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Background The mechanistic target of rapamycin inhibitors everolimus and sirolimus have activity against multiple manifestations of tuberous sclerosis complex and are approved to treat astrocytomas, angiomyolipomas, lymphangioleiomyomatosis, and epilepsy. Cannabidiol is a novel antiepileptic medication. There is lack of information regarding drug-drug interactions between mechanistic target of rapamycin inhibitors and cannabidiol in clinical practice. Methods We reviewed patients with tuberous sclerosis complex who were treated with a mechanistic target of rapamycin inhibitor (everolimus, sirolimus) and cannabidiol. Clinical information, mechanistic target of rapamycin inhibitor and cannabidiol dosing, concomitant antiepileptic drugs, as well as laboratory and adverse events were reviewed before and after initiation of cannabidiol. Results A total of 25 patients were treated with cannabidiol and a mechanistic target of rapamycin inhibitor (18 everolimus, seven sirolimus). All mechanistic target of rapamycin inhibitor levels were drawn as troughs. Levels were significantly higher in 76% patients after cannabidiol treatment (P = 0.0003). Median change from baseline was +9.8 ng/mL for everolimus and +5.1 ng/mL for sirolimus. Adverse events occurred in 40%, with diarrhea being the most frequent adverse event occurring in three patients. No severe adverse events occurred during the treatment period. Conclusions Cannabidiol resulted in increased serum levels of everolimus and/or sirolimus. Some patients experienced doubling or tripling of their mechanistic target of rapamycin inhibitor trough following the addition of cannabidiol. In some cases, this resulted in clinical toxicity, as well as laboratory abnormalities. Awareness of this interaction can lead clinicians to evaluate serum levels and other safety laboratory studies more closely, and thereby avoid potentially significant adverse effects. In patients known to be prone to mechanistic target of rapamycin inhibitor toxicity, preemptive reduction in dose may be warranted upon initiation of cannabidiol.

Renal cysts occur in approximately 50% of patients with tuberous sclerosis complex, but their clinical significance and response to treatment are unknown. Abdominal imaging of 15 patients with tuberous sclerosis complex-associated renal cystic disease who had received mammalian target of rapamycin inhibitor therapy for other tuberous sclerosis complex-related indications was evaluated. Reductions in cyst number, sum diameter, and volume were observed.

Neurosurgical resection is the standard treatment for subependymal giant-cell astrocytomas in patients with the tuberous sclerosis complex. An alternative may be the use of everolimus, which inhibits the mammalian target of rapamycin, a protein regulated by gene products involved in the tuberous sclerosis complex.Patients 3 years of age or older with serial growth of subependymal giant-cell astrocytomas were eligible for this open-label study. The primary efficacy end point was the change in volume of subependymal giant-cell astrocytomas between baseline and 6 months. We gave everolimus orally, at a dose of 3.0 mg per square meter of body-surface area, to achieve a trough concentration of 5 to 15 ng per milliliter.We enrolled 28 patients. Everolimus therapy was associated with a clinically meaningful reduction in volume of the primary subependymal giant-cell astrocytoma, as assessed on independent central review (P0.001 for baseline vs. 6 months), with a reduction of at least 30% in 21 patients (75%) and at least 50% in 9 patients (32%). Marked reductions were seen within 3 months and were sustained. There were no new lesions, worsening hydrocephalus, evidence of increased intracranial pressure, or necessity for surgical resection or other therapy for subependymal giant-cell astrocytoma. Of the 16 patients for whom 24-hour video electroencephalography data were available, seizure frequency for the 6-month study period (vs. the previous 6-month period) decreased in 9, did not change in 6, and increased in 1 (median change, -1 seizure; P=0.02). The mean (±SD) score on the validated Quality-of-Life in Childhood Epilepsy questionnaire (on which scores can range from 0 to 100, with higher scores indicating a better quality of life) was improved at 3 months (63.4±12.4) and 6 months (62.1±14.2) over the baseline score (57.8±14.0). Single cases of grade 3 treatment-related sinusitis, pneumonia, viral bronchitis, tooth infection, stomatitis, and leukopenia were reported.Everolimus therapy was associated with marked reduction in the volume of subependymal giant-cell astrocytomas and seizure frequency and may be a potential alternative to neurosurgical resection in some cases, though long-term studies are needed. (Funded by Novartis; ClinicalTrials.gov number, NCT00411619.).

Objective Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in multiple organs. Five to 15% of affected individuals display subependymal giant cell astrocytomas, which can lead to substantial neurological and postoperative morbidity due to the production of hydrocephalus, mass effect, and their typical location adjacent to the foramen of Monro. We sought to see whether therapy with oral rapamycin could affect growth or induce regression in astrocytomas associated with TSC. Methods Five subjects with clinically definite TSC and either subependymal giant cell astrocytomas (n = 4) or a pilocytic astrocytoma (n = 1) were treated with oral rapamycin at standard immunosuppressive doses (serum levels 5–15ng/ml) from 2.5 to 20 months. All lesions demonstrated growth on serial neuroimaging studies. Magnetic resonance imaging scans were performed before and at regular intervals following initiation of therapy. Results All lesions exhibited regression and, in one case, necrosis. Interruption of therapy resulted in regrowth of subependymal giant cell astrocytomas in one patient. Resumption of therapy resulted in further regression. Treatment was well tolerated. Interpretation Oral rapamycin therapy can induce regression of astrocytomas associated with TSC and may offer an alternative to operative therapy of these lesions. Ann Neurol 2006

