Non-pharmacological therapeutic needs in people with Dravet syndrome.

Dravet syndrome (DS) is a genetic rare disease, which is usually caused by a mutation in the SCN1A gene. DS is characterised by a drug-resistant epilepsy and by cognitive and behavioural disturbances. Thus, DS patients require both pharmacological and non-pharmacological treatments. However, there is a paucity of studies on non-pharmacological therapies and their potential benefits. The main aim of this study was to describe the non-pharmacological therapy modalities received by DS patients and their socio-economic impact on the family. Thus, we designed an online survey addressed to caregivers of DS patients. Our results indicated that up to 91.9% of the surveyed patients required non-pharmacological therapies, which were mainly directed to treat cognitive, sensory and motor impairments. In many cases, the economic costs of these therapies were borne entirely by the families. Nevertheless, patients required a deployment of resources not only at a health care level, but also at an educational level.

A tool for Dravet syndrome-associated neuropsychiatric comorbidities evaluation (DANCE).

BACKGROUND: Dravet syndrome (DS) is a rare and severe form of epilepsy that begins in infancy, which is primarily caused by pathogenic variants in the SCN1A gene. DS is characterized by prolonged and frequent drug-resistant seizures, as well as developmental delays and behavioral problems. The identification of these comorbidities is based on clinical interview and relies on healthcare professionals (HCPs) experience. METHODS: We assembled a group of expert HCPs and caregivers to create a screening checklist for assessing DS-Associated Neuropsychiatric Comorbidities (DANC). The checklist includes questions related to cognitive and psychiatric domains, motor skills, and the impact of DS on families' daily lives. We administered the checklist to 24 caregivers of DS patients from Belgium, France, and Spain. After piloting, we obtained feedback from expert HCPs and caregivers to refine the checklist. RESULTS: DS patients showed a wide array of neuropsychiatric symptoms related to DS. The most common cognitive domains reported were attention difficulties and multitasking problems (18/24 caregivers), and impulsivity (17/24), while the most common psychiatric symptoms were temper tantrums (14/24), mood swings (13/24) and autism spectrum disorder (12/24). Balance and coordination problem have been reported in almost all patients with a statement of only 4/23 with complete mobility. Most patients were dependent on others for self-care and eating, and presented sleeping disturbances. Caregivers reported high levels of stress in the family unit, both between siblings and parents. Results show that the main concerns of parents were the behavior and the cognition of the person with DS. The quantitative feedback results showed good-to-very good scores on usefulness, ease of completion, clarity and comprehensiveness of the checklist. CONCLUSIONS: This pilot study suggests that the DANCE checklist could be a useful screening tool in daily practice for neuropsychiatric comorbidities facilitating their diagnosis and treatment, and empowering both caregivers and patients.

Compartmentalized primary cultures of dorsal root ganglion neurons to model peripheral pathophysiological conditions.

Neurosensory disorders such as pain and pruritus remain a major health problem greatly impacting the quality of life, and often increasing the risk of mortality. Current pre-clinical models to investigate dysfunction of sensory neurons have shown a limited clinical translation, in part, by failing to mimic the compartmentalized nociceptor anatomy that exhibits a central compartment containing the soma and a peripheral one harboring the axon endings with distinct molecular and cellular environmental composition. Thus, there is a need to validate compartmentalized preclinical neurosensory models for investigating the pathophysiology of peripheral sensory disorders and to test drug candidates. Here, we have addressed this issue and developed a microfluidic-based preclinical nociceptor model and validated it for investigating inflammatory and neuropathic peripheral disorders. We show that this model reproduces the peripheral sensitization and resolution produced by an inflammatory soup and by the chemotherapeutic drug paclitaxel. Furthermore, compartmentalized nociceptor primary cultures were amenable to co-culture with keratinocytes in the axonal compartment. Interaction of axonal endings with keratinocytes modulated neuronal responses, consistent with a crosstalk between both cell types. These findings pave the way towards translational pre-clinical sensory models for skin pathophysiological research and drug development.

Is TRPA1 Burning Down TRPV1 as Druggable Target for the Treatment of Chronic Pain?

Over the last decades, a great array of molecular mediators have been identified as potential targets for the treatment of chronic pain. Among these mediators, transient receptor potential (TRP) channel superfamily members have been thoroughly studied. Namely, the nonselective cationic channel, transient receptor potential ankyrin subtype 1 (TRPA1), has been described as a chemical nocisensor involved in noxious cold and mechanical sensation and as rivalling TRPV1, which traditionally has been considered as the most important TRP channel involved in nociceptive transduction. However, few TRPA1-related drugs have succeeded in clinical trials. In the present review, we attempt to discuss the latest data on the topic and future directions for pharmacological intervention.

The social and emotional burden of Dravet syndrome on Spanish caregivers.

Background: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy that presents with frequent and prolonged seizures resistant to treatment as well as cognitive problems such as behavioral and developmental delays. However, there is a lack of scientific literature on the impact of this condition on caregivers and the family unit. Objectives: To find out the social and emotional impact of DS on the family unit, to provide a comprehensive understanding of the disease's effects on both the family and caregivers. Materials and methods: A tailored online survey was administered to Spanish DS families, collecting data on the employment, financial, emotional, and social status of patients and caregivers. Results: A total of 112 Spanish caregivers participated in the study. The mean age of the 112 parents was 46.61 years, and 77.68 % of them were mothers. The majority of caregivers had to quit their jobs or reduce their working hours to take care of their child with DS, being the most of them mothers. Most of the caregivers felt that they were not well-informed by healthcare professionals (HCPs) and the Spanish National Health System (NHS). Despite access to resources, families often face financial strain and challenges in obtaining sufficient support, highlighting the need for enhanced social, economic, and psychological backing. In addition, both sentimental and social relationships were negatively impacted in the vast majority of respondents. Conclusions: The study advocates for policy reforms, integrated social services, community programs, and multidisciplinary efforts to improve the quality of life and social integration for those affected by DS.

Navigating Dravet syndrome in Spain: A cross-sectional study of diagnosis, management, and care coordination.

OBJECTIVES: Dravet syndrome (DS) is a rare form of refractory epilepsy that begins in the first year of life. Approximately 85% of patients have a mutation in the SCN1A gene, which encodes a voltage-gated sodium channel. The main objective of the present work was to assess the degree of knowledge of DS among Spanish primary care (PC) professionals, the communication flow between them and the pediatric neurologists (PNs), and the services available and resources offered to patients in Spain when searching for a diagnosis and adequate treatment. METHODS: Two anonymized online surveys on DS diagnosis and patient management in PC were conducted with Spanish PC pediatricians (PCPs) and caregivers of DS patients in Spain. RESULTS: Most PCPs are aware of genetic epilepsy but lack full knowledge of DS and patient advocacy groups (PAGs). Access to epilepsy treatments varies among regions, with many referrals to hospitals and pediatric neurologists. Diagnosis is often delayed, with misdiagnoses and frequent emergency room (ER) visits. Treatment involves multiple drugs, and sodium channel blockers are used, which are contraindicated in DS treatment. Improved training, resources, and communication are needed for early diagnosis. SIGNIFICANCE: To improve the care and treatment of DS patients in Spain, early diagnosis is required and, possibly, specific efforts aimed at identifying patients in adulthood, generating socio-sanitary structures that integrate social and health services to provide comprehensive care, taking into account the different features and comorbidities of the disease. PLAIN LANGUAGE SUMMARY: Dravet syndrome (DS) is a form of genetic epilepsy that starts within the first year of life. We present a study showing that, while family doctors are aware of genetic epilepsies, many don't have a complete understanding of DS. Unfortunately, getting the right diagnosis can take a long time, leading to unnecessary visits to the emergency room. Patients often need several medications, and sometimes they're given drugs that aren't recommended for DS. The takeaway is that training for doctors, more resources, and improved communication could help creating better healthcare systems and therefore give easier access to the right therapies.

TRPM8 contributes to sex dimorphism by promoting recovery of normal sensitivity in a mouse model of chronic migraine.

TRPA1 and TRPM8 are transient receptor potential channels expressed in trigeminal neurons that are related to pathophysiology in migraine models. Here we use a mouse model of nitroglycerine-induced chronic migraine that displays a sexually dimorphic phenotype, characterized by mechanical hypersensitivity that develops in males and females, and is persistent up to day 20 in female mice, but disappears by day 18 in male mice. TRPA1 is required for development of hypersensitivity in males and females, whereas TRPM8 contributes to the faster recovery from hypersensitivity in males. TRPM8-mediated antinociception effects required the presence of endogenous testosterone in males. Administration of exogenous testosterone to females and orchidectomized males led to recovery from hypersensitivity. Calcium imaging and electrophysiological recordings in in vitro systems confirmed testosterone activity on murine and human TRPM8, independent of androgen receptor expression. Our findings suggest a protective function of TRPM8 in shortening the time frame of hypersensitivity in a mouse model of migraine.