Introduction
Tuberous sclerosis complex (TSC)—a representative hereditary neurocutaneous syndrome—is a genetic disorder affecting numerous organs including the brain, eyes, heart, kidneys, lungs, and skin. The hallmark of TSC is the involvement of the central nervous system (CNS) with a wide clinical spectrum varying from severe intellectual disability and intractable epilepsy to normal intelligence and lack of seizures. CNS involvement in patients with TSC is mainly associated with epilepsy, intellectual disability, and autism spectrum disorder (ASD) [
1-
3]. Furthermore, many of the multidimensional problems experienced by patients with TSC change over time, substantially affecting quality of life. Thus, an overall understanding of physical, cognitive, and mental health is necessary to ensure continuous and systematic management of symptoms in this population [
3,
4]. To further this aim, the neurocognitive panel of the 2012 International TSC Consensus Conference recommended that individuals with TSC should be screened for comorbid conditions once per year [
5]. In 2015, De Vries et al. [
6] proposed the Tuberous Sclerosis-Associated Neuropsychiatric Disorders (TAND) checklist.
In the present study, we aimed to investigate trends of neurocognitive and socioemotional disorders in Korean children with TSC using a Korean version of the TAND.
Discussion
Curatolo et al. [
2] described TAND as an umbrella term encompassing diverse impairments at the behavioral, psychiatric, cognitive, learning, neuropsychological, and psychosocial levels. In the present study we tried to focus on diverse aspects of TSC patients not only on epilepsy but also on other neuropsychiatric problems using the Korean version of TAND checklist. We directly communicated with the original authors of TAND-related articles [
6,
7] and translated with back-translation process over 10 months and at last administered it to 58 Korean children with TSC. We observed considerable challenges in behavioral, psychiatric, cognitive, learning, neuropsychological, and psychosocial functioning in TSC patients using it.
TSC is known to be associated with developmental delays, as well as cognitive, learning, and behavioral disorders that are independent of epilepsy [
1,
2,
8,
9]. But these TAND characteristics are not frequently evaluated, treated, or managed in a systematic fashion, resulting in a gap between the clinical needs of patients and available treatment options. To reduce the treatment gap, neuropsychiatric assessment should be performed at each lifespan stage in clinical setting in treating TSC patients [
6,
10].
Diverse behavioral problems can be seen on TSC patients and shared experience of these characteristics can be helpful to dealing with these patients for the parents and clinicians.
In psychiatric level, ASD occurs in 40% to 50% of patients, and 30% to 50% of patients are diagnosed with ADHD. Previous studies have also reported that psychiatric disorders such as anxiety/panic disorder, depression, OCD, and SPR are often comorbid with TSC [
2]. Comparing with that, in the present study, ASD, ADHD, and anxiety occurred in 10.3% (6/58), 12.1% (7/58), and 6.8% (4/58) of patients, respectively. These values are much lower than those reported by previous studies, although we suspect underreporting due to limited awareness of psychiatric disorders in the patient population. Future studies should aim to enhance awareness of comorbid psychiatric disorders in pediatric patients with TSC using screening tests such as the TAND checklist; subsequent intensive evaluation and intervention should then occur as necessary.
In intellectual level, 28 (80.0%) of the 35 patients whose IQ was assessed with a formal intelligence test had intellectual disability in the present study. Intellectual disabilities are reported that majorly correlated with intractable epilepsy in TSC patients, 60.7% of these patients had intractable epilepsy with previous treatments including using ≥3 drugs, KD, or surgery. Cognitive impairment in TSC patients is revealed to be more severe in patients whose seizures begin at an earlier age, those with drug-resistant epilepsy, those who experience various seizure types, and those with more brain tubers [
11-
13]. Cognitive impairment also tends to be more severe as the number of drugs increased. A similar trend was also observed in patients who had attempted to follow a KD or had undergone surgery for drug-resistant epilepsy, and in patients diagnosed with IS or LGS. [
14,
15]. One of the seven patients with normal or borderline intelligence had no history of epilepsy, whereas the rest were confirmed to have focal epilepsy that was well-controlled with drug therapy.
Learning disability belongs to the different aspect of TSC. In academic issue, learning disability occurs in 30% of school-aged patients with TSC. Even if intelligence is normal, patients often experience challenges with reading, writing, arithmetic, and spelling, which necessitates individualized learning plans [
2,
6]. Although none of the seven patients with normal intelligence reported learning-related problems, many patients with cognitive impairment did experience learning challenges. More than half of school-aged patients with TSC experienced challenges with mathematics or spelling (65.6% and 56.3%, respectively), and as many as 28.2% of patients reported difficulties with reading and writing. These findings are consistent with previously published results [
3,
6,
8].
Some studies have previously revealed the following frequently documented neuropsychological issues in patients with TSC: memory impairment, challenges with maintaining or shifting attention, challenges with multi-tasking, and impairments in visuospatial working memory, executive function, and orientation [
2,
6]. We also observed that patients experienced challenges with multi-tasking (27/58, 46.6%), as well as impairments in executive function (26/58, 44.8%), attentiveness (23/58, 39.7%), and visuospatial task performance (23/58, 39.7%). An examination of cases in which formal neuropsychological tests were performed following evaluation with the TAND checklist revealed a discrepancy between neuropsychological conditions reported by guardians on the TAND checklist and the results of formal tests.
The limitations of this study include its small sample size and one-time point assessment. Larger longitudinal observations and correlations between the TAND checklist and formal neuropsychological evaluations could support more reliable and useful information for the assessment and treatment of individuals of TSC. Accordingly, future studies should investigate the correlation between the results of the TAND checklist and formal neuropsychological tests to identify the source of this discrepancy.
In this study, we performed the first translation and administration of the TAND checklist Korean version. The screening results will aid clinicians in referring patients for further evaluation and in subsequent treatment planning. The translation of the checklist in Korean will also aid in across country comparisons. Future studies should investigate the validity of the TAND checklist by examining correlations between TAND responses and the results of formal neuropsychological tests.