Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

OBJECTIVE: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC. METHODS: Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD. RESULTS: The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%). SIGNIFICANCE: Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.

Lacosamide use in the treatment of refractory epilepsy in tuberous sclerosis complex.

Lacosamide (LCS) was approved by the United States Food and Drug Administration (FDA) in 2008 as adjunctive therapy to other anti-epileptic drugs (AEDs) to treat focal-onset seizures, with or without secondary generalization. Its role in the treatment of epilepsy in individuals with tuberous sclerosis complex (TSC) has yet to be determined. This study evaluates LCS treatment of focal-onset refractory epilepsy in patients with TSC. From November 2009 to June 2014, 46 TSC patients followed by a single neurologist were treated with LCS. Forty-eight percent were responders (seizure reduction ≥50%). No significant differences between responders and non-responders in demographic characteristics were found. LCS appears to be an effective and safe treatment of refractory focal onset seizures in TSC. Determining the long-term tolerability and efficacy of LCS in TSC patients requires additional clinical experience.

Similar trends in serum VEGF-D levels and kidney angiomyolipoma responses with longer duration sirolimus treatment in adults with tuberous sclerosis.

CONTEXT: We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up. OBJECTIVE: To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS). DESIGN AND INTERVENTION(S): Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0-12 months. During months 12-24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus. SETTING: Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1). PATIENTS: There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients. MAIN OUTCOME MEASURE(S): We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups. RESULTS: At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787 ± 426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971 ± 4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p=0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed. TRIAL REGISTRATION: Clinical trials.gov NCT00126672.

Clobazam therapy of refractory epilepsy in tuberous sclerosis complex.

Clobazam (CLB) was recently approved by the FDA, but has not been evaluated in tuberous sclerosis complex (TSC). We retrospectively reviewed a cohort of patients with TSC and refractory epilepsy who started CLB over a 5-year period. Clinical characteristics and number of tubers on MRI were assessed. Duration of therapy, therapeutic response and adverse events were recorded. CLB was prescribed in 29 adults and children of whom 72% were cognitively impaired, with a median age at seizure onset of 5 months. Mean duration of CLB therapy was 17.3 months with a 12 and 24-month estimated retention rate of 82% and 68%, respectively. Twenty patients (69%) reported a good response (>50% seizure reduction) at the end of the titration, and six patients (21%) remained good responders after 12 months of CLB therapy. Adverse events occurred in 13 patients, predominantly somnolence and behavioral disorders. One quarter of the responders reported improvement in behavior. No predictive factor for a good response could be identified. CLB appears to be a well-tolerated and valuable option for treatment of refractory epilepsy in TSC.

Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease.

BACKGROUND: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. METHODS: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. RESULTS: 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). CONCLUSIONS: Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. TRIAL REGISTRATION: Clinicaltrials.gov NCT00126672.

The neurology of benign paroxysmal torticollis of infancy: report of 10 new cases and review of the literature.

Benign paroxysmal torticollis is an under-recognized cause of torticollis of early infancy. The attacks usually last for less than 1 week, recur from every few days to every few months, improve by age 2 years, and end by age 3. There very frequently is a family history of migraine. We did a detailed analysis of 10 cases of benign paroxysmal torticollis, seen over 5 years, and compared our findings with those in the 103 cases in the literature. Detailed neurodevelopmental assessments, available only in our cases, showed accompanying gross motor delays in 5/10 children, with additional fine motor delays in 3/5. As the benign paroxysmal torticollis improved, so did the gross motor delays in 3/5, and the fine motor delays in 1/3. In all of our cases, at least 2 other family members had migraine. Benign paroxysmal torticollis is likely an age-sensitive, migraine-related disorder, commonly accompanied by delayed motor development.