Neuropathic Itch Research Articles

New insights into the pathophysiology and treatment of chronic itch in patients with end‐stage renal disease, chronic liver disease, and lymphoma

Chronic itch associated with systemic diseases continues to be one of the most bothersome dermatological symptoms accompanying end-stage renal disease (ESRD), chronic liver diseases, and lymphoma. The International Forum for the Study of Itch has recently issued a consensus paper on different types of chronic pruritus, including pruritus in systemic diseases that can present with or without secondary skin changes.1Various types of itch have been described based on the origin of the itch, which could be skin-related, neuropathic, systemic, or psychogenic.2 At any given time patients with these systemic diseases may have more than one origin, for example, patients with end-stage renal disease (ESRD) could have neuropathic itch due to nerve fibers damage, as well as itch associated with skin inflammation such as perforating folliculitis. Itch adversely affects quality of life of patients, leading to sleep deprivation and depression that further augment itch. Chronic itch associated with systemic diseases range from mild to intractable, which is defined as a chronic itch state in which the cause cannot be removed or treated, and no relief or cure has been found in the generally accepted course of medical practice.3 In the last decade, there are significant advances in our understanding of specific itch neuronal pathways, mediators and relevant receptors, opening the field for development of new antipruritic strategies. The purpose of this review is to highlight the new findings related to the pathophysiological mechanisms and the treatment of itch associated with the most common systemic diseases including ESRD, chronic liver disease and lymphoma.

NEUROPATHIC PRURITUS FOLLOWING WALLENBERG SYNDROME

Seo et al.1 provide a useful image of facial self-injury after lateral medullary infarct and correctly note that few neurologists know that Wallenberg syndrome can include neuropathic itch. Additional information may be indicated. Understanding the pathophysiology of TTS, and of neuropathic itch in general, is rudimentary. This syndrome of unilateral, self-induced facial ulcers from neuropathic itch is known as trigeminal trophic syndrome (TTS). All patients with lateral medullary lesions should be questioned about itching and scratching to prevent self-injury and to prevent unnecessary and potentially harmful tests and treatments for wrong diagnoses.2 Dermatologists biopsy these lesions to exclude carcinoma, infection, and granulomatous disorders, but they do not send their biopsies for labeling of cutaneous axons (e.g., against PGP9.5) which would reveal the true cause: loss of small-fiber innervation.3 Lateral medullary infarction remains a major cause of TTS. Central lesions reportedly cause 21% of TTS, usually from vertebrobasilar strokes. Uncommon central causes include cerebellopontine-angle tumors and Sjogren disease.4 Development of lesions in all trigeminal divisions, as here, suggests a central process. Pontine trigeminal lesions cause weakened chewing or reduced facial touch with preserved pain sensation, but never TTS. Only …

Dermatomal scratching after intramedullary quisqualate injection: correlation with cutaneous denervation.

Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation. This study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.

Disease mechanisms in neuropathic itch

Itch, also known as pruritus, is an unpleasant cutaneous sensation that provokes the desire to scratch. Itch is a common symptom of inflammatory skin disorders, but it can also occur in neurological diseases associated with injury to nervous tissue, in the absence of any skin disease and without any notable physiological stimuli in the periphery. This 'neuropathic' type of itch occurs either in combination with neuropathic pain or independently and is thought to be underdiagnosed. In this Review, we describe the physiological characteristics of specific neuronal systems in the PNS and CNS that transmit and process pruriceptive information, and we consider pathological changes that occur in these systems after nerve lesions. We then introduce a classification system for itch and highlight the similarities and differences between neuropathic itch and neuropathic pain. A summary of neuropathic syndromes in the PNS and CNS that are associated with itch is presented. Finally, we propose appropriate treatment strategies for neuropathic itch, in view of the fact that this condition has different mechanisms of itch generation to other types of itch and consequently requires different therapies.

Post Herpetic Itching—A Treatment Dilemma

To present a case of severe disabling postherpetic itching (PHI) and discuss possible mechanisms and management. We report on a 22-year-old male patient with a history of non-Hodgkin lymphoma, chronic renal failure peritoneal dialysis dependent, presented with a disabling pruritus around his left eye and forehead. Two months before, he was diagnosed with herpes zoster ophtalmicus. His itching intensity was 10/10 on a visual analog scale and he reported no pain. The neurologic examination showed a hyposensitivity to touch around his left eye. Our patient suffered of PHI who responded successfully to a combination of antihistamine and an antiepileptic agent. The mechanism of postherpetic neuralgia and PHI are not well understood and no single best treatment for postherpetic neuralgia and PHI is known. Clinical experience suggested that neuropathic itch may be more resistant to treatment than neuropathic pain. This immunocompromized patient with a severe disabling PHI responded to antihistaminic and anticonvulsant treatment.

Neuropathic and psychogenic itch

Neuropathic and psychogenic itch are two entities that have not been well studied. Neuropathic itch is related to pathology located at any point along the afferent pathway of the nervous system. It could be related to damage to the peripheral nervous system, such as in postherpetic neuropathy, brachioradial pruritus, notalgia paresthetica, and in central nervous system damage as a result of spinal cord tumors and demyelinization diseases such as multiple sclerosis. It has many clinical features similar to neuropathic pain. Patients complain of itch, which coincides with burning sensation, aching, and stinging. Psychogenic itch is related to psychologic abnormalities e.g., itch in obsessive compulsive disorders, depression, and delusions of parasitosis. Although no controlled studies have been conducted for treatment of neuropathic and psychogenic itch, medications that are part of the treatment armentarium for neuropathic pain, depression, and anxiety seem to be effective.

Cutaneous innervation before and after one treatment period of acupuncture

The effect of acupuncture on nociceptive pain is well documented, but effects on nociceptive itch have been contradictory. To evaluate possible effects of acupuncture on the occurrence, distribution and function of sensory nerve fibres in human skin. Ten subjects were treated by inserting 10 acupuncture needles subcutaneously at the upper lateral aspect of one buttock. The subjects were recruited from an acupuncture clinic and were undergoing specific acupuncture treatment for their disorders. The needles were stimulated (rotated to and fro) twice during the twice-weekly 25-min sessions over 5 weeks. Skin biopsies, diameter 3 mm, were taken before and 3-6 days after local acupuncture. Antibodies to the pan-neuronal marker protein gene product 9.5 (PGP 9.5), calcitonin gene-related peptide (CGRP), vanilloid receptor 1 (VR1) and mu- and delta-opioid receptors were employed to study sensory unmyelinated nerve fibres that transmit nociceptive pain and itch. A histamine prick test using planimetry was used to record experimental itch after acupuncture on the treated area and on the corresponding control skin, and a visual analogue scale was used to evaluate itch. The mean +/- SEM number of CGRP-immunoreactive nerve fibres per biopsy section was reduced from 36.0 +/- 3.3 to 21.3 +/- 4.0 (P = 0.05) after the treatment. PGP 9.5-immunoreactive nerve fibres were found both in the epidermis and in the subpapillary dermis. The mean +/- SEM total number of PGP 9.5-immunoreactive nerve fibres decreased from 249.8 +/- 16.7 to 211.8 +/- 12.0 (P = 0.03). The PGP 9.5-immunoreactive nerve fibres occurring in the dermis appeared more fragmented after the acupuncture compared with pretreatment. VR1 immunoreactivity was found both in the free nerve fibres and in kite-like formations, possibly mast cells, throughout the dermis, sometimes occurring around hair follicles. The mean +/- SEM number of VR1-immunoreactive elements was not significantly influenced by acupuncture, at 33.5 +/- 4.6 vs. 43.0 +/- 4.4 (P = 0.09). No immunoreactivity was found in the skin against mu- and delta-opioid receptors with the antibodies used in this study. Neither histamine-induced itch nor cutaneous responses were influenced by acupuncture. The present data indicate an effect of acupuncture on neuropathic itch but not histamine-mediated itch. Our findings support the opinion that the pain-relieving effects of acupuncture partly depend on its effect on the peripheral innervation.

Brachioradialer Pruritus

We report on a female patient with brachioradial pruritus, in whom the cause could be verified by purposeful diagnostics (e. g., MRI). The clinical symptoms with localized itching result from circumscribed nerve root compression and hyperexcitation of the nerve fibers. Under treatment with gabapentin, an anticonvulsant with a very good analgesic and good antipruritic effect, the itch ceased and the skin changes healed. This case shows that this special form of neuropathic itch requires targeted therapy, which apart from symptomatic treatment should primarily focus on remedying the cause, if feasible.

Neuroanatomy and neurophysiology of itch

The specific pathway of "pure," histaminergic itch is traced from the mechano-insensitive nerve fibers in the skin to their central cortical projections. Neuropathic itch created at different levels of this anatomical pathway is reviewed. In this review the present author discusses damage to pruritoceptors in the skin, entrapment syndromes, damage to spinal ganglia, nerve root impingement, injury of the spinal cord, and cerebral damage in the distribution of the middle cerebral artery, capsula interna, or thalamus. Itch in inflamed skin resulting from interactions between nerve transmitters and other mediators of inflammation is described.

Underlying Disease May Drive Neuropathic Itch

Underlying Disease May Drive Neuropathic Itch

Central neuropathic itch from spinal-cord cavernous hemangioma: a human case, a possible animal model, and hypotheses about pathogenesis

Cavernous hemangiomas (cavernomas) of the spinal cord are rare congenital malformations that comprise less than 5% of all intramedullary lesions. Despite this rarity, we describe the third case of central neuropathic itch associated with intramedullary cavernoma. Since fewer than 10 cases of central spinal itch from all causes have been published, this concurrence suggests the possibility of a specific association. A middle-aged man developed chronic disabling neuropathic itch and pain affecting his left shoulder and arm after frank hemorrhage of a midcervical cavernoma. We hypothesize that the relatively rostro-dorsal location of his lesion increased its likelihood of causing itch as well as pain. The microscopic pathology of cavernomas, specifically their gliotic rim containing hemosiderin-laden phagocytes, fosters ectopic firing of nearby neurons and makes cranial cavernomas highly epileptogenic. We hypothesize that these pathological features predispose cavernomas to cause central itch if they are located near, but spare, the central itch projection neurons in lamina I of the dorsal horn. Quisqualate injections into the deeper layers (neck) of the dorsal horns of rats produce pathologically similar lesions. Such rats develop unilateral dermatomal hyperalgesia and self-injurious scratching and biting (autotomy). Although this pathological grooming is currently interpreted as a response to chronic pain, we propose that it more likely models scratching provoked by central neuropathic itch, as seen in our patient and others. Study of quisqualate-injected rats may provide leads towards new treatments for neuropathic itch.

Epidural clonidine relieves intractable neuropathic itch associated with herpes zoster-related pain

Objective: We present a case of intense herpes zoster-related pain and itching in the ophthalmic division of the trigeminal nerve (V1). Successful pain and itch management was achieved after insertion of a high thoracic epidural catheter with a continuous infusion of bupivacaine and clonidine. Case Report: A 73-year-old woman with metastatic malignant melanoma developed acute herpes zoster-related pain and itching unresponsive to conventional oral medications. The patient described severe and frequent attacks of lancinating pain occurring in the dermatomal distribution of the left ophthalmic division of the trigeminal nerve. She also had