1.
Changing Landscape of Dravet Syndrome Management: An Overview.
Samanta, D
Neuropediatrics. 2020;(2):135-145
Abstract
Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is a severe developmental and epileptic encephalopathy caused by loss-of-function mutations in one copy of SCN1A (haploinsufficiency), located on chromosome 2q24, with decreased function of Nav1.1 sodium channels in GABAergic inhibitory interneurons. Pharmacoresistant seizures in DS start in the infancy in the form of hemiclonic febrile status epilepticus. Later, other intractable seizure types develop including myoclonic seizures. Early normal development in infancy evolves into moderate to severe intellectual impairment, motor impairment, behavioral abnormalities, and later a characteristic crouching gait. Clobazam, valproate, levetiracetam, topiramate, zonisamide, ketogenic diet, and vagus nerve stimulation had been shown to be effective, but even with polytherapy, only 10% of patients get adequate seizure control. The author provides a narrative review of the current treatment paradigm as well as recent advances in the management of DS based on a comprehensive literature review (MEDLINE using PubMed and OvidSP vendors with appropriate keywords to incorporate recent evidence), personal practice, and experience. In recent years, the treatment paradigm of DS is changing with the approval of pharmaceutical-grade cannabidiol oil and stiripentol. Another novel antiepileptic drug (AED), fenfluramine, had also shown excellent efficacy in phase 3 studies of DS. However, these AEDs primarily control seizures without addressing the underlying pathogenesis and other important common comorbidities such as cognitive impairment, autistic behavior, neuropsychiatric abnormalities, and motor impairment including crouching gait. Several agents targeted for DS are in the developmental stage: TAK935, lorcaserin, clemizole, huperzine analog, ataluren, selective sodium channel modulators and activators, antisense oligonucleotide therapy, and adenoviral vector therapy. As DS is associated with a high risk of sudden unexpected death in epilepsy, seizure detection devices can be used in this population for testing and clinical validation of these devices.
2.
Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies.
Sachdev, M, Miller, WC, Ryan, T, Jollis, JG
American heart journal. 2002;(6):1065-73
Abstract
BACKGROUND Fenfluramine-derivative diet pills were withdrawn from the market in 1997 because of an association with valvular regurgitation, but subsequent estimates of the prevalence of this condition have varied widely. We systematically reviewed evidence regarding the prevalence of valvular disease after fenfluramine exposure. METHODS We searched multiple databases with multiple search terms. Conference proceedings from 1997 onward were searched by index. Authors of eligible studies were contacted to identify unpublished works. Selection criteria were liberally determined. Ten of the identified 11 articles met these criteria. Reviewers assessed the studies' methodologic quality by use of a standard form to evaluate selection, attrition, performance, and detection bias. The studies were analyzed in 2 groups on the basis of length of exposure (<90 days or >90 days). The Mantel-Haenszel method was used to summarize data. Quantitative and qualitative tests for heterogeneity were performed. Tests for publication bias were also done. RESULTS Tests for heterogeneity were nonsignificant after removing 1 outlier trial. The pooled prevalence of valvular regurgitation meeting Food and Drug Administration criteria (at least mild aortic regurgitation or at least moderate mitral regurgitation) among patients treated for >90 days was 12.0% compared with 5.9% for the unexposed group (prevalence odds ratio 2.2, 95% CI 1.7-2.7). The combined analyses also identified a small but statistically significant increase in mitral regurgitation not previously identified by individual studies (exposed 3.5%, unexposed 1.8%, prevalence odds ratio 1.6, 95% CI 1.05-2.3). Among patients exposed for <90 days, a trend toward more regurgitation was not statistically significant by either combined Food and Drug Administration criteria (exposed 6.8%, unexposed 5.8%, prevalence odds ratio 1.4, 95% CI 0.8-2.4) or by individual valve. CONCLUSIONS These data indicate that fenfluramine-associated valvular regurgitation is less common than initially reported, but still present in 1 of 8 patients treated for >90 days.
3.
Anorectic drugs and pulmonary hypertension from the bedside to the bench.
Michelakis, ED, Weir, EK
The American journal of the medical sciences. 2001;(4):292-9
Abstract
Anorectic drugs have been used for more than 30 years as an aid in weight reduction for obese persons. The use of aminorex, an amphetamine analog that increases norepinephrine levels in the central nervous system, led to an epidemic of primary pulmonary hypertension (PPH) in Europe in the late 1960s and early 1970s. The use of fenfluramine and later dexfenfluramine [drugs that inhibit 5-hydroxytryptamine (5-HT) release and reuptake and increases 5-HT and thus 5-HT secretion in the brain] was associated with a second epidemic of PPH. All of these drugs have been voluntarily withdrawn from the market. The pathogenesis of PPH in patients treated with these agents is uncertain, but recent evidence suggests that potassium channel abnormalities and vasoactive and proliferative properties of 5-HT may play a role. There is increasing experimental evidence suggesting that aminorex, fenfluramine and dexfenfluramine inhibit 4-aminopyridine-sensitive currents in potassium channels resulting in vasoconstriction in pulmonary resistance vessels and perhaps smooth muscle cell proliferation. 5-HT causes pulmonary artery vasoconstriction and smooth muscle cell proliferation. Its levels are known to be high in those with fenfluramine-induced PPH. However, a firm cause-and-effect relationship has not yet been established. One potentially beneficial effect of the epidemics of anorectic-related PPH is that it may have provided important insights into the causes of PPH unrelated to anorectic agents.