Researchers at the Sant Pau Research Institute (IR Sant Pau) have published a study in Epilepsy & Behavior documenting a high frequency of neuropsychiatric symptoms in adults with tuberous sclerosis complex (TSC), a rare, multisystem genetic disorder with highly variable clinical expression. While the condition primarily affects the nervous system, it can also impact other organs such as the kidneys, heart, skin, and lungs.
The study provides an in-depth analysis of the cognitive and emotional profiles of 28 adult patients with confirmed TSC and no severe intellectual disability, highlighting an unmet clinical need. Although most participants exhibited significant emotional, cognitive, or behavioral alterations, only a minority had received specialized mental health care.
The most common symptoms included mood swings (reported in 80% of cases), excessive shyness (70%), and sleep and attention disorders (60%). Additionally, half of the patients reported low self-esteem. Despite this symptom burden, only four individuals—14% of the sample—had received psychiatric or psychological care. “Our patients have many problems in these neuropsychiatric domains, but they don’t seek help for them. And unfortunately, we don’t have the resources to monitor them more closely either because there are so many gaps in mental health care that this ends up being an unmet need,” explains Dr. Alba Sierra, researcher in the Epilepsy Group at IR Sant Pau, neurologist at Hospital Sant Pau, and corresponding author of the study.
TSC is caused by mutations in the TSC1 or TSC2 genes, which lead to abnormal activation of the mTOR pathway and the formation of hamartomas—benign masses made up of normal but disorganized cells. These can develop in different organs. When they affect the central nervous system, they may cause epilepsy, intellectual disability, and neuropsychiatric disorders.
While the impact of epilepsy in TSC has been widely studied, emotional and cognitive symptoms—collectively known as TAND (TSC-Associated Neuropsychiatric Disorders)—have received less attention, especially in adults. “Disease severity is highly variable: some people have mild symptoms and are diagnosed by chance in adulthood, while others experience severe epilepsy, intellectual disability, and multi-organ involvement. That’s why we included a wide age range, from 18 to 65 years. This disease can manifest at any point in life,” notes Dr. Sierra.
The study combined a clinical evaluation with an extensive neuropsychological battery. All patients underwent standardized intelligence testing (WAIS-IV) and cognitive screening (MoCA), along with specific scales to assess anxiety, depression, quality of life, and subjective health perception. The researchers also used the TAND-L checklist to detect symptoms across different domains, from behavior to academic skills. Clinically, the study considered epilepsy history, infantile spasms, findings from MRI and EEG, and genetic profile when available.
Results showed a clear link between epilepsy severity and duration and poorer cognitive performance. Significant associations were also observed with other clinical factors. For example, patients with a history of infantile spasms or mutations in the TSC2 gene had more impaired cognitive profiles and greater emotional and academic difficulties. Additionally, the presence of hamartomas in the frontal and parietal lobes was associated with behavioral, learning, and other specific cognitive impairments.
“We found that epilepsy isn’t the only factor driving these symptoms. Genetics and the location of brain hamartomas also play a role. The impact is multifactorial,” emphasizes Dr. Sierra.
Beyond the clinical findings, the study encourages reflection on the current care model for TSC patients. Traditionally, neurology appointments have focused on controlling epileptic seizures, without systematically addressing neuropsychiatric symptoms. “We tend to focus heavily on purely neurological symptoms, and perhaps haven’t explored these other issues—ones that directly affect quality of life—as much. This study draws attention to the need to look beyond the seizures,” adds Dr. Sierra.
In line with this more holistic perspective, the team underscores the need for multidisciplinary care. TSC doesn’t just impact the brain—it can lead to serious complications in vital organs, including kidney failure, cardiac issues, or lung disease. “Follow-up has to be comprehensive. A systemically involved disease like this requires joint work among specialists. It’s the only way to ensure high-quality care,” concludes Dr. Sierra.
The study opens the door to future research aimed at tracking the progression of these symptoms over time. Longitudinal studies could provide more in-depth insight into how neuropsychiatric alterations evolve with age and help develop more effective, personalized intervention strategies.
Toscano-Prat C, García-Sánchez C, Ros-Castelló V, Barguilla-Arribas A, Saladich IG, Rodríguez-Clifford K, Torra-Balcells R, Boronat S, Sierra-Marcos A. Cognitive and neuro-psychiatric profile in adult patients with epilepsy secondary to Tuberous Sclerosis Complex. Epilepsy Behav. 2025;166:110380. https://doi.org/10.1016/j.yebeh.2025.110380
