Neuropathic Itch Research Articles

Neuroimmune communication regulating pruritus in atopic dermatitis

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only induces itch but further aggravates/perpetuates inflammation, skin barrier disruption, and pruritus as well. Thus, targeted therapies for neuroimmune circuits as well as pathway inhibitors (eg, kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or in topical form. Understanding neuroimmune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction, and pruritus.

Characterisation of the pathophysiology of neuropathy and sensory dysfunction in a mouse model of recessive dystrophic epidermolysis bullosa.

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.

Dorsal root ganglion neurostimulation: a target for treatment for intractable neuropathic itch?

Intractable itch is a severe, relentless, and debilitating chronic itch that is not curable by any known means. Ordinary medical measures usually are not helpful for these patients who often suffer from neural hypersensitization. These patients have often exhausted numerous treatments and still suffer from intractable pruritus. As chronic pain and chronic pruritus share many similarities, the use of medical treatments that reduce neural sensitization in intractable chronic pain may similarly help intractable chronic itch. One of the fastest growing treatments for chronic pain management is spinal neuromodulation. To our knowledge, the use of these modalities has not been applied to chronic intractable itch. The dorsal root ganglion (DRG) has recently become a target for neuromodulation. Through this review, we evaluate the rationale behind the use of the DRG electrical stimulation modality for chronic pain and assess its potential utility for patients with chronic, intractable pruritus. Given the similarities between chronic pain and chronic pruritus and the success of DRG neurostimulation in chronic pain, it may prove worthwhile to explore the efficacy of the modality for specific conditions presenting with chronic intractable pruritus.

26622 The impact of neuropathic itch on patients’ quality of life

The negative impact of chronic itch on patients’ quality of life (QoL) has been well established in literature, with similar burden of disease and effects on self-esteem as the more well-studied chronic pain. However, most studies to date have focused on chronic inflammatory pruritic conditions, like atopic dermatitis and psoriasis. Neuropathic pruritus, a subset of pruritic conditions including notalgia paresthetica, brachioradial pruritus, scalp dysthesia, postherpetic neuralgia, and itch secondary to spinal cord compression/injury, is unique from other chronically itchy conditions as it is less frequently associated with visible primary dermatologic findings but can be just as bothersome and debilitating.

Association of Neuropathic Itch With Patients’ Quality of Life

Association of Neuropathic Itch With Patients’ Quality of Life

Neuropathic Itch: Routes to Clinical Diagnosis.

Neuropathic itch occurs due to damage of neurons of the peripheral or central nervous system. Several entities, including metabolic, neurodegenerative, orthopedic, infectious, autoimmune, malignant, and iatrogenic conditions, may affect the somatosensory system and induce neuropathic itch. Due to the complex nature of neuropathic itch, particularly concerning its clinical presentation and possible etiological factors, diagnostic work-up of this condition is challenging. A detailed medical history, especially in regard to the itch, and a comprehensive physical examination are relevant to detect characteristic signs and symptoms of neuropathic itch and to rule out other possible causes for chronic itch. Complementary diagnostic exams, especially laboratory tests, determination of the intraepidermal nerve fiber density via a skin biopsy and radiological examinations may be indicated to confirm the diagnosis of neuropathic itch and to identify underlying etiological factors. Functional assessments such as quantitative sensory testing, nerve conduction studies, evoked potentials, or microneurography may be considered in particular cases. This review article provides a comprehensive overview of the diagnostic work-up recommended for patients with neuropathic itch.

