Epilepsy in tuberous sclerosis complex: Findings from the TOSCA Study

Abstract

Summary Objective To present the baseline data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with emphasis on the characteristics of epilepsies associated with tuberous sclerosis complex (TSC). Methods Retrospective and prospective patients’ data on all aspects of TSC were collected from multiple countries worldwide. Epilepsy variables included seizure type, age at onset, type of treatment, and treatment outcomes and association with genotype, seizures control, and intellectual disability. As for noninterventional registries, the study protocol did not specify any particular clinical instruments, laboratory investigations, or intervention. Evaluations included those required for diagnosis and management following local best practice. Results Epilepsy was reported in 83.6% of patients (1852/2216) at baseline; 38.9% presented with infantile spasms and 67.5% with focal seizures. The mean age at diagnosis of infantile spasms was 0.4 year (median <1 year; range <1‐30 years) and at diagnosis of focal seizures was 2.7 years (median 1 year; range <1‐66 years). A total of 1469 patients (79.3%) were diagnosed with epilepsy <2 years. The rate of infantile spasms was higher in patients with a TSC2 mutation than in patients with a TSC1 mutation (47.3% vs 23%). ɣ‐aminobutyric acid (GABA)ergic drugs were the most common treatment modality for both infantile spasms (78.7%) and focal seizures (65.5%). Infantile spasms and focal seizures were controlled in 76.3% and 58.2% of patients, respectively. Control of seizures was associated with lower rates of intellectual disability in both groups. Significance This registry reports the largest international cohort of patients with TSC. Findings confirmed the typical onset pattern of infantile spasms and other focal seizures in the first 2 years of life, and the high rates of infantile spasms in patients with TSC2 mutation. Our results underscored the occurrence of focal seizures at all ages, including an onset that preceded emergence of infantile spasms. Seizure control was shown to be associated with lower rates of intellectual disability but did not preclude the presence of intellectual disability.

Diagnosis of Tuberous Sclerosis Complex and Epilepsy Outcomes in Children with Fetal Cardiac Rhabdomyoma: A Long Term Follow-up Study

“…This is similar figure as those given by Jozwiak et al [15] and Wu et al [16], and tuberous sclerosis registry to increase disease awareness (TOSCA) study on large population also reported that epilepsy developed in 86.3% of patients and 79.3% were diagnosed with epilepsy before 2 years [17]. In addition, a high incidence of infantile spasms (78.6%) was observed in this study, which is different from the result of the TOSCA study: 38.9% presented with infantile spasms and 67.5% with focal seizures [17]. Twenty-one of patients with infantile spasms (95.5%) received vigabatrin as the first treatment and achieved subsequent seizure freedom.…”

A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC)

“…Subependymal giant cell astrocytomas (SEGAs) were found in 24.4% of the TOSCA population. SEGA can obstruct the intraventricular space and lead to noncommunicating hydrocephalus requiring surgery (22.4% of those [20][21][22][23][24][25] The prevalence rate (32.9%, 35.9%) of pharmacoresistant epilepsy is similar to general population with focal epilepsy [26,27]. A mutation in the TSC2 gene is a risk factor for infantile spasms (47.3% vs. 23% with TSC1 in TOSCA) as well as an earlier manifestation of epilepsy, a higher seizure frequency, and pharmacological refractoriness [28].…”

“…In general, seizures in patients with TSC are often detected before the third year of life , [21,22,42], but can also develop for the first time in adulthood (up to 12% of cases). The most common seizure type in TSC are localization-related or focal seizures (67.5%), followed by epileptic ("infantile") spasms in 38 to 49% [21,22,26] of individuals with TSC: Epileptic spasms typically begin between 4 and 8 months of age and later transform into other seizure types; they define West syndrome, a severe epileptic encephalopathy which is common in children with TSC. The majority of individuals with TSC characterized in the TOSCA registry had cortical tubers (88.2%) or subependymal nodules (SEN; 78.2%).…”

The great mimicker: Phenotypic overlap between constitutional mismatch repair deficiency and Tuberous Sclerosis complex

“…We can speculate on the reasons for the lack of these features in our CMMRD patients with tuber-like lesions. Firstly even in TSC it is known that developmental delay is largely attributed to prolonged seizure activity 17 so that the lack of seizures in our CMMRD patients may explain the lack of developmental delay. As for seizures: since the number of tubers in TSC partially correlates with epilepsy, 18 it is possible that CMMRD patients are less prone to seizures due to the relatively low counts of tuber-like lesions (up to seven in this cohort).…”

“…It has also been shown in TSC that different kinds of tubers may have different epileptogenic potential. 17 It is possible that the lesions seen in CMMRD belong to a relatively benign subtype with low epileptogenic potential.…”