.39 0.00 0.00
NS NS NS NS NS NS NS 0.02 NS NS 0.01 NS NS NS NS NS NS
ASD Z autism spectrum disorders; NS Z not significant; SD Z standard deviation; SEGA Z subependymal giant cell astrocytoma; TSC Z tuberous sclerosis complex. a ManneWhitney U test.
relationship between TSC and ASD on the basis of the direct consequence of deficient hamartin and tuberin. However, the exact mechanism between TSC2 gene dysfunction and the presence of autistic behavior remains unclear. As for the relationship between the total tuber counts and mentality, we do not reveal their association. The higher tuber count may have a negative impact on cognition.15 However, some studies have revealed that other factors, such as a history of infantile spasms, higher tuber burden, and early age of seizure onset, are associated with poor mental outcome, instead of tuber counts alone.14,26 The present study may support the latter viewpoint. More than half of our patients with epilepsy have more than one seizure type, which was dominantly simple partial and complex partial seizures, excluding infantile spasms. In addition, nearly 90% of our patients had seizure onset prior to age 1 year. Furthermore, although epilepsy in patients with TSC was considered to be difficult to be controlled, approximate 20% of cases in our study became seizure free under antiepileptic drug treatment. We also demonstrated the negative association between cognitive outcome and age of seizure-onset. Jansen et al14 also found that seizure onset prior to the first birthday is related to poor mentality. Recently, Chu-Shore et al,6 whose sample size is larger, had similar results. Nearly two-thirds of their patients had seizure onset prior to age 1 year, and about 30% of their patients reached seizure remission. Seizure onset prior to age 3 years was negatively correlated to their cognitive outcome in their cohort.27 A much higher prevalence of SEGA in TSC was noted in our study. The main neuropathological findings in TSC are tubers, subependymal nodule, and SEGA. However, subependymal nodule and SEGA may not be distinguished easily based on the findings of MRI. The wider range of patient age in the present study may also contribute to the
higher prevalence of SEGA in our study. Growth of the gadolinium-enhanced lesions near the foramen of Monro may suggest SEGA.28 In conclusion, our data support an underlying role of genetic, physiologic, and structural abnormalities in the development of ASD in TSC. Our results reveal that tubers in the temporal lobe and insular area are associated with ASD. The presence of cystic-like tubers on MRI may also offer a structural marker for ASD.
Funding The authors received no financial support for the research, authorship, and/or publication of this article
Acknowledgments We thank all of the physicians and consultants in the National Taiwan University Tuberous Sclerosis Complex (NTUH TSC) Study Group who participated in the study.
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