Notaljia Parestetikalı Hastalardaki Omurga Patolojileri ve Güçlendirme Egzersizlerinin Kaşıntıyı Gidermede Olumlu Etkisi: Olgu Serisi

Objectives: Notalgia paresthetica is a subgroup of localized neuropathic chronic itch and is due to a nerve entrapment limited to the corresponding dermatome. Neuropathic itching often includes signs of sensitive skin syndrome (numbness, burning, stinging, tingling, etc.). It does not respond to antipruritic treatments used in other itchy dermatoses. The relationship between neuropathic itching and spinal pathology has been reported in many studies. Degenerative disc hernias may play a role in chronic itching localized to the back, hand, and brachioradial areas. We aimed to remind these patients we encountered in our clinical practice. Material and Methods: The files of 12 patients with notalgia paresthetica who applied to our dermatology outpatient clinic between 2016-2018 were reviewed. Diagnostic criteria are: No primary skin lesions in the affected skin area, the absence of any other itchy skin disease, detection of spinal pathology compatible with the itching area in magnetic resonance imaging, no other history of systemic disease or medication to explain itching. Results: Spinal canal stenosis, herniated nucleus pulposus, dural sac compression, and non-compressive bulging and protrusions were seen as spinal pathology. Itching completely disappeared in one of the four patients who conformed to the program, and the itch severity decreased in the other three patients. Conclusion: It should be kept in mind that itching may be of neuropathic origin in patients with localized chronic itching. Spine strengthening and stretching exercises may be a good option as primary or adjuvant therapy in neuropathic itching due to spinal pathology. Advanced clinical studies are needed.

Neuropathic Itch

Neurologic insults as varied as inflammation, stroke, and fibromyalgia elicit neuropathic pain and itch. Noxious sensation results when aberrantly increased afferent signaling reaches percept-forming cortical neurons and can occur due to increased sensory signaling, decreased inhibitory signaling, or a combination of both processes. To treat these symptoms, detailed knowledge of sensory transmission, from innervated end organ to cortex, is required. Molecular, genetic, and behavioral dissection of itch in animals and patients has improved understanding of the receptors, cells, and circuits involved. In this review, we will discuss neuropathic itch with a focus on the itch-specific circuit.

Neuropathic pruritus associated with brain disorders

Various types of brain pathology may be associated with neuropathic pruritus. While the mechanisms behind neuropathic itch is not well understood, damage to the itch processing centers and circuits of the brain may lead to changes in signaling in both top-down and bottom-up pathways that results in the distortion of itch sensation. Patients with brain pathologies such as such as stroke, brain tumors, spongiform encephalopathies, multiple sclerosis, trigeminal trophic syndrome, and systemic diseases such as end-stage renal diseases and primary biliary cholangitis have reported neuropathic itch of different characteristics. Commonly involved areas of the brain that, when damaged, are associated with neuropathic itch are the primary somatosensory cortex, precuneus, hippocampus, amygdala, periaqueductal gray, thalamus, insula, nucleus accumbens, Gasserian ganglion, cerebellum, cingulate cortex, prefrontal cortex, medulla, frontotemporal, and parietal lobe. Treatments for neuropathic pain, depression and seizures, such as kappa opioids, gabapentinoids, tricyclic antidepressants, and ketamine, are commonly used to treat neuropathic pruritus and are found to be effective.

The Neuropathic Itch Caused by Pseudorabies Virus.

Pseudorabies virus (PRV) is an alphaherpesvirus related to varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV1). PRV is the causative agent of Aujeskzy’s disease in swine. PRV infects mucosal epithelium and the peripheral nervous system (PNS) of its host where it can establish a quiescent, latent infection. While the natural host of PRV is the swine, a broad spectrum of mammals, including rodents, cats, dogs, and cattle can be infected. Since the nineteenth century, PRV infection is known to cause a severe acute neuropathy, the so called “mad itch” in non-natural hosts, but surprisingly not in swine. In the past, most scientific efforts have been directed to eradicating PRV from pig farms by the use of effective marker vaccines, but little attention has been given to the processes leading to the mad itch. The main objective of this review is to provide state-of-the-art information on the mechanisms governing PRV-induced neuropathic itch in non-natural hosts. We highlight similarities and key differences in the pathogenesis of PRV infections between non-natural hosts and pigs that might explain their distinctive clinical outcomes. Current knowledge on the neurobiology and possible explanations for the unstoppable itch experienced by PRV-infected animals is also reviewed. We summarize recent findings concerning PRV-induced neuroinflammatory responses in mice and address the relevance of this animal model to study other alphaherpesvirus-induced neuropathies, such as those observed for VZV infection.

