Everolimus as a therapeutic option in refractory epilepsy in children with tuberous sclerosis: a systematic review.

BACKGROUND: Tuberous sclerosis (TS) is a multisystem genetic disease in which epilepsy is a frequent manifestation and is often difficult to control. Everolimus is a drug with proven efficacy in the treatment of other conditions related to TS, and some evidence suggests that its use benefits the treatment of refractory epilepsy in these patients. OBJECTIVE: To evaluate the efficacy of everolimus in controlling refractory epilepsy in children with TS. METHODS: A literature review was conducted in the Pubmed, BVS, and Medline databases, using the descriptors Tuberous sclerosis, Children, Epilepsy, and Everolimus. Original clinical trials and prospective studies published in Portuguese or English in the last decade that evaluated the use of everolimus as an adjuvant therapy in the control of refractory epilepsy in pediatric patients with TS were included. RESULTS: Our search screened 246 articles from electronic databases, 6 of which were chosen for review. Despite the methodological variations between the studies, most patients benefited from the use of everolimus to control refractory epilepsy, with response rates ranging from 28.6 to 100%. Adverse effects were present in all studies leading to dropouts of some patients; however, the majority were of low severity. CONCLUSION: The selected studies suggest a beneficial effect of everolimus in the treatment of refractory epilepsy in children with TS, despite the adverse effects observed. Further studies involving a larger sample in double-blind controlled clinical trials should be performed to provide more information and statistical credibility.

ANTECEDENTES: A esclerose tuberosa (ET) é uma doença genética multissistêmica na qual a epilepsia é a manifestação neurológica mais frequente, sendo muitas vezes de difícil controle. O everolimo é uma droga com eficácia comprovada no tratamento de outras condições relacionadas à ET, e indícios sugerem benefícios de seu uso também no controle da epilepsia refratária nesses pacientes. OBJETIVO: Avaliar a eficácia do everolimo no controle da epilepsia refratária em crianças com ET. MéTODOS: Revisão de literatura nas bases de dados Pubmed, BVS e Medline, utilizando os descritores Tuberous sclerosis, Children, Epilepsy e Everolimus. Incluíram-se ensaios clínicos originais e estudos prospectivos publicados em português ou inglês na última década e que avaliassem o uso do everolimo como terapia adjuvante no controle da epilepsia refratária em pacientes pediátricos com ET. RESULTADOS: Nossa busca rastreou 246 artigos nas bases de dados, dos quais 6 foram escolhidos para a revisão. Apesar das variações metodológicas entre os estudos, a maioria dos pacientes tiveram benefício no uso do everolimo para controle da epilepsia refratária, com taxas de resposta variando entre 28.6 e 100%. Os efeitos adversos estiveram presentes em todos os estudos, levando à desistência de alguns pacientes, contudo a maioria foi de baixa gravidade. CONCLUSãO: Os estudos selecionados sugerem efeito benéfico do everolimo no tratamento da epilepsia refratária em crianças com ET, apesar dos efeitos adversos observados. Novos estudos envolvendo uma amostra maior em ensaios clínicos controlados duplo-cegos devem ser realizados para fornecer mais informações e credibilidade estatística.

Use of cannabidiol in the treatment of epilepsy: Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex.

OBJECTIVE: The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures. METHODS: This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses. RESULTS: Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%. CONCLUSIONS: This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.

Everolimus as a possible prenatal treatment of in utero diagnosed subependymal lesions in tuberous sclerosis complex: a case report.

