Functional neurological signs in hypermobile Ehlers-Danlos syndrome and hypermobile spectrum disorders with suspected neuropathic pain.

BACKGROUND: The hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are connective tissue disorders characterized by generalized joint hypermobility, associated with chronic pain and several symptoms, such as fatigue, dysautonomia, as well as psychiatric co-morbidities. Clinical observations of unusual manifestations during systematic sensory testing raised the question of a possible co-existence with a functional neurological disorder (FND). Hence, this study aimed to assess the presence of positive functional neurological signs (FNS) in a cohort of patients with hEDS/HSD. METHODS: The clinical data of hEDS/HSD patients (N = 24) were retrospectively analyzed and compared to a prospectively recruited age-/sex-matched healthy control group (N = 22). Four motor- and three sensory-positive FNS were assessed. RESULTS: Twenty-two patients (92%) presented at least one motor or sensory FNS. Five patients (21%) presented only a single FNS, 14 presented between 2 and 4 FNS (58%), and 3 patients presented 5 or more FNS (12%). None of the healthy controls presented motor FNS, and only two presented a sensory FNS. CONCLUSIONS: The presence of FNS in hEDS/HSD deserves better clinical detection and formal diagnosis of FND to offer more adequate care in co-morbid situations. In fact, FND can severely interfere with rehabilitation efforts in hEDS/HSD, and FND-targeted physical therapy should perhaps be combined with EDS/HSD-specific approaches.

Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice.

Microglia, resident immune cells in the central nervous system, play a role in neuroinflammation and the development of neuropathic pain. We found that the stimulator of interferon genes (STING) is predominantly expressed in spinal microglia and upregulated after peripheral nerve injury. However, mechanical allodynia, as a marker of neuropathic pain following peripheral nerve injury, did not require microglial STING expression. In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice. STING activation in female mice leads to increase in proinflammatory cytokines that may counteract the analgesic effect of ADU-S100. Microglial STING expression and type I interferon-ß (IFN-ß) signaling were required for the analgesic effects of STING agonists in male mice. Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ß, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males.

Potassium channel modulation in macrophages sensitizes dorsal root ganglion neurons after nerve injury.

Macrophages and satellite glial cells are found between injured and uninjured neurons in the lumbar dorsal root ganglia (DRG). We explored the mechanism of neuro-immune and neuron-glia crosstalk leading to hyperexcitability of DRG neurons. After spared nerve injury (SNI), CX3CR1+ resident macrophages became activated, proliferated, and increased inward-rectifying potassium channel Kir 2.1 currents. Conditioned medium (CM) by macrophages, obtained from DRG of SNI mice, sensitized small DRG neurons from naïve mice. However, treatment with CM from GFAP+ glial cells did not affect neuronal excitability. When subjected to this macrophage-derived CM, DRG neurons had increased spontaneous activity, current-evoked responses and voltage-gated NaV 1.7 and NaV 1.8 currents. Silencing Kir 2.1 in macrophages after SNI prevented the induction of neuronal hyperexcitability from their CM. Blocking vesicular exocytosis or soluble tumor necrosis factor in CM or interfering with the downstream intracellular p38 pathway in neurons, also prevented neuronal hyperexcitability. Blocking protein trafficking in neurons reduced the effect of CM, suggesting that the hyperexcitable state resulted from changes in NaV channel trafficking. These results suggest that DRG macrophages, primed by peripheral nerve injury, contribute to neuron-glia crosstalk, NaV channel dysregulation and neuronal hyperexcitability implicated in the development of neuropathic pain.

Characterisation of GFAP-Expressing Glial Cells in the Dorsal Root Ganglion after Spared Nerve Injury.

