Abstract
Objectives: To review the clinical and radiological correlation of the central nervous system manifestations of tuberous sclerosis complex (TSC).
Methods: All patients under the age of 18 years with TSC seen at the Department of Pediatrics, Sidra Medicine, Doha, Qatar, between January 2003 and February 2021 were included in this retrospective study. Severity of epilepsy was determined using the early childhood epilepsy severity score (E-CHESS) tool.
Results: The study sample included 38 patients (50% male), 8 (21%) of whom were native to Qatar. The median age at diagnosis was 4 (range: 0-72) months. A family history of TSC was present in 10 (26%) cases, while 33 (86%) patients had a TSC2 gene mutation. Common presentations included seizures (79%), rhabdomyoma (26%), and developmental delay (13%). On MRI scans, cortical tubers were seen in all patients, subependymal nodules in 37 (97%), and subependymal giant cell astrocytoma was diagnosed in 8 (21%) cases. A total of 30 children developed epilepsy, 9 of whom had favorable and 21 had unfavorable E-CHESS scores, and 6 required pharmaceutical management. A total of 13 children were diagnosed with autistic spectrum disorder and 12 with attention deficit hyperactivity disorder.
Conclusion: Multidisciplinary management and further research is needed to optimize the care and quality of life of TSC affected individuals and their families.
Tuberous sclerosis complex (TSC) is a rare, genetic disorder present in 1 in 6,000 to 1 in 10,000 live births, with an estimated prevalence of 1 in 20,000.1 It is inherited in an autosomal dominant manner in approximately one third of those affected, and as the result of a de novo mutation in the remaining cases. There is a wide variation in presentation among individuals belonging to different families or even within the same family.2 Central nervous system (CNS), skin, heart and kidneys bear the brunt of clinical manifestations of TSC.3,4 All patients with TSC carry loss-of-function germline mutations in either of the 2 tumor-suppressor genes, TSC1 which encode for the protein hamartin or TSC2 which encode for the protein tuberin.5 These proteins regulate cell proliferation and differentiation, the loss of which can lead to the abnormal development and generation of cells through faulty, inefficient, or the absent protein products. Accordingly, mutations in either the TSC1 or TSC2 gene lead to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway, which is a signaling cascade that modulates a variation of intracellular function including cell growth and proliferation, protein synthesis, and metabolism. Hyperactivation of this pathway leads to growth dysregulation that ultimately results in clinical manifestations of TSC.4
Epilepsy and developmental delay are the most well-recognized features of TSC. An ensemble of neuro-psychiatric manifestations experienced by TSC patients is known as TSC associated neuropsychiatric disorders (TAND) which includes behavioural, intellectual, neuropsychiatric, academic and psychosocial difficulties.6 It also includes specific conditions such as autistic spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). An attractive mechanism of pathophysiology of TAND, in common with other manifestations of TSC, is provided by mTOR dysregulation. Early reports of neuropsychiatric response with the use of mTOR inhibitor therapy support this hypothesis.7
Neuroradiological features of TSC include cortical/subcortical hamartomas (tubers) and subependymal nodules (SENs) in over 80% of patients.8 Subependymal nodules were found in the ependymal lining of the lateral and third ventricles. They grow at variable pace throughout childhood, usually peaking around puberty.9 In approximately 10-15% of cases, those present around the foramen of Monro have a higher likelihood of developing into subependymal giant cell astrocytomas (SEGAs).9,10 Cortical tubers and SENs have long been considered the epileptogenic focus in TSC patients. Further understanding of the TSC neurobiology has led to the recognition of the perituberal cortex as epileptogenic foci through cellular dysplasia and mTOR signalling.11
Qatar is a high-income developing country populated by 3.1 million people. Only 10-11% of the population are native to Qatar, while the remaining 89-90% are expatriates. Approximately 32.5% of Qatari children are within the 0-14 age group.12,13 Comprehensive healthcare is delivered to the entire population through the Qatar National Health Services via government funds and employer-issued insurance system. Per capita healthcare resources (physician and hospital beds) are within the highest in the region and are similar to those in most developed countries.14 The population is mostly urbanized with highly accessible healthcare facilities including neuroradiologic facilities. Currently, the management of TSC patients is carried out by a core team of physicians from clinical genetics, pediatric neurology, oncology, and nephrology, who carry out the diagnostic evaluation, surveillance, and treatment where necessary. Referral to other specialists/teams is carried out based on patients’ individual needs.