INTRODUCTION: The association between cardiac rhabdomyoma and intraventricular tumors and/or subcortical nodules is characteristic of tuberous sclerosis complex (TSC). Patients with TSC may have refractory seizures, autistic behavior, and cognitive decline. CASE REPORT: The patient received the fetal diagnosis of TSC at the age of 19 weeks of gestations, where presented at prenatal ultrasound cardiac and brain tumors. Fetal MRI showed a lesion in the right and left lateral ventricles near the foramen of Monro associated with subependymal lesions along the entire ependyma of the lateral ventricles and several subcortical tubercles, and the fetal Doppler echocardiogram revealed three cardiac lesions. The fetus underwent intrauterine treatment with everolimus and presented regression and subsequent stabilization of the cardiac and brain lesions; additionally, the patient did not develop seizures or autism and presented good neuropsychomotor development. CONCLUSION: It is the first evidence that mTOR inhibitors may help to prevent neurological complications associated with TSC.

The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures.

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

Everolimus for severe arrhythmias in tuberous sclerosis complex related cardiac rhabdomyomas.

Intracardiac rhabdomyoma is the most common primary cardiac tumor in children. Most cases are associated with tuberous sclerosis complex (TSC). Most of them are asymptomatic in the neonate and do not require treatment. However, some develop cardiovascular symptoms such as arrhythmias, heart failure, and ventricular inflow/outflow tract obstruction in the neonatal period with early death. Many of these tumors are not candidates for surgical resection and medical management is limited. Treatment with mammalian target of rapamycin (mTOR) inhibitor is currently approved for the management of central nervous tumors and angiomyolipoma in TSC. Two patients with malignant arrhythmias related to nonsurgical multiple rhabdomyomas associated with TSC who were successfully treated with an mTOR inhibitor were described. Everolimus therapy showed significant regression of rhabdomyomas with rapid improvement of arrhythmias and heart failure prior to tumor shrinkage.

Improvement in Renal Cystic Disease of Tuberous Sclerosis Complex After Treatment with Mammalian Target of Rapamycin Inhibitor.

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.

Safety of Everolimus in Patients Younger than 3 Years of Age: Results from EXIST-1, a Randomized, Controlled Clinical Trial.

OBJECTIVES: To assess the long-term safety of everolimus in young children with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA). STUDY DESIGN: EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (EXIST-1) was a multicenter, randomized, double-blind phase 3 study with an open-label extension evaluating the efficacy and tolerability of everolimus in patients with TSC-associated SEGA. Everolimus was initiated at 4.5 mg/m(2)/day and titrated to blood trough levels of 5-15 ng/mL. Post hoc analysis of safety data (adverse events [AEs]) was performed in a subgroup of patients aged <3 years at everolimus initiation. RESULTS: Eighteen patients (median age 1.82 years) were included; 16 were still receiving everolimus at the analysis cut-off date of January 11, 2013. Median everolimus exposure was 31.1 months (range, 11.5-39 months). One patient discontinued treatment because of AEs (ie, Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection). AEs were reported in all patients, but events were mostly grade 1/2 in severity; 12 patients (66.7%) experienced grade 3 events, and 2 patients (11.1%) reported grade 4 events. The most common AEs were stomatitis, cough, pharyngitis, and pyrexia; no new safety issues were identified in this population. Serious AEs were reported in 50% of patients; these were suspected to be medication related in 4 patients (22.2%). CONCLUSIONS: Everolimus appears to be a safe therapeutic option for patients aged <3 years with TSC-associated SEGA. The small sample size in this subpopulation limits interpretation of the results; additional studies in the pediatric population are needed and are underway. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00789828.

Unilateral eyelid angiofibroma with complete blepharoptosis as the presenting sign of tuberous sclerosis.

Tuberous sclerosis is a multisystem autosomal-dominant disease characterized by hamartomatous growths in the brain, skin, kidneys, eyes, and heart, but it may affect almost any organ. Retinal hamartomas are 1 of the major diagnostic criteria for tuberous sclerosis and occur in approximately 50% of patients. Nonretinal findings include angiofibromas of the eyelid, strabismus, and pseudo-colobomas of the lens and iris. We report a case of a newborn with congenital eyelid angiofibroma mimicking complete congenital blepharoptosis that was revealed by central nervous system imaging to be part of the tuberous sclerosis complex.