Satellite glial cells (SGCs), enveloping primary sensory neurons' somas in the dorsal root ganglion (DRG), contribute to neuropathic pain upon nerve injury. Glial fibrillary acidic protein (GFAP) serves as an SGC activation marker, though its DRG satellite cell specificity is debated. We employed the hGFAP-CFP transgenic mouse line, designed for astrocyte studies, to explore its expression within the peripheral nervous system (PNS) after spared nerve injury (SNI). We used diverse immunostaining techniques, Western blot analysis, and electrophysiology to evaluate GFAP+ cell changes. Post-SNI, GFAP+ cell numbers increased without proliferation, and were found near injured ATF3+ neurons. GFAP+ FABP7+ SGCs increased, yet 75.5% of DRG GFAP+ cells lacked FABP7 expression. This suggests a significant subset of GFAP+ cells are non-myelinating Schwann cells (nmSC), indicated by their presence in the dorsal root but not in the ventral root which lacks unmyelinated fibres. Additionally, patch clamp recordings from GFAP+ FABP7-cells lacked SGC-specific Kir4.1 currents, instead displaying outward Kv currents expressing Kv1.1 and Kv1.6 channels specific to nmSCs. In conclusion, this study demonstrates increased GFAP expression in two DRG glial cell subpopulations post-SNI: GFAP+ FABP7+ SGCs and GFAP+ FABP7- nmSCs, shedding light on GFAP's specificity as an SGC marker after SNI.

Somatosensory profiling of patients undergoing alcohol withdrawal: Do neuropathic pain and sensory loss represent a problem?

INTRODUCTION: Chronic heavy alcohol use is known to cause neurological complications such as peripheral neuropathy. Concerning the pathophysiology, few sural nerve and skin biopsy studies showed that small fibers might be selectively vulnerable to degeneration in alcohol-related peripheral neuropathy. Pain has rarely been properly evaluated in this pathology. The present study aims at assessing pain intensity, potential neuropathic characteristics as well as the functionality of both small and large nerve sensitive fibers. METHODS: In this observational study, 27 consecutive adult patients, hospitalized for alcohol withdrawal and 13 healthy controls were recruited. All the participants underwent a quantitative sensory testing (QST) according to the standardized protocol of the German Research Network Neuropathic Pain, a neurological examination and filled standardized questionnaires assessing alcohol consumption and dependence as well as pain characteristics and psychological comorbidities. RESULTS: Nearly half of the patients (13/27) reported pain. Yet, pain intensity was weak, leading to a low interference with daily life, and its characteristics did not support a neuropathic component. A functional impairment of small nerve fibers was frequently described, with thermal hypoesthesia observed in 52% of patients. Patients with a higher alcohol consumption over the last 2 years showed a greater impairment of small fiber function. DISCUSSION: Patients report pain but it is however unlikely to be caused by peripheral neuropathy given the non-length-dependent distribution and the absence of neuropathic pain features. Chronic pain in AUD deserves to be better evaluated and managed as it represents an opportunity to improve long-term clinical outcomes, potentially participating to relapse prevention.

[Chronic pain : from symptom to disease]. / La douleur chronique : du symptôme à la maladie.

At last, chronic pain, with its consequences and impact for patients and society, is now considered as a disease in its own in the 11th revision of the international classification of diseases (ICD). We present here in the light of two clinical cases, why the diagnosis of chronic primary pain is useful and how to utilize these new codes. We hope to rapidly see the awaited impact on the healthcare system (from the patient care to insurance issues), as on research and teaching.

La douleur chronique avec ses conséquences et son impact pour les patients et la société est enfin considérée comme une maladie à part entière dans la 11e révision de la Classification internationale des maladies (CIM). Nous présentons ici, à l'aide de deux vignettes, l'utilité du diagnostic de douleur chronique primaire et la façon d'utiliser les nouveaux codes. Nous espérons que l'impact attendu soit rapidement visible tant sur le système de santé (de la prise en charge des patients aux questions assécurologiques), que sur la recherche et l'enseignement.

[Tapering of opioid-based pain treatment for chronic pain patients in an outpatient setting]. / Sevrage en ambulatoire d'un traitement par opiacés chez des patients souffrant de douleur chronique.

Caring for chronic pain patients under opioid therapy is challenging. Opioid treatments above 50 milligrams morphine equivalents (MME) per day are associated with an increased risk of morbidity and mortality. A tapering or a discontinuation should be discussed. Shared decision-making with individualized goals and motivational interviewing principles should be used. Tapering should be slow, with initial rate based on the duration of opioid use and with regular monitoring of patients. Inability to taper may require further reassessment of opioid dependence. Temporary increases in pain may occur at the start of tapering, but pain may improve or remain unchanged upon completion of tapering.

