Everolimus for the treatment of refractory seizures associated with tuberous sclerosis complex (TSC): current perspectives

Iris E Overwater,1 André B Rietman,2 Agnies M van Eeghen,3 Marie Claire Y de Wit11Department of Pediatric Neurology and ENCORE Expertise Center, Erasmus MC, Rotterdam, the Netherlands; 2Department of Child and Adolescent Psychiatry/Psychology and ENCORE Expertise Center, Erasmus MC, Rotterdam, the Netherlands; 3Heeren Loo Care Group and ENCORE Expertise Center, Erasmus MC, Rotterdam, the NetherlandsAbstract: Up to 90% of patients with tuberous sclerosis complex (TSC) have epilepsy, and in over half of patients seizure control cannot be achieved by regular antiepileptic drugs. The underlying problem is mTOR hyperactivation due to loss of function of the TSC proteins. Treatment with everolimus, an mTOR inhibitor, has been shown to be of great benefit to TSC patients, both in reducing tumor growth and as a treatment for intractable epilepsy. Up to 40% of TSC patients with intractable epilepsy show a clinically relevant seizure response to everolimus. It has not yet fully lived up to its promise as a disease-modifying drug, however, as half of TSC patients with intractable epilepsy do not show a clinically relevant seizure frequency reduction. There is no evidence yet of a positive effect on the cognitive and neuropsychiatric deficits in TSC patients. In preclinical studies, mTOR inhibition can rescue abnormal neuronal migration and synapse formation that is caused by mTOR hyperactivation. These studies show a critical time window that suggests that mTOR inhibition may be most beneficial in young children. The trials done so far have not studied treatment in children under 2 years of age, although case series suggest that the safety profile is similar to that in older children. Further studies into the optimal time window, dosing schedules and possibly combination with other drugs may further improve the benefit of everolimus for TSC patients.Keywords: mTOR, epileptogenesis, epileps

Risk of Decline in Upper-Body Function and Symptoms Among Older Breast Cancer Patients

BACKGROUND: Decline in upper-body function and development of upper-body symptoms are adverse effects of breast cancer therapy and may affect functional independence, particularly among older survivors. The long-term risks and predictors are poorly understood. OBJECTIVE: To characterize the risk of decline in upper-body function and development of symptoms over 4 years of follow-up. DESIGN: We used a prospective cohort design. PARTICIPANTS: Six hundred and forty-four early stage breast cancer patients 65 years old or older at surgery enrolled in Rhode Island, North Carolina, Minnesota, and Los Angeles between 1996 and 1999. MEASUREMENTS: Upper-body function and symptoms were self-reported at baseline, 6, 15 months, and annually thereafter to 51 months after surgery. RESULTS: One half of the participants had a decline in upper-body function and one-quarter developed upper-body symptoms. Breast cancer patients were 5-fold more likely to have a decline in upper-body function over 4 years of follow-up than a similar cohort without breast cancer. Better baseline mental health protected against a decline in upper-body function (odds ratio [OR]=0.93, 95% confidence interval [CI] 0.88 to 0.97 for 8-point higher mental health index). Baseline obesity (OR for body mass index [BMI] ≥30 kg/m(2) vs <30 kg/m(2)=2.5, CI=1.6 to 4.0) and axillary node dissection (OR for axillary dissection vs not=3.9, CI=1.1 to 14) predicted the development of upper-body symptoms. CONCLUSIONS: Primary care physicians should address upper-body function and symptoms with older breast cancer patients, and inform them that these complications of breast cancer treatment are common

Cognitive and Electrophysiological Correlates of Working Memory Impairments in Neurofibromatosis Type 1.

From PubMed via Jisc Publications RouterHistory: accepted 2021-04-21Publication status: aheadofprintFunder: Manchester Biomedical Research Centre (GB); Grant(s): IS-BRC-1215-20007Funder: Newlife - The Charity for Disabled Children; Grant(s): SG/15-16/06Neurofibromatosis 1 (NF1) is a single gene disorder associated with working Memory (WM) impairments. The aim of this study was to investigate P300 event-related potential (ERP) associated with WM in NF1. Sixteen adolescents with NF1 were compared with controls on measures of WM and EEG was recorded during a WM nback task. The NF1 group showed poorer performance on measures of WM as compared to the control group. No group differences were observed in P300 amplitude at Pz, but P300 latency was shorter in the NF1 group. Topographic analyses of P300 amplitude showed group differences indicating neural processing differences in the NF1 group relative to controls, which possibly contribute to the cognitive deficits seen in this population

Interpreting joint moments and powers in gait

Gait analysis is becoming an increasingly important tool to provide a quantitative description of a patient's gait deviations. It is not only used to diagnose walking disorders but also for treatment selection and evaluation. While spatiotemporal, kinematic, and EMG parameters are commonly used to describe movement and muscle activity, kinetic measures are less often evaluated, even though they give insight into the moments and powers that drive human walking. As such, kinetic parameters are able to connect abnormal movement to underlying muscle malfunction and bony malalignment. This chapter focuses on the role of joint moments and powers of the lower extremities in clinical gait analysis. After a brief introduction of normal kinetic patterns, the clinical interpretation of abnormal joint moments and powers is described. Next, typical deviations in lower limb kinetics are illustrated for several patient populations, including stroke, cerebral palsy, Duchenne muscular dystrophy, anterior cruciate ligament (ACL) injury, and osteoarthritis (OA), and for patients walking with prostheses or orthotics. This section also illustrates the clinical usefulness of specific kinetic parameters in these patient populations, including their sensitivity to treatment and ability to predict treatment outcome. The chapter illustrates that the role of kinetics within clinical gait analysis deserves more attention, and potential applications should be further pursued