Pregabalin for postherpetic itch: a case report

BackgroundPostherpetic itch has not commonly received attention as a complication of herpes zoster because pain predominates over itch in most patients with herpes zoster. Most cases of postherpetic itch are mild; however, cases of severe postherpetic itch reducing quality of life are rare.Case presentationA 52-year-old woman complained of severe itch in her left pinna and cheek 1 month after the first onset of herpes zoster at the same site. Owing to her scratching, she developed ulcers on her left pinna and cheek. Pregabalin was prescribed, and the itch subsided immediately, with the ulcers disappearing within 1 month.DiscussionSevere itch was thought to be caused by neural injury from herpes zoster. Pregabalin may be a useful treatment option for neuropathic itch induced by herpes zoster.

Persistent genital arousal disorder: a special sense neuropathy.

Introduction:Persistent genital arousal (PGAD) is a syndrome of unprovoked sexual arousal/orgasm of uncertain cause primarily reported in female patients. Most patients are referred for mental-health treatment, but as research suggests associations with neurological symptoms and conditions, there is need to analyze cases comprehensively evaluated by neurologists.Methods:The IRB waived consent requirements for this retrospective university-hospital study. We extracted and analyzed neurological symptoms, test, and treatment results from all qualifying participants' records and recontacted some for details.Results:All 10 participants were female; their PGAD symptoms began between ages 11 to 70 years. Two patterns emerged: 80% reported daily out-of-context sexual arousal episodes (≤30/day) that usually included orgasm and 40% reported lesser, often longer-lasting, nonorgasmic arousals. Most also had symptoms consistent with sacral neuropathy—70% had urologic complaints and 60% had neuropathic perineal or buttock pain. In 90% of patients, diagnostic testing identified anatomically appropriate and plausibly causal neurological lesions. Sacral dorsal-root Tarlov cysts were most common (in 4), then sensory polyneuropathy (2). One had spina bifida occulta and another drug-withdrawal effect as apparently causal; lumbosacral disc herniation was suspected in another. Neurological treatments cured or significantly improved PGAD symptoms in 4/5 patients, including 2 cures.Conclusions:Although limited by small size and referral bias to neurologists, this series strengthens associations with Tarlov cysts and sensory polyneuropathy and suggests new ones. We hypothesize that many cases of PGAD are caused by unprovoked firing of C-fibers in the regional special sensory neurons that subserve sexual arousal. Some PGAD symptoms may share pathophysiologic mechanisms with neuropathic pain and itch.

Neutrophils promote CXCR3-dependent itch in the development of atopic dermatitis.

Chronic itch remains a highly prevalent disorder with limited treatment options. Most chronic itch diseases are thought to be driven by both the nervous and immune systems, but the fundamental molecular and cellular interactions that trigger the development of itch and the acute-to-chronic itch transition remain unknown. Here, we show that skin-infiltrating neutrophils are key initiators of itch in atopic dermatitis, the most prevalent chronic itch disorder. Neutrophil depletion significantly attenuated itch-evoked scratching in a mouse model of atopic dermatitis. Neutrophils were also required for several key hallmarks of chronic itch, including skin hyperinnervation, enhanced expression of itch signaling molecules, and upregulation of inflammatory cytokines, activity-induced genes, and markers of neuropathic itch. Finally, we demonstrate that neutrophils are required for induction of CXCL10, a ligand of the CXCR3 receptor that promotes itch via activation of sensory neurons, and we find that that CXCR3 antagonism attenuates chronic itch.

Neuropathic Pain and Itch Mechanisms Underlying Allergic Conjunctivitis.