La prise en charge des patients souffrant de douleurs chroniques et traités par des opiacés pose souvent un défi aux cliniciens. Les traitements par des opiacés au-delà de 50 milligrammes d'équivalents de morphine (MME) par jour sont associés à des taux de morbidité et mortalité élevés. Une réduction ou un arrêt doivent être discutés. Cette approche doit se faire en collaboration avec le patient, avec des objectifs individualisés, utilisant des principes d'entretien motivationnel. La diminution doit être lente en tenant compte de la durée préalable du traitement et suivie de manière régulière. L'incapacité à réduire progressivement peut nécessiter l'évaluation d'une possible dépendance. Des augmentations temporaires de la douleur peuvent survenir au début de la réduction, mais la douleur peut rester inchangée ou même s'améliorer une fois la réduction terminée.

Association between chronic pain and physical activity in a Swiss population-based cohort: a cross-sectional study.

OBJECTIVE: To assess the bidirectional association between chronic pain and both subjectively and objectively measured physical activity (PA). DESIGN: Cross-sectional study. SETTING: Population-based sample in Lausanne, Switzerland, May 2014 to April 2017. PARTICIPANTS: Non-stratified, representative sample of the population of Lausanne (Switzerland) aged 35-75 years. Participants were excluded if they had missing data for the pain or the PA questionnaires, for accelerometry (defined as >20% of non-wear time or duration <7 days) or for covariates. PRIMARY OUTCOMES: Primary outcomes were association between chronic pain and previous, subjectively assessed PA (questionnaire), and subsequent, objectively assessed PA (accelerometry). Daily pain, pain duration, number of painful sites and pain intensity were assessed by questionnaire. PA was assessed by questionnaire 2 weeks prior and by accelerometry 2 weeks after completion of the pain questionnaire. PA was further categorised as sedentary (SED), light and moderate-to-vigorous PA. RESULTS: 2598 participants (52.9% women, mean age 60.5 years) had subjectively assessed PA. Multivariable analysis showed time spent in SED to be negatively associated with the number of painful sites: adjusted mean±SE 528±5, 522±7 and 502±7 min/day for 0, 1-2 and 3+ painful sites, respectively, p for trend <0.005. No other association was found between chronic pain and subjectively assessed PA categories. 2205 participants (52.8% women, mean age 61.7 years) had accelerometry-derived PA. No significant association between chronic pain and subsequent objectively assessed PA was found after multivariable analyses. CONCLUSION: In this Swiss population-based cohort, no consistent association was found between chronic pain and PA. Hence, in the general population, chronic pain does not significantly impact time spent in PA.

[Chronic cancer pain: pathophysiology and ICD-11 classification]. / Douleurs chroniques liées au cancer : physiopathologie et classification CIM-11.

Chronic cancer pain is one of the most common symptoms affecting oncology patients and cancer survivors. Epidemiological trends show that its recognition and management are increasingly important. The ICD-11 provides a better analysis of this problem based on the pathophysiological characteristics of cancer-related pain. This article proposes to review the mechanisms of cancer-related pain in relation to this classification.

La douleur chronique liée au cancer est l'un des symptômes les plus fréquents chez les patients oncologiques et survivants d'un cancer. L'évolution épidémiologique montre que sa reconnaissance et sa prise en charge représentent des enjeux grandissants. La CIM-11 (Classification internationale des maladies) permet une meilleure analyse de cette problématique en se basant sur les caractéristiques physiopathologiques de la douleur liée au cancer. Cet article propose de rappeler, à la lumière de cette classification, les mécanismes de la douleur associée à un cancer.

[Cancer pain therapy: beyond conventional pharmacological approaches]. / Traitement de la douleur cancéreuse : au-delà des approches médicamenteuses conventionnelles.

Pain management in oncology is evolving progressively thanks to integrative approaches. In accordance with the type of pain and patient specifics, treatment possibilities are thus multiplied by combining conventional pharmacology, interventional approaches, physical and psychological treatments as well as complementary medicines, in a holistic perspective. International Societies Guidelines and scientific literature lend their support to such treatment plans. This article covers a number of interventional treatments and complementary options that are available. Their relevance is all the more important in view of the necessity to limit secondary effects and long-term opioids, especially in cancer survivors.