This retrospective cohort study was carried out by our team to examine the presentation, neurological, and radiological features of TSC.
Methods
We retrospectively reviewed electronic medical records at Sidra Medicine and Hamad General Hospital, Doha, Qatar. Data of patients 0-18 years old who were referred to pediatric neurology for TSC evaluation between January 2003 and February 2021 were included in the sample used for analyses. The study protocol was approved by the institutional review board of Sidra Medicine (IRB No.: 1500797).
We used the standardized diagnostic criteria as indicated by the 2012 International Tuberous Sclerosis Complex Consensus Conference for TSC.3 Patients who did not fit the criteria for TSC were excluded from analysis while the remaining patients underwent genetic assessment, which involved a detailed family history and pedigree analysis, as well as blood testing for the TSC1 and TSC2 genes at accredited commercial laboratories. Their electronic medical records were also analyzed and data pertaining to gender, age at TSC diagnosis, familial history of TSC, developmental milestones, presence and type (and age of first presentation) of epilepsy, presence of tubers, SEN and SEGA on neuroimaging, and neurological examination findings at last follow-up were recorded. Subependymal giant cell astrocytoma diagnosis was based on size, location, and behavior over time. Lesions close to the foramen of Monro, causing or likely to cause obstruction, exceeding 5 mm in diameter (or demonstrating an increase in size by 5 mm) were considered SEGA, whereas smaller, non-obstructive lesions were denoted as SENs.
The epilepsy severity and response to therapy was assessed by using the early childhood epilepsy severity score (E-CHESS).15 According to the most recent documented evaluation, a note was made of the period of seizure occurrence, frequency, count of seizure types, status epilepticus occurrence and duration, amount of anticonvulsant medications used, and response to treatment.
The TAND checklist (developed by the Neuropsychiatry Panel at the 2012 Tuberous Sclerosis Complex International Consensus Conference, as reported by de Vries et al6) was used to record the manifestations. The assessment was carried out at the behavioral, intellectual, neuropsychological, psychiatric, academic, and psychosocial levels. Families were interviewed and feedback to the TAND questionnaire were recorded by the specialized clinical nurse after the child’s follow-up appointments at the hospital or over the telephone at a mutually convenient time.
Statistical analysis
Patient and disease attributes are expressed in numerical and percentage form per attribute. Standard statistical tests were carried out to calculate numbers, percentages, and median values. The Statistical Package for the Social Sciences, version 25.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis.
Results
As shown in Table 1, providing a summary of patient and disease characteristics, the final analysis involved 38 patients with TSC as 4 children did not fulfill the diagnostic criteria for TSC. Median age at diagnosis for the remaining cohort was 4 (range: 0-72) months. A total of 8 (21%) children were native to Qatar, and the remaining 30 were expatriates. In 24 (63%) cases, the TSC diagnosis was carried out in Qatar, whereas the remaining 14 patients had already been diagnosed elsewhere before relocating to Qatar. Family history of TSC were seen in 10 (26.3%) patients.
- Patients and disease characteristics (N=38).
Epileptiform seizures were the predominant presenting feature, and were present in 30 (79%) cases, including infantile spasms, affecting 14 (37%) of these children. This was followed by cardiac rhabdomyoma (RM, n=8, 26%), developmental delay/learning disability (4 cases, 13%), and hypopigmented spots (4 cases, 13%). As indicated in Table 1, at least 2 major diagnostic criteria were present in all patients, including hypomelanotic skin lesions (76%) and angiofibroma (52%), SEN (97%), cortical dysplasia (76%), SEGA (26%), multiple renal cysts (76%), and cardiac RM.
The TSC1 and TSC2 gene mutation analyses revealed that 33 (87%) individuals had an alteration in the TSC2 gene, while only one patient had a TSC1 gene mutation, and the remaining 4 (10%) patients had negative genetic results (Tables 1 & 2).
- Presenting clinical and radiological features for all patients with tuberous sclerosis.