Seizures are a common neurologic symptom of tuberous sclerosis complex. The use of levetiracetam as adjunctive antiepileptic therapy was assessed in 20 patients with tuberous sclerosis complex aged 2 to 19 years. In this retrospective evaluation, 40% of patients treated with levetiracetam achieved a seizure reduction of more than 50%. Levetiracetam was generally well tolerated, and adverse events were relatively uncommon in patients who responded to treatment. The most commonly reported adverse events were behavioral problems. Unstable gait, insomnia, poor appetite, and increased seizure frequency were also reported. Based on these results, the use of levetiracetam as adjunctive antiepileptic therapy can reduce seizure frequency in patients with tuberous sclerosis complex. ( J Child Neurol 2006;21:53—57).

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.

Angelman's syndrome, a genetic disorder involving a defect in the DNA coding for subunits of the gamma-aminobutyric acid (GABA) type A receptor, often is associated with intractable epilepsy. Topiramate is a novel anticonvulsant that enhances GABAergic neurotransmission. Five children with Angelman's syndrome and epilepsy were treated with topiramate for clinical indications. The drug was effective and well tolerated, possibly because of its GABAergic properties. Further studies are necessary to confirm and elucidate this observation.

A recent phase 1/2 study demonstrated that treatment with the mammalian target of rapamycin inhibitor everolimus reduced subependymal giant cell astrocytoma volume by 30% in 75% of the patients, all of whom were poor candidates for surgical resection. Of the enrolled patients, 4 had had previous surgery to remove subependymal giant cell astrocytoma, and the outcomes for these patients were retrospectively analyzed and are presented here. All 4 experienced over 50% initial reduction in the volume of their subependymal giant cell astrocytoma after 2 to 3 years of therapy with everolimus. Although the volume of 1 patient’s subependymal giant cell astrocytoma returned to baseline volume 36 months after initiating everolimus, they have remained asymptomatic with no recurrent hydrocephalus. Further surgery has been avoided in all cases to date. This course of treatment offers a new and welcome option for these difficult-to-treat patients.

Behavioral and psychiatric comorbidity are common in tuberous sclerosis complex (TSC), but information regarding psychopharmacologic management is lacking.We reviewed clinical records of patients evaluated over a 20-month period at a large, quaternary referral center specializing in the comprehensive management of patients with TSC. Data were collected regarding psychiatric diagnoses, psychopharmacologic medications used to treat these disorders, and clinical response to treatment at follow-up.There were 113 encounters by 62 pediatric and adult patients with TSC, which were included in the present analysis. Behavioral and anxiety disorders were most prevalent, as were autism spectrum disorders and attention-deficit/hyperactivity disorder. Antipsychotics, antidepressants, and anticonvulsants with mood-stabilizing properties were the most often prescribed psychoactive medications and were associated with an overall improvement or stabilization of psychiatric symptoms 65% of the time.Psychiatric comorbidity, especially behavioral disorders, is very common among patients with TSC. Pharmacologic treatment can be very effective and should be considered for optimal disease management in affected individuals.

To determine vigabatrin's effectiveness and the prevalence of symptomatic visual impairment (i.e., impairment affecting the ability to perform everyday activities) associated with its therapy in pediatric epilepsy, we retrospectively reviewed medical records of 156 patients receiving vigabatrin at Cincinnati Children's Medical Center from 1998-2010. In addition to demographics and vigabatrin dosing information, data included seizure type/frequency at presentation and subsequent follow-up. Of 156 patients, we excluded 35 because their medical records were insufficient to permit verification of the exact duration or timing of vigabatrin treatment. To evaluate efficacy (n = 121/135), we used a 5-point scale (0-4) to compare seizure frequency at several time points. To evaluate visual impairment (n = 63), we reviewed serial ophthalmologic evaluations at baseline and during treatment for patients in whom they were clinically indicated. Mean age at treatment initiation was 1.8 years (range, 0.1-29.2 years). Treatment duration ranged from 0.7-101.0 months, with an estimated average daily dose of 79 mg/kg/day. Tuberous sclerosis complex was the commonest seizure etiology (83%). Partial-onset seizure, alone or with infantile spasms, was the commonest seizure type (84%). Seizure frequency decreased from 3.7 ± 0.6 S.D. at baseline to 1.8 ± 1.7 S.D. at 6 months (P0.001). Responses to vigabatrin did not differ by tuberous sclerosis complex or nontuberous sclerosis complex etiology, and were sustained for 5 years. Sixty-three patients (∼50% of all patients evaluated) underwent clinically indicated ophthalmologic assessments during the review period. In our clinical judgment, no cases of clinically relevant vigabatrin-associated visual impairment occurred. Vigabatrin was effective for refractory childhood partial-onset epilepsy, and was not associated with symptomatic vision loss.