La prise en charge de la douleur en oncologie s'enrichit progressivement grâce à une approche intégrative. Celle-ci permet d'élargir la palette des outils thérapeutiques du praticien en combinant, selon les caractéristiques de la douleur et les spécificités du patient, les approches conventionnelles et complémentaires dans une vision holistique du patient. Les recommandations des sociétés internationales et la littérature scientifique s'étayent dans cette direction. Cet article couvre une partie des thérapies interventionnelles et des options complémentaires possibles. Leur pertinence est d'autant plus grande dans l'optique de limiter les effets secondaires des traitements médicamenteux et les opioïdes au long cours, prioritairement chez les patients en rémission ou avec une maladie contrôlée.

Potassium Channels Kv1.3 and Kir2.1 But Not Kv1.5 Contribute to BV2 Cell Line and Primary Microglial Migration.

(1) Background: As membrane channels contribute to different cell functions, understanding the underlying mechanisms becomes extremely important. A large number of neuronal channels have been investigated, however, less studied are the channels expressed in the glia population, particularly in microglia. In the present study, we focused on the function of the Kv1.3, Kv1.5 and Kir2.1 potassium channels expressed in both BV2 cells and primary microglia cultures, which may impact the cellular migration process. (2) Methods: Using an immunocytochemical approach, we were able to show the presence of the investigated channels in BV2 microglial cells, record their currents using a patch clamp and their role in cell migration using the scratch assay. The migration of the primary microglial cells in culture was assessed using cell culture inserts. (3) Results: By blocking each potassium channel, we showed that Kv1.3 and Kir2.1 but not Kv1.5 are essential for BV2 cell migration. Further, primary microglial cultures were obtained from a line of transgenic CX3CR1-eGFP mice that express fluorescent labeled microglia. The mice were subjected to a spared nerve injury model of pain and we found that microglia motility in an 8 µm insert was reduced 2 days after spared nerve injury (SNI) compared with sham conditions. Additional investigations showed a further impact on cell motility by specifically blocking Kv1.3 and Kir2.1 but not Kv1.5; (4) Conclusions: Our study highlights the importance of the Kv1.3 and Kir2.1 but not Kv1.5 potassium channels on microglia migration both in BV2 and primary cell cultures.

Characterization of the Mercapturic Acid Pathway, an Important Phase II Biotransformation Route, in a Zebrafish Embryo Cell Line.

In view of the steadily increasing number of chemical compounds used in various products and applications, high-throughput toxicity screening techniques can help meeting the needs of 21st century risk assessment. Zebrafish (Danio rerio), especially its early life stages, are increasingly used in such screening efforts. In contrast, cell lines derived from this model organism have received less attention so far. A conceivable reason is the limited knowledge about their overall capacity to biotransform chemicals and the spectrum of expressed biotransformation pathways. One important biotransformation route is the mercapturic acid pathway, which protects organisms from harmful electrophilic compounds. The fully functional pathway involves a succession of several enzymatic reactions. To investigate the mercapturic acid pathway performance in the zebrafish embryonic cell line, PAC2, we analyzed the biotransformation products of the reactions comprising this pathway in the cells exposed to a nontoxic concentration of the reference substrate, 1-chloro-2,4-dinitrobenzene (CDNB). Additionally, we used targeted proteomics to measure the expression of cytosolic glutathione S-transferases (GSTs), the enzyme family catalyzing the first reaction in this pathway. Our results reveal that the PAC2 cell line expresses a fully functional mercapturic acid pathway. All but one of the intermediate CDNB biotransformation products were identified. The presence of the active mercapturic acid pathway in this cell line was further supported by the expression of a large palette of GST enzyme classes. Although the enzymes of the class alpha, one of the dominant GST classes in the zebrafish embryo, were not detected, this did not seem to affect the capacity of the PAC2 cells to biotransform CDNB. Our data provide an important contribution toward using zebrafish cell lines, specifically PAC2, for animal-free high- throughput screening in toxicology and chemical hazard assessment.

Prehospital Use of Ketamine in Mountain Rescue: A Survey of Emergency Physicians of a Single-Center Alpine Helicopter-Based Emergency Service.

