RESUMO
ABSTRACT: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic condition in which mutations in the type VII collagen gene ( COL7A1 ) lead to decreased expression of this anchoring protein of the skin, causing the loss of stability at the dermo-epidermal junction. Most patients with RDEB experience neuropathic pain and itch due to the development of a small fibre neuropathy, characterised by decreased intraepidermal innervation and thermal hypoaesthesia. To understand the physiopathology of this neuropathy, we used a mouse model of RDEB (Col7a1 flNeo/flNeo ) and performed a detailed characterisation of the somatosensory system. Col7a1 flNeo/flNeo mice showed a decrease in heat sensitivity, an increase in spontaneous scratching, and a significant decrease in intraepidermal nerve fibre density in the hindpaw; these changes were distal because there was no significant loss of unmyelinated or myelinated fibres in the nerve trunk. Of interest, we observed a decrease in axon diameter in both myelinated and unmyelinated fibres. This axonal damage was not associated with inflammation of the dorsal root ganglion or central projection targets at the time of assessment. These results suggest that in RDEB, there is a distal degeneration of axons produced by exclusive damage of small fibres in the epidermis, and in contrast with traumatic and acute neuropathies, it does not induce sustained neuroinflammation. Thus, this animal model emphasizes the importance of a healthy cutaneous environment for maintenance of epidermal innervation and faithfully replicates the pathology in humans, offering the opportunity to use this model in the development of treatments for pain for patients with RDEB.
Assuntos
Epidermólise Bolhosa Distrófica , Neuropatia de Pequenas Fibras , Animais , Colágeno Tipo VII/genética , Colágeno Tipo VII/metabolismo , Modelos Animais de Doenças , Epidermólise Bolhosa Distrófica/complicações , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Humanos , Camundongos , Mutação/genética , Pele/metabolismo , Neuropatia de Pequenas Fibras/metabolismoRESUMO
RESUMEN INTRODUCCIÓN: La enfermedad de Fabry (EF) es una enfermedad genética, causada por el déficit de la enzima alfa galactosidasa A (α-Gal A), lo que provoca la acumulación de glicoesfingolípidos en los tejidos. Sus manifestaciones clínicas son variables. Estudios en mujeres heterocigotas reportan la existencia de dolor neuropático como manifestación de neuropatía de fibra pequeña. OBJETIVO: Determinar la presencia de neuropatía de fibra pequeña en mujeres heterocigotas para la EF, mediante la prueba cuantitativa sensorial. MATERIALES Y MÉTODOS: Se evaluaron 33 mujeres heterocigotas para EF y 33 mujeres sanas, con características demográficas similares. A todas se les aplicó la prueba cuantitativa sensorial (Quantitative Sensory Testing por medio de la detección de umbrales de frío (Colà Detection Threshold), calor (Warm Detection Threshold), dolor inducido por calor (Heat-pain Detection Thresholds) y vibración (Vibratory Detection Threshold) en los miembros superior e inferior, utilizando un sistema asistido por computador versión IV (CASE IV, WR Medical Electronics Co., Stillwater, MN). Adicionalmente, al grupo de mujeres heterocigotas para EF, se le evaluó la percepción subjetiva de dolor neuropàtico mediante el cuestionario de síntomas sensitivos neuropáticos positivos (Positive Neuropathic Sensory Symptom). Los resultados de la prueba cuantitativa sensorial se compararon entre los grupos. También se estableció la correlación entre la prueba cuantitativa sensorial y los resultados del cuestionario de síntomas sensitivos neuropáticos positivos. RESULTADOS: Se encontró una diferencia estadísticamente significativa en las pruebas de vibración (p = 0,008), calor (p = 0,017) y dolor inducido por calor (p = 0,04) en el miembro inferior en las mujeres heterocigotas para EF, comparado con el grupo control. Se encontró una correlación inversa estadísticamente significativa entre la intensidad del dolor quemante y el dolor inducido por calor en el miembro inferior (p = 0,018, r = -0,48) y entre la intensidad del dolor al ser rozado o tocado y el dolor inducido por calor en el miembro inferior (p = 0,006, r = -0,49). CONCLUSIÓN: En las mujeres heterocigotas para EF, las pruebas objetivas para establecer la presencia de neuropatía de fibra pequeña son anormales en miembros inferiores y se correlacionan con los síntomas sensitivos.
SUMMARY INTRODUCTION: Fabry disease is a genetic condition caused by alpha-galactosidase A deficiency triggering glycosphingolipid accumulation in tissues. Clinical manifestations are variable. Studies in heterozigous females report the existence of neuropathic pain as manifestation of small fiber neuropathy. OBJECTIVE: To determine presence of small fiber neuropathy in heterozigous females with Fabry disease through Quantitative Sensory Testing (QST). MATERIALS AND METHODS: 33 heterozigous females with fabry disease and 33 healthy females with similar demographic characteristics were evaluated. QST was performed to every female evaluating Cold detection Threshold (CDT), Warm Detection Threshold (WDT), Heat-pain Detection Threshold (HPDT) and Vibratory Detection Threshold (VDT) in upper and lower limbs through Computer Assisted Sensory Examination software (CASE IV, WR Medical Electronics Co., Stillwater, MN). Subjective perception of neuropathic pain was measured through Positive Neuropathic Sensory Symptom questionnaire (P-NSS) in heterozigous females with Fabry disease. QST results were compared between groups. Correlations between QST and P-NSS were established. RESULTS: Statistically significant differences were observed in VDT (p= 0,008), WDT (p= 0,017) and HPDT (p= 0,04) in lower limbs of heterozigous females with Fabry disease compared with control group. Negative correlation was found among burning pain intensity and HPDT at lower limbs (p= 0,018, r= -0,48) and among pain intensity to light touch and HPDT in lower limbs (p= 0,006, r=-0,49). CONCLUSIONS: Objective tests to establish presence of small fiber neuropathy in heterozigous females with Fabry disease are abnormal at lower limbs and correlate with sensory symptoms.