Among the constellation of symptoms that characterizes allergic conjunctivitis, many (eg, burning and stinging) can be attributed to chronic neuropathic pain. Cumulative data support that these hallmark symptoms might be linked to the effects of allergen-induced neuromodulation. This review investigates the key characteristics of neuropathic itch and pain in allergic conjunctivitis and their underlying pathogenic mechanisms. A literature review was conducted using a PubMed search focusing on allergic conjunctivitis, neurogenic inflammation, neuropathic itch, and neuropathic pain. Articles were reviewed, and those discussing clinical course, pathophysiology, and neuronal regulation of chronic neuropathic symptoms as related to allergic disease were summarized. Recent evidence suggests that some symptoms of allergic conjunctivitis may be better represented as a chronic neuropathic disorder. We found that neurogenic mechanisms may have a significant role in chronic ocular surface inflammation from allergic inflammation. Manifestations may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic transition, which is in turn associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain. Current goals in the management of allergic conjunctivitis aim to minimize the inflammatory cascade associated with the allergic response in the initial stages of the pathogenic mechanism. Based on the mechanistic data reviewed herein, the recognition that neuronal inflammation explains many of the symptoms in allergic conjunctivitis opens new frontiers for drug discovery.

Psychotropic Drugs for the Management of Chronic Pain and Itch.

Clinical observations have shown that patients with chronic neuropathic pain or itch exhibit symptoms of increased anxiety, depression and cognitive impairment. Such patients need corrective therapy with antidepressants, antipsychotics or anticonvulsants. It is known that some psychotropic drugs are also effective for the treatment of neuropathic pain and pruritus syndromes due to interaction with the secondary molecular targets. Our own clinical studies have identified antipruritic and/or analgesic efficacy of the following compounds: tianeptine (atypical tricyclic antidepressant), citalopram (selective serotonin reuptake inhibitor), mianserin (tetracyclic antidepressant), carbamazepine (anticonvulsant), trazodone (serotonin antagonist and reuptake inhibitor), and chlorprothixene (antipsychotic). Venlafaxine (serotonin-norepinephrine reuptake inhibitor) is known to have an analgesic effect too. The mechanism of such effect of these drugs is not fully understood. Herein we review and correlate the literature data on analgesic/antipruritic activity with pharmacological profile of these compounds.

Neuropathic itch.

Neuropathic itch is clinically important but has received much less attention as compared to neuropathic pain. In the past decade, itch-specific pathways have been characterized on a cellular and molecular level, but their exact role in the pathophysiology of neuropathic itch is still unclear. Traditionally, mutually exclusive theories for itch such as labeled line, temporal/spatial pattern, or intensity theory have been proposed, and experimental studies in mice mainly favor the specificity theory of itch. By contrast, results in humans also suggest a role for spatial and temporal patterns in neuropathic itch. Rarefication of skin innervation in neuropathy could provide a "spatial contrast" discharge pattern, and axotomy could induce de novo expression of the itch-specific spinal neuropeptide, gastrin-releasing peptide, in primary afferent nociceptors, thereby modulating itch processing in the dorsal horn. Thus, clinical neuropathy may generate itch by changes in the spatial and temporal discharge patterns of nociceptors, hijacking the labeled line processing of itch and abandoning the canonical scheme of mutual exclusive itch theories. Moreover, the overlap between itch and pain symptoms in neuropathy patients complicates direct translation from animal experiments and, on a clinical level, necessitates collaboration between medical specialities, such as dermatologists, anesthesiologists, and neurologists.