A total of 32 (84.2%) patients had at least one seizure, 30 (78.9%) of whom were diagnosed with epilepsy. At the most recent evaluation, 6 (20%) patients were experiencing daily seizures, 10 (33%) had seizures at least once a week, while the remaining 14 (46%) had less frequent or no seizures during the evaluation period. A total of 25 (65.8%) individuals had one seizure type, the most common form being infantile spasms (IS) seen in 14 (46.6%) patients, followed by tonic-clonic seizures (12 cases, 40%). Complete cessation of seizures was achieved in 19 (63%) patients and partial cessation of seizures was achieved in 8 (21.1%) patients, while 3 (10%) patients showed no response to anticonvulsive therapy. A total of 15 (50%) patients were given 1-2 anti-epileptic drugs (AEDs), whereas 12 (40%) required more than 2 AEDs. Three patients were no longer receiving AED treatment by the last evaluation, while 2 patients undergone epilepsy surgery with effective epilepsy control (albeit with AED). Valproate and clobazam (13 patients each) were the 2 most frequently used AEDs, followed by vigabatrin (10), levetiracetam (8), topiramate (6), carbamazepine (4), lacosamide (2), clonidine (2) and ethosuximide (1). Vigabatrin was the AED of choice for patients with infantile spasms (10). Nine (27%) patients had a favorable E-CHESS score, which was unfavorable in 21 (73%) cases. Table 2 and 3 summarized these findings.
- Frequency of tuberous sclerosis associated neuropsychiatric disorders features among tuberous sclerosis patients (n=29).
In our cohort, the TSC neuroimaging features included tubers (97.3%), SENs (97.3%), and SEGA (26.3%). Although tubers were distributed throughout the cerebral hemispheres, the frontal lobes were the most commonly involved region (seen in 8/38 patients, 21%). Six (15%) patients had a cerebellar tuber in addition to the supratentorial lesions. Subependymal nodules were distributed around the ependymal lining of lateral ventricles, and were labeled as SEGA in 8 (21%) cases due to their location and size. Five (62.5%) patients with SEGA received mTOR inhibitor therapy due to an increase in SEGA size and current or impending obstruction to the cerebrospinal fluid (CSF) flow. After a median follow-up period of 56 (range: 0-101) months, 2 of these lesions showed clinically significant progression requiring surgical management, 2 showed radiological regression within one year of starting treatment mTOR inhibitor everolimus, while the remaining 4 remained stable over the follow-up period. One patient requiring surgical resection continued receiving everolimus treatment with stable residual SEGA, while the other had a postoperative cerebrovascular accident (CVA). In the latter case, everolimus was withheld after surgical excision and the residual SEGA subsequently remained stable. No progression was seen in any of the other patients treated with everolimus. Summaries of these findings can be found in Tables 2 & 3.
As shown in Table 4, at least one TAND feature was observed in 32 (84%) patients, while more than 4 TAND features were seen in 27 patients. At the behavioral level, the most common TAND manifestations were poor language development (72%), poor attention span (62%), and poor eye contact (44%). Psychiatrically, ASD (42%) and ADHD (24%) were the 2 most frequently observed features. At the academic level, 69% of children experienced difficulties in writing and spelling, while 65% each had difficulties in reading and mathematics. At the neuropsychological level, 51% of children had problems with memory, 41% with multitasking, 38% with visuospatial tasks, and 34% with cognitive flexibility. Finally, at the psychosocial level, family stress was observed in 31% of cases.
- Severity of epilepsy and response to therapy using the “early childhood epilepsy severity score” (N=30).
Discussion
Several researchers from the Gulf region have published reports on various aspects of TSC in recent years.16 The median age of 4 months at diagnosis in our cohort is lower than previously reported, likely due to available genetic screening and diagnosis of RM on antenatal maternal scans.17 In addition, Qatar’s small population and ready access to specialist services may play a role in early diagnosis.