Assuntos
Limiar Sensorial , Medição da Dor , Doença de Fabry , Terapia de Reposição de Enzimas , Neuropatia de Pequenas Fibras , NeuralgiaRESUMO
This perspective article focuses on dorsal root ganglia (DRG) as potential fibromyalgia main pain source. Humans possess 31 pairs of DRG lying along the spine. These ganglia have unique anatomical and physiological features. During development, DRG are extruded from the central nervous system and from the blood-brain barrier but remain surrounded by meningeal layers and by cerebrospinal fluid. DRG house the pain-transmitting small nerve fiber nuclei; each individual nucleus is tightly enveloped by metabolically active glial cells. DRG possess multiple inflammatory/pro-nociceptive molecules including ion channels, neuropeptides, lymphocytes, and macrophages. DRG neurons have pseudo-unipolar structure making them able to generate pain signals; additionally, they can sequester antigen-specific antibodies thus inducing immune-mediated hyperalgesia. In rodents, diverse physical and/or environmental stressors induce DRG phenotypic changes and hyperalgesia. Unfolding clinical evidence links DRG pathology to fibromyalgia and similar syndromes. Severe fibromyalgia is associated to particular DRG ion channel genotype. Myalgic encephalomyelitis patients with comorbid fibromyalgia have exercise-induced DRG pro-nociceptive molecules gene overexpression. Skin biopsy demonstrates small nerve fiber pathology in approximately half of fibromyalgia patients. A confocal microscopy study of fibromyalgia patients disclosed strong correlation between corneal denervation and small fiber neuropathy symptom burden. DRG may be fibromyalgia neural hub where different stressors can be transformed in neuropathic pain. Novel neuroimaging technology and postmortem inquest may better define DRG involvement in fibromyalgia and similar maladies. DRG pro-nociceptive molecules are attractive fibromyalgia therapeutic targets.
Assuntos
Fibromialgia , Neuralgia , Neuropatia de Pequenas Fibras , Fibromialgia/complicações , Gânglios Espinais , Humanos , HiperalgesiaRESUMO
ABSTRACT Objective: reveal experiences of cancer patients undergoing neurotoxic chemotherapy. Method: phenomenology-based, qualitative study, carried out with nine adult patients in antineoplastic neurotoxic treatment, interviewed in June and July 2018. The testimonies were analyzed using an empirical comprehensive model. Results: the following categories were delineated: nerves on edge: perception of limitations caused by neuropathic pain induced by chemotherapy; chemotherapy drains me of energy; the suffering of starting again; the suffering of enduring it; alone in a desert, I heard the cry of my silence; chemotherapy: an infusion of hope; and there is no suffering on earth that heaven cannot heal. Conclusion: the study presented various meanings of suffering that emerge from experiences with neurotoxic treatment and found that many dimensions of suffering interpenetrate, making it impossible to disassociate them.
RESUMEN Objetivo: revelar experiencias de pacientes con cáncer que se sometieron a terapia con quimioterápicos neurotóxicos. Método: Estudio cualitativo fundamentado en la fenomenología, realizado con nueve pacientes adultos tratados con antineoplásicos neurotóxicos, entrevistados entre junio y julio de 2018. Los testimonios fueron analizados según el modelo empírico-comprensivo. Resultados: se determinaron las categorías: Con los nervios a flor de piel -percepción de limitaciones provocadas por el dolor neuropático inducido por la quimioterapia-, La quimioterapia que acaba con mi energía; El sufrimiento de recomenzar; El sufrimiento de soportar; Solo, en un desierto, oí el grito de mi silencio; Quimioterapia -una infusión de esperanza-; y No hay sufrimiento en la tierra que el cielo no pueda curar. Conclusión: el estudio presentó varios significados de sufrimiento que surgen de la experiencia con el tratamiento neurotóxico, manifestando que muchas de las dimensiones del sufrimiento se entrecruzan, siendo imposible disociarlas.
RESUMO Objetivo: desvelar experiências de pacientes com câncer que se submeteram à terapia com quimioterápicos neurotóxicos. Método: estudo qualitativo, fundamentado na fenomenologia, realizado com nove pacientes adultos em tratamento com antineoplásicos neurotóxicos, entrevistados em junho e julho de 2018. Os depoimentos foram analisados segundo o modelo empírico-compreensivo. Resultados: foram reveladas as categorias: com os nervos à flor da pele - percepção das limitações provocadas pela dor neuropática induzida pela quimioterapia; a quimioterapia que acaba com a minha energia; o sofrimento de recomeçar; o sofrimento de suportar; sozinho, em um deserto, ouvi o grito do meu silêncio; quimioterapia - uma infusão de esperança; e, não há sofrimentos na terra que o céu não possa curar. Conclusão: o estudo apresentou vários significados de sofrimento que emergem da experiência com o tratamento neurotóxico, relatando que muitas das dimensões do sofrimento interpenetram-se, sendo impossível dissociá-las.