David Neal Franz

2004 Background: TS is a potentially devastating disorder characterized by hamartoma formation in multiple organ systems. SEGAs develop in 5-15% of TS patients and represent a significant medical risk, including the potential for sudden death secondary to acute hydrocephalus (as a result of their location adjacent to the foramen of Monro). Neurosurgical resection is the current standard treatment and no effective alternative has been identified. Methods: Patients ≥3 years with a definitive TS diagnosis and evidence of serial SEGA growth (on MRI) were eligible for this prospective, open-label, phase II study. The primary efficacy endpoint was change in SEGA volume from baseline to 6 months (mo). Everolimus dose (3 mg/m² QD orally) was titrated subject to tolerability to achieve target trough concentrations of 5-15 ng/mL. Results: 28 patients were enrolled between 1/07 and 12/08; median duration of treatment was 22 mo (range 5-34). Everolimus was associated with a clinically meaningful reduction in SEGA volume (p<0.001); marked reductions were seen within the initial 3 mo and subsequently sustained or further improved (see table). No patient developed new lesions, worsening hydrocephalus, or worsening signs or symptoms of increased intracranial pressure; none required surgical resection or other therapy for SEGA. Of 16 patients for whom video-EEG data were available, 9 experienced decreases in seizure frequency (across all types of seizure), 6 reported no change (all were event-free at both timepoints), and 1 patient experienced an increase (median change -1.0, p=0.012). Grade 3 adverse drug reactions were single cases of sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia; no grade 4 events were reported. Conclusions: Everolimus is effective in TS-associated SEGA with 78% of patients achieving the prespecified ≥30% reduction at 6 mo; it is also well tolerated and offers a viable alternative to surgical resection.

Lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH) produce cystic and nodular disease, respectively, in the lungs of patients with tuberous sclerosis. The objective of this study was to prospectively characterize the prevalence, clinical presentation, and genetic basis of lung disease in TSC. We performed genotyping and computerized tomographic (CT) scanning of the chest on 23 asymptomatic women with tuberous sclerosis complex (TSC). Cystic pulmonary parenchymal changes consistent with LAM were found in nine patients (39%). These patients tended to be older than cyst-negative patients (31.9 ± 7.6 yr versus 24.8 ± 11.6 yr, p = 0.09). There was no correlation between presence of cysts and tobacco use, age at menarche, history of pregnancy, or estrogen-containing medications. Three of the cyst-positive patients had a prior history of pneumothorax. Pulmonary function studies revealed evidence of gas trapping but normal spirometric indices in the cyst-positive group. All nine cyst-positive patients had angiomyolipomas (AML), which were larger (p < 0.05) and more frequently required intervention (p = 0.08) than cyst-negative patients (8 of 14 with AMLs, p < 0.05). Ten patients (43%) had pulmonary parenchymal nodules. Pulmonary nodules were more common in women with cysts (78% versus 21%, p < 0.05), and 52% of all patients had either cystic or nodular changes. TSC2 mutations were identified in all cyst-positive patients who were tested (n = 8), whereas both TSC1 and TSC2 mutations were found in patients with nodular disease. Correlation of the mutational and radiographic data revealed one pair of sisters who were discordant for cystic disease, two mother– daughter pairs who were discordant for nodular disease, and no clear association between cyst development and a specific mutational type. This prospective analysis demonstrates that cystic and nodular pulmonary changes consistent with LAM and MMPH are common in women with TSC.

Summary:  Purpose: Lamotrigine (LTG), a newer antiepileptic drug (AED), has activity against both partial‐onset and generalized seizures. Its reported benefits for behavior, and its effectiveness in Lennox–Gastaut syndrome and other forms of refractory epilepsy, make it a logical choice for treatment of epilepsy in tuberous sclerosis complex (TSC). We present our experience with LTG therapy of epilepsy in 57 patients with TSC.Methods: Patients fulfilled the diagnostic criteria for clinically definite TSC. LTG was initiated and increased until improvement in seizure frequency was noted, intolerable side effects occurred, or maximal doses were reached. Seizure frequency and behavioral changes were recorded during LTG therapy and compared with those prior to the introduction of LTG.Results: Twenty‐four (42%) were seizure free, and 21 (37%) had a >50% reduction in seizure frequency. Eighteen (32%) had subjectively improved behavior and/or alertness with daily activities. Thirty‐eight (67%) had no change in this regard, whereas one (2%) became worse. Responders were more likely to not have a history of infantile spasms, and to have experienced only partial seizures (p < 0.05). Otherwise no phenotypic correlations with response were apparent.Conclusions: Among patients with TSC and epilepsy, LTG was effective and well tolerated, including as initial monotherapy. Improved alertness and behavior were apparent in many patients. The incidence of side effects is similar to that reported for other pediatric populations with symptomatic partial epilepsy. The usefulness of LTG in TSC may relate to an underlying defect of glutamatergic neurotransmission in partial epilepsy.