Genotype/phenotype in tuberous sclerosis complex: associations with clinical and radiologic manifestations.

OBJECTIVES: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC. METHODS: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance). RESULTS: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder. SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD.

Severity of manifestations in tuberous sclerosis complex in relation to genotype.

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) commonly present with significant neurologic deficits, including seizures, autism, and intellectual disability. Previous evidence suggests that the TSC2 mutation genotype may be associated with a more severe disease phenotype. This study evaluates the association of the TSC1 and TSC2 genotype with patient and disease characteristics in a retrospective review of a large TSC Natural History Database consisting of 919 patients with TSC. METHODS: Univariate logistic regression was conducted to evaluate the association of the TSC1 and TSC2 gene mutations with patient and disease characteristics. RESULTS: As compared to patients with the TSC1 mutation, patients with the TSC2 mutation were younger (p = 0.02), more likely to have partial epilepsy (odds ratio (OR) 1.74, p = 0.0015), complex partial seizures (OR 2.03, p = 0.02), infantile spasms (IS) (OR 1.67, p = 0.01), subependymal giant-cell astrocytomas (SEGAs) (OR 1.64, p = 0.01), and intellectual disability (OR 2.90, p = 0.0002). SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. Our findings confirm and supplement existing literature that TSC2 mutation is likely to be associated with a more severe, earlier presenting TSC phenotype, including infantile spasms.

Vigabatrin for partial-onset seizure treatment in patients with tuberous sclerosis complex.

Vigabatrin (VGB) has been shown to be particularly effective in the treatment of infantile spasms for those with tuberous sclerosis complex (TSC). However, many patients with TSC continue to have treatment-resistant seizures. For many patients with TSC, partial-onset seizures are prominent. Therefore, we examined the efficacy and tolerability of VGB for treatment of refractory partial-onset seizures. We performed a retrospective cohort study on 49 TSC patients with treatment-resistant seen at our center from 1997 to 2010, examined seizure outcomes, and reported adverse effects. We found that 13 (24.5%) patients became seizure-free or experienced a >90% decrease in seizure episode frequency with the addition of VGB to their regimens. Only one patient stopped VGB use because of excess sedation. The remaining 21 patients discontinued VGB use because of lack of efficacy. We conclude that VGB may be a safe and effective treatment in TSC patients with refractory partial-onset seizures.

Bilateral intracranial electroencephalographic monitoring immediately following corpus callosotomy.

Although many patients with medically refractory focal epilepsy are candidates for resective surgery, patients with multifocal epilepsy and symptomatic generalized epilepsy remain difficult to treat medically and surgically. Corpus callosotomy has been utilized since 1940 for the treatment of seizures, with reports of efficacy in multiple seizure types. Previous studies have demonstrated subsequent lateralization of bilateral/bisynchronous epileptiform activity following callosotomy. To investigate the efficacy of bilateral intracranial electroencephalographic studies immediately following corpus callosotomy, we retrospectively identified 26 patients who underwent corpus callosotomy at our center, 18 of whom had intracranial monitoring following corpus callosotomy. Five of the 18 had focal resections following intracranial electroencephalography (EEG). No patients were seizure free following callosotomy or resection. No differences in postoperative outcomes were seen between patients with intracranial EEG versus those without.

Forced spousal intercourse after seizures.

Hypersexuality, a feature of Klüver-Bucy syndrome, is a rare but dramatic postictal symptom of temporal lobe epilepsy. We describe a 39-year-old patient with uncontrolled partial epilepsy who developed postictal periods of hypersexual aggression toward his wife after nocturnal convulsions. Following these seizures, he would have forced intercourse with his wife, followed by tremendous guilt and remorse when informed of his actions in the morning. Nocturnal convulsions and postictal hypersexuality resolved with a combination of lamotrigine and levetiracetam, more sleep, and stress management. The temporal features of the hypersexual behavior with respect to convulsions and the resolution of the behavior with seizure control support that aggressive hypersexuality can occur as a transient postictal behavioral change. The more intense nature of his symptoms compared with previously reported cases may reflect the occurrence of symptoms after tonic-clonic rather than partial seizures.

Early manifestations of renal disease in patients with tuberous sclerosis complex.

OBJECTIVES: Renal manifestations are the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC), and include renal cysts, angiomyolipomas, fat-poor lesions, and malignant tumors. These lesions begin in childhood and often lead to chronic kidney disease (CKD). Little is known on the incidence of early modifiable risk factors of CKD, such as proteinuria and hypertension, or subtle decreases in glomerular filtration rate that correspond to the early stages of CKD in children with TSC. The impact of genotype on these early manifestations of CKD has not been investigated. DESIGN: Retrospective chart review of 84 children and young adults with TSC. MEASUREMENTS: This study assessed the prevalence of hypertension, renal impairment, and proteinuria, as well as the genotype-phenotype correlations. RESULTS: Children and young adults with TSC2 mutations had a significantly higher rate of renal lesions, hypertension (36% vs 14%), and decreased renal function than those with TSC1 mutations. CONCLUSION: On the basis of estimated glomerular filtration rate and blood pressure, our findings are consistent with the hypothesis that TSC2 mutations are associated with more severe early renal involvement in children. There is a compelling need for close collaboration of nephrologists and neurologists to provide care to pediatric patients with TSC to improve screening and management of early manifestations of renal disease.