232 Sex differences in the perception of itch and quality of life in patients with chronic pruritus

Epidemiological studies have shown that chronic pain and its characteristics distribute differently between females and males. We believe it is also important to report the distinctions between females and males suffering from chronic itch. We administered a cross-sectional survey to obtain information on patients with chronic pruritus seen at the Department of Dermatology at the University of Miami and at Temple University from 2015 to 2018. The study included data collected from 254 patients, including 168 female and 86 male subjects. The most common category of chronic itch was inflammatory itch (58.7%, n=149), followed by neuropathic itch (18.5%, n=47). Both inflammatory and neuropathic itch were more common in females. Chronic pruritus average intensity was significantly higher in females than in males (8 vs 7.7; P<0.05). This difference between females and males was also significant for current pruritus (7.7 vs 7.6; P<0.05). Females experienced more severe pruritus—more often described as dreadful, unbearable, hurting, oppressive—than males (P<0.05). Meanwhile, sleep disturbances were significantly worse in males than in females (2.9 vs 2.8; P<0.05). The overall quality of life mean score was significantly higher in females than in males (3.6 vs 3.3; P<0.05). Although there was a difference in the “symptoms” and “functioning” subcategories of the quality of life survey between males and females, only the “emotional” subcategory significantly affected females (3.9) more than males (3.4), P<0.001. Significant differences exist between females and males with chronic pruritus in terms of itch intensity, quality of life, and itch characteristics. Our results indicate that females have higher overall itch intensity than males, which is consistent with results from other recent studies from Germany. Understanding the differences between females and males with chronic pruritus can help health care providers to better manage patients and personalize treatment plans.

Notalgia paresthetica and neuropathic itch. Case report

ABSTRACT BACKGROUND AND OBJECTIVES: Notalgia paresthetica is a neuropathic sensory syndrome located in the dorsal region between T2-T6 dermatomes and is characterized by a chronic evolution with periods of remission and exacerbation. The objective of this study was to demonstrate a case of notalgia paresthetica, from its clinical and laboratory investigation to the treatment adopted. CASE REPORT: A 77-year-old female patient, retired, attended the Outpatient Pain Service of the University Hospital of the Federal University of Maranhao. The main complaint was severe pruritus in the right dorsal region with extension to the breasts, associated with intermittent pain, burning, shock and tingling, worsening with physical effort and movement. Her sleep quality worsened because of the pain. At the physical examination, no pain was reported on palpation of the site, with mild hypoesthesia in T5 and T6 dermatomes, without altering the thermal sensitivity. She denied a history of skin lesions. The patient received conservative pharmacological treatment, with significant improvement in pain and sleep quality after six months. CONCLUSION: Notalgia paresthetica is a syndrome of unknown etiology, and the lack of studies makes it difficult to optimize the indications and recommendations to direct the treatment. This report illustrates the handling of a case of paresthetica notalgia where gabapentin was used as therapeutic management for pain control, for which it proved to be efficient.

Distinct behavioral response of primary motor cortex stimulation in itch and pain after burn injury

It is still unclear whether chronic neuropathic pain and itch share similar neural mechanisms. They are two of the most commonly reported challenges following a burn injury and can be some of the most difficult to treat. Transcranial direct current stimulation (tDCS) has previously been studied as a method to modulate pain related neural circuits. Therefore, we aimed to test the effects of tDCS on post-burn neuropathic pain and itch as to understand whether this would induce a simultaneous modulation of these two sensory manifestations. We conducted a pilot randomized controlled clinical trial comprised of two phases of active or sham M1 tDCS (Phase I: 10 sessions followed by a follow-up period of 8 weeks; Phase II: additional 5 sessions followed by a follow-up period of 8 weeks, and a final visit 12 months from baseline). Pain levels were assessed with the Brief Pain Inventory (BPI) and levels of itch severity were assessed with the Visual Analogue Scale (VAS). Measurements were collected at baseline, after the stimulation periods, at 2, 4 and 8-week follow up both for Phase I and II, and at the final visit. Sixteen patients were assigned to the active group and 15 to the sham group. Ten sessions of active tDCS did not reduce the level of pain or itch. We identified that itch levels were reduced at 2-week follow-up after the sham tDCS session, while no placebo effect was found for the active group. No difference between active and sham groups was observed for pain. We did not find any treatment effects during Phase II. Based on these findings, it seems that an important placebo effect occurred during sham tDCS for itch, while active M1 tDCS seems to disrupt sensory compensatory mechanisms. We hypothesize that pain and itch are complementary but distinct mechanisms of adaptation after peripheral sensory injury following a burn injury and need to be treated differently.

The 8% capsaicin - a hot medicine for neuropathic itch.

Linked article: This is a commentary on M.P. Pereira et al., pp. 1535–1541 in this issue. To view this article visit https://doi.org/10.1111/jdv.14857