[Sickness and quality of life in adults with Duchenne muscular dystrophy].

Duchenne muscular dystrophy (DMD) is a rare inherited disease. Most patients are unable to move independently and rely on respiratory support before the age of thirty. They suffer from contractures, cardiomyopathy, and osteoporosis. Many adults with DMD experience severe pains daily and have a limited social life, compared to healthy peers. Adult patients with DMD are satisfied with life, see themselves as happy and independent. Care providers rate quality of life lower than the patients do themselves. This review aims to help clinicians be aware of this bias when considering invasive and life-prolonging procedures.

Clinical trials in pediatric ALS: a TRICALS feasibility study.

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

[Problematic use of capsaicin patches as pain relief during labour].

Some pregnant women use capsaicin patches placed on the lower back as pain relief during labour. The effect of prescription capsaicin patches for treatment of neuropathic pain is pharmacologically documented. There are no studies on the effect of capsaicin patches on labour pain. In this case report, capsaicin patches placed on the lower back prevented epidural analgesia during labour and spinal anaesthesia for suturing of perineal rupture due to oedema and erythema of the skin. Due to lack of evidence, neuraxial anaesthesia after the use of capsaicin patches on the lower back are contraindicated.

Prediction of survival in amyotrophic lateral sclerosis: a nationwide, Danish cohort study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials. OBJECTIVE: This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort. METHODS: The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS') was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS' was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis. RESULTS AND CONCLUSIONS: Both ΔFS' and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS', is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.

[Neurological symptoms in pregnant women without any diagnosed neurological disease].

The frequency of neurological symptoms in pregnant women without previously diagnosed or newly diagnosed chronic neurological disease is low (2%) but important. Diagnosis of diseases in pregnancy can be difficult due to the physiological changes during pregnancy. This review summarises the symptoms of pregnant women with either unique or especially pregnancy-related neurological disease. If these conditions are not diagnosed and treated properly, this may result in increased morbidity and higher mortality rates in these otherwise healthy women and their children.

Heterozygous mutations in GTP-cyclohydrolase-1 reduce BH4 biosynthesis but not pain sensitivity.

Human studies have demonstrated a correlation between noncoding polymorphisms of "the pain protective" haplotype in the GCH1 gene that encodes for GTP cyclohydrolase I (GTPCH1)-which leads to reduced tetrahydrobiopterin (BH4) production in cell systems-and a diminished perception of experimental and clinical pain. Here, we investigate whether heterozygous mutations in the GCH1 gene which lead to a profound BH4 reduction in patients with dopa-responsive dystonia (DRD) have any effect on pain sensitivity. The study includes an investigation of GCH1-associated biomarkers and pain sensitivity in a cohort of 22 patients with DRD and 36 controls. The patients with DRD had, when compared with controls, significantly reduced levels of BH4, neopterin, biopterin, and GTPCH1 in their urine, blood, or cytokine-stimulated fibroblasts, but their pain response with respect to non-painful stimulation, (acute) stimulus-evoked pain, or pain response after capsaicin-induced sensitization was not significantly different. A family-specific cohort of 11 patients with DRD and 11 controls were included in this study. The patients with DRD were heterozygous for the pain protective haplotype in cis with the GCH1 disease-causing mutation, c.899T>C. No effect on pain perception was observed for this combined haplotype. In conclusion, a reduced concentration of BH4 is not sufficient to alter ongoing pain sensitivity or evoked pain responses.

Epidermal nerve fiber length density estimation using global spatial sampling in healthy subjects and neuropathy patients.

Assessment of intraepidermal nerve fiber density (IENFD) has become a useful tool for the investigation of patients with suspected small-fiber neuropathy (SFN). Here, we estimate epidermal nerve fiber lengths in 12 patients with SFN and 36 healthy controls using global spatial sampling and compare the lengths with IENFD and axonal swelling ratios. Skin biopsies were analyzed on 50-µm-thick free-floating sections immunostained for the neuronal cytoplasmic marker PGP 9.5. Mean IENFD in SFN patients was 2.22 ± 1.63 mm versus 7.51 ± 2.17 mm in controls; mean length density was 112 ± 82.6 mm in SFN patients versus 565 ± 240 mm in controls (p < 0.001 for both). The correlation between the nerve fiber length and the IENFD was r = 0.16 for healthy subjects and r = 0.39 for patients, suggesting that these variables provide different quantitative information. There were significant differences in axonal swelling ratios between healthy subjects and patients, that is, per IENFD and per nerve fiber length. Together, these results suggest that, although length estimation requires more time and additional equipment, it is as effective as IENFD in differentiating SFN patients from healthy subjects. Estimating nerve fiber length may increase mechanistic understanding beyond IENFD estimation and improve efficiency in diagnosing SFN.

Early diagnosis of peripheral nervous system involvement in Fabry disease and treatment of neuropathic pain: the report of an expert panel.

BACKGROUND: Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen. METHODS: An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain. RESULTS: We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e.g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients. CONCLUSIONS: Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.

Awareness of Fabry disease among rheumatologists--current status and perspectives.

Fabry disease is an inherited disorder of lipid metabolism caused by deficient activity of the lysosomal enzyme α-galactosidase A. Burning peripheral pain with triggered crises of excruciating pain and gastrointestinal dysmotility point to Fabry small fiber neuropathy; angiokeratoma, corneal deposits, and hypohidrosis are other common early manifestations. Progressive dysfunction of the kidneys, heart, and/or brain develops in adulthood. Diagnosis is often delayed which is of great concern, as therapeutic outcomes with enzyme replacement therapy are generally more favorable in early stages of Fabry disease. Results of a survey among 360 rheumatologists and pediatricians clinically managing patients with rheumatologic conditions demonstrate that Fabry manifestations are generally poorly recognized and that awareness of appropriate diagnostic tests is low. To raise awareness about the musculoskeletal aspects of Fabry disease among rheumatologists, the International Musculoskeletal Working Group on Lysosomal Storage Disorders has reviewed the current knowledge. We propose a diagnostic algorithm with burning pain in hands and feet and triggered attacks of excruciating pain as keystones. Evidence of autonomic nerve dysfunction and simple temperature sensitivity testing can provide important diagnostic clues. Multi-systemic involvement should be explored by taking a detailed medical history, including family history, and performing a thorough physical examination and appropriate laboratory workup. Confirmatory tests include the α-Gal A enzyme activity assay (males) and genetic testing (females). We propose that medical specialists use our diagnostic algorithm when evaluating individuals with peripheral neuropathic pain.

[Pain and genetics]. / Smerter og genetik.

Genetic factors can explain a significant amount of the variance in the perception of pain, sensitivity to painful stimuli and development of chronic pain. Twin studies, association studies and linkage analysis have located DNA sequences and SNPs that may be involved in the regulation of pain. Individual genes have an influence on the reaction to experimental painful stimuli, and certain genes are probably involved in painful clinical conditions. Optimal pain control and counselling of patients may be achievable through research into the genetic mechanisms involved in pain.