The frequencies of sporadic and familial cases were the same as reported previously. We also found higher incidence of TSC2 gene mutations, which is consistent with the findings yielded by many previous studies. A higher prevalence of TSC2 mutations compared to TSC1 has been reported by other researchers.16,18 Mutations in the TSC1 and TSC2 genes are responsible for pathological constitutive activation of the highly conserved PI3K-mTOR pathway leading to the development of hamartomas (benign tumors) in various organs including the CNS.3,19 In mice, homozygous loss of TSC2 leads to embryonic lethality, while those with heterozygous TSC2 have normal survival, but are prone to develop tumors in various organs including kidney, liver, and lungs.20,21 The TSC1 acts as stabilizer of TSC2, while TSC2 in the complex acts as GTPase activating protein.22 Clinically, TSC1 mutations lead to a milder form of illness, while TSC2 mutations are associated with high tuber count and severer form.23 The high frequency of TSC2 mutations in our cohort may thus be responsible for the severe clinical, radiological, and neuropsychiatric manifestations of the disease reported here.
The prevalence of epilepsy and the type of seizures observed in our patients were in line with those reported in pertinent literature, including a high frequency of ISs.24-26 We found E-CHESS to be a reliable tool for monitoring the severity of epilepsy, evaluating treatment adequacy, and predicting the degree of intellectual impairment, as was originally intended by Humphrey et al.15 The epilepsy severity and effective seizure control determine the neurocognitive outcome in TSC patients. This was confirmed by our cohort having a high frequency of TAND at behavioral, intellectual, academic, and psychiatric levels. In a study carried out in Italy based on a sample size similar to ours, Toldo et al27 found that 84% of their patients had at least one TAND and 78% had 4 TAND features. In agreement with our findings, TAND features were found in all domains with some variations that could be explained by cultural norms or inter-observer variation. De Vries et al28 reported a 21% incidence of ASD and 19% incidence of ADHD in TSC patients within the context of tuberous sclerosis registry to increase disease awareness. This multi-center and international disease registry has been designed to provide deeper insights into the TSC manifestations and management.28 While higher ASD and ADHD frequencies (ranging between 30-60%) have been reported by other researchers, our findings were in line with those obtained in the above studies. Interestingly, none of our patients were reported to have anxiety or depressive disorders, possibly due to the younger age of our cohort and parental reluctance to report mental health problems.
Tubers, RMLs, and SENs are present in the majority of TSC patients. The number and location of tubers correlate to the severity of epilepsy and the degree of cognitive deficit. Although RMLs have no prognostic implications with respect to TSC severity, tubers are believed to be responsible for symptomatic epilepsy in approximately 75% of patients.31 The frequency with which tubers, SENs, and SEGAs were observed in our cohort was similar to that reported previously.32 The frequency with which tubers, SENs, and SEGAs were observed in our cohort was similar to that reported previously.31,33,34 A total of 5 (62.5%) of the patients with SEGA in our cohort received everolimus, and only 2 (25%) of these required surgical management. It is reasonable to assume that more patients would have required neurosurgical intervention in the absence of mTOR inhibitor treatment. However, as our sample size was small, a longitudinal study with a larger sample would be required to reach a definitive conclusion.
Study strengths & limitations
Our results will provide a baseline for future research into TSC manifestations and management. In common with all retrospective studies, we were limited by the quality of data recorded in the electronic medical records. Some of the subjective manifestations, especially TAND, are likely to have been under-reported, due to social stigma. Details of the presentation are subject to recall bias.
In conclusion, we have reported the clinical and radiological features of TSC in pediatric patients seen at Sidra Medicine and Hamad General Hospital, Doha, Qatar. While the incidence and phenotype of the disease were similar to those seen in other populations, a genotypically more severe form of the disease was seen more frequently in our cohort. Diagnostic work-up, management, and surveillance for radiological features were carried out according to the internationally accepted guidelines. We have demonstrated that everolimus has an established role in the treatment of SEGA and as a disease modifying agent for several other TSC manifestations.
As the national referral center for children with TSC, a multidisciplinary management approach (described earlier) has evolved at Sidra Medicine, Doha, Qatar. This can be further improved in the future by expanding the core team, and extending the management to age specific specialist teams.
Acknowledgment
The authors gratefully acknowledge the editing and administrative support by Maraeh Angela, Research and Quality coordinator, Sidra Medicine, Doha, Qatar. The authors also would like to thank First Editing (www.firstediting.com) for the English language editing.
Footnotes
Disclosure. Authors have no conflict of interests, and the work was not supported or funded by any drug company.
- Received September 8, 2024.
- Accepted October 7, 2024.
- Copyright: © Saudi Medical Journal
This is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.
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