[Familial clinical manifestation in patients with neuromesoectodermic defect]. / Manifestação clínica familiar em pacientes com defeito neuromesoectodérmico.

We relate the association of two distinct cases of neuromesoectodermosis occurred in a family, one manifested as neurofibromatosis type 1 and the other as tuberous sclerosis. The two anomalies at cousins, caused by different genetic mutations and transmitted by autosomal dominant inheritance, suggest a possible relation between them. Also, clinical manifestations are described, their consequences and the diagnostic criteria of both illnesses, emphasizing the importance of the precocious diagnosis.

Manifestação clínica familiar em pacientes com defeito neuromesoectodérmico / Familial clinical manifestation in patients with neuromesoectodermic defect

Relatamos a associação de dois casos distintos de neuromesoectodermose ocorridos em uma mesma família, um manifestado através da neurofibromatose tipo 1 e outro através da esclerose tuberosa. O encontro de dois distúrbios entre primos de primeiro grau, ocasionados por diferentes mutações genéticas e transmitidos por herança autossômica dominante, sugere uma possível correlação entre eles. Também são descritas as manifestações clínicas, suas conseqüências e os critérios diagnósticos das duas doenças, visando ressaltar a importância do diagnóstico precoce.

We relate the association of two distinct cases of neuromesoectodermosis occurred in a family, one manifested as neurofibromatosis type 1 and the other as tuberous sclerosis. The two anomalies at cousins, caused by different genetic mutations and transmitted by autosomal dominant inheritance, suggest a possible relation between them. Also, clinical manifestations are described, their consequences and the diagnostic criteria of both illnesses, emphatizing the importance of the precocious diagnosis.

Vigabarina no tratamento da epilepsia de difícil controle em pacientes com síndrome de West e esclerose tuberosa / Vigabatrin in the treatment of epilepsy in patients with West syndrome and tuberous sclerosis

OBJETIVO: é relatar a eficácia da vigabatrina no controle das convulsões, bem como as alterações eletrencefalográficas em crianças com esclerose tuberosa e síndrome de West. MÉTODO: Estudo retrospectivo, com dados clínicos, de neuroimagem e de eletrencefalograma. RESULTADOS: Sete pacientes foram acompanhados e o tempo médio de seguimento foi 10 anos. Dos pacientes, quatro eram do sexo feminino e todos eram de cor branca. A média de idade de início das convulsões foi 3,4 meses. Todos usaram associações de vários anticonvulsivantes; no mínimo duas drogas por esquema terapêutico, e cada paciente utilizou pelo menos dois esquemas diferentes. O uso de vigabatrina como monoterapia ou em associação iniciou em média aos 7 anos de idade ou 4 anos após início dos sintomas. Cinco dos sete pacientes que iniciaram vigabatrina ficaram sem crise. CONCLUSÃO: Vigabatrina mostrou-se eficaz no controle das crises, levando a um melhor prognóstico

[Vigabatrin in the treatment of epilepsy in patients with West syndrome and tuberous sclerosis]. / Vigabatrina no tratamento da epilepsia de difícil controle em pacientes com síndrome de West e esclerose tuberosa.

PURPOSE: To report the efficacy of vigabatrin in seizures control, as well as the electroencephalographic abnormalities in children with tuberous sclerosis and West syndrome. METHOD: Retrospective study, with clinical, neuroimaging, and electroencephalographic data. RESULTS: Seven patients were followed, and the median time of follow-up was 10 years. Four of them were females and all were white. The mean age of seizures onset was 3.4 months. All patients used antiepileptic drugs associations, at least 2 drugs each therapeutic scheme, each one of the patients have used at least two different schemes. Vigabatrin as monotherapy or adjuvant was started in a mean age of seven years or 4 years after the onset of symptoms. Five from seven patients on vigabatrin became seizure free. CONCLUSION: Vigabatrin was efficient in seizures control, leading to a better prognosis.