Effectiveness and safety of everolimus treatment in patients with tuberous sclerosis complex in real-world clinical practice.

BACKGROUND: The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC. RESULTS: The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment. CONCLUSIONS: Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.

Prevalence of Renal Angiomyolipomas and Spontaneous Bleeding Related to Angiomyolipomas in Tuberous Sclerosis Complex Patients in France and Norway-a Questionnaire Study.

OBJECTIVE: To estimate the prevalence of renal angiomyolipomas (AMLs) and AML-related bleedings among patients with tuberous sclerosis complex and to gather information about associated treatments. METHODS: A questionnaire survey was undertaken by the French Reference Centre for Tuberous Sclerosis Complex and distributed through university hospitals and the patients' association (2009-2011). The questionnaire was then distributed to patients registered by the Norwegian National Centre for Rare Epilepsy-Related Disorders (2013-2014). Risk of bleeding was estimated by Kaplan-Meier analysis. RESULTS: We included 357 patients (France, n = 257; Norway, n = 100); 189 (54%) reported having AMLs, 111 (32%) reported not having AMLs, and 50 (14%) reported not knowing whether they had AMLs. Twenty-five patients (France, n = 19; Norway, n = 6) reported that they have had bleeding. Age at first bleeding (known in 22 patients) was 27.6 ± 8.5 years. Fifteen patients (France, n = 11; Norway, n = 4) experienced first bleeding between 20 and 30 years. Bleeding-free survival was similar in France and Norway (P = .471). The bleeding-free survival rate at 72 years was 81% (95% confidence interval: 68-89) in the overall population and 66% (95% confidence interval: 43-82) in patients with AMLs. Bleeding treatment (known in 24 patients) consisted of conservative measures (n = 9), embolization (n = 8), nephrectomy (n = 4), embolization and nephrectomy (n = 2), or partial nephrectomy (n = 1). Fifteen French patients reported prophylactic treatment. In Norway, this information was known only in patients with renal bleeding and was reported in two. CONCLUSION: Fifty-four percent of the patients reported having AMLs and 7% (25/357) reported bleeding. Sixty-eight percent of first bleedings occurred between 20 and 30 years. Bleedings were managed conservatively in 38% of the patients and 62% needed active treatment.

Landau-Kleffner syndrome in Norway: long-term prognosis and experiences with the health services and educational systems.

We have conducted a retrospective study based on the medical records of 19 children with Landau-Kleffner syndrome and semistructured interviews of their parents. There was considerable heterogeneity in the children's symptoms. Eleven children were followed for more than 10 years (mean=14.4 years); four have normal language, four have moderate language problems, and three have no functional verbal language today. Late-onset language decline, short duration of the initial aphasic period, and marked fluctuations in speech abilities appeared to be associated with a positive outcome with respect to future language skills. The parents reported having to argue strongly with the health authorities and educational system to obtain a correct diagnosis and receive adequate help. Their main concern was not being taken seriously when they expressed their worries, and they expressed a strong wish for someone who could ensure that appropriate support measures were implemented and who could coordinate assistance.