INTRODUCTION: Although ketamine use in emergency medicine is widespread, studies investigating prehospital use are scarce. Our goal was to assess the self-reported modalities of ketamine use, knowledge of contraindications, and occurrence of adverse events associated with its use by physicians through a prospective online survey. METHODS: The survey was administered to physicians working for Air-Glaciers, a Swiss alpine helicopter-based emergency service, and was available between September 24 and November 23, 2018. We enrolled 39 participants (participation rate of 87%) in our study and collected data regarding their characteristics, methods of ketamine use, knowledge of contraindications, and encountered side effects linked to the administration of ketamine. We also included a clinical scenario to investigate an analgesic strategy. RESULTS: Ketamine was considered safe and judged irreplaceable by most physicians. The main reason for ketamine use was acute analgesia during painful procedures, such as manipulation of femur fractures. The doses of ketamine administered with or without fentanyl ranged from 0.2 to 0.7 mg·kg-1 intravenously. Most physicians reported using fentanyl and midazolam along with ketamine. The median dose of midazolam was 2 (interquartile range 1-2) mg for a 70-kg adult. Monitoring and oxygen administration were used infrequently. Hallucinations were the most common adverse events. Knowledge of ketamine contraindications was poor. CONCLUSIONS: Ketamine use was reported by mountain rescue physicians to be safe and useful for acute analgesia. Most physicians use fentanyl and midazolam along with ketamine. Adverse neuropsychiatric events were rare. Knowledge regarding contraindications to the administration of ketamine should be improved.

[Medical cannabinoids and their indications in chronic pain]. / Les cannabinoïdes et leurs indications en antalgie chronique.

Democratization of the cannabis consumption and its derivatives incite patients to ask ever more for medical cannabinoid prescriptions, especially in the context of chronic pain. Its use is only validated in certain limited cases, in particular spasticity linked to multiple sclerosis and refractory epilepsies. All other prescriptions require a special request to the OFSP. Moreover, cannabinoid intake may produce several dose-dependent side effects that require a close monitoring with a slow and gradual initiation of its dosage. In the absence of clear medical evidence, many other mechanisms of action need to be investigated with ongoing and future studies to clarify their indication.

La démocratisation de la consommation de cannabis et de ses dérivés pousse les patients à être de plus en plus demandeurs de prescriptions de cannabis à usage médical, d'autant plus dans le cadre de douleurs chroniques. Il convient alors de rappeler que son utilisation n'est validée que dans certains cas restreints, notamment dans la spasticité liée à la sclérose en plaques et les épilepsies réfractaires. Toute autre prescription nécessite une demande spéciale à l'Office fédéral de la santé publique. Par ailleurs, la prise de cannabinoïdes étant liée à nombre d'effets secondaires dose-dépendants, son administration nécessite une surveillance rapprochée et une initiation lente et progressive. En l'absence d'évidence médicale claire, il reste de nombreuses pistes encore à développer pour cibler leur indication.

Biotransformation Capacity of Zebrafish (Danio rerio) Early Life Stages: Functionality of the Mercapturic Acid Pathway.

Zebrafish (Danio rerio) early life stages offer a versatile model system to study the efficacy and safety of drugs or other chemicals with regard to human and environmental health. This is because, aside from the well-characterized genome of zebrafish and the availability of a broad range of experimental and computational research tools, they are exceptionally well suited for high-throughput approaches. Yet, one important pharmacokinetic aspect is thus far only poorly understood in zebrafish embryo and early larvae: their biotransformation capacity. Especially, biotransformation of electrophilic compounds is a critical pathway because they easily react with nucleophile molecules, such as DNA or proteins, potentially inducing adverse health effects. To combat such adverse effects, conjugation reactions with glutathione and further processing within the mercapturic acid pathway have evolved. We here explore the functionality of this pathway in zebrafish early life stages using a reference substrate (1-chloro-2,4-dinitrobenzene, CDNB). With this work, we show that zebrafish embryos can biotransform CDNB to the respective glutathione conjugate as early as 4 h postfertilization. At all examined life stages, the glutathione conjugate is further biotransformed to the last metabolite of the mercapturic acid pathway, the mercapturate, which is slowly excreted. Being able to biotransform electrophiles within the mercapturic acid pathway shows that zebrafish early life stages possess the potential to process xenobiotic compounds through glutathione conjugation and the formation of mercapturates. The presence of this chemical biotransformation and clearance route in zebrafish early life stages supports the application of this model in toxicology and chemical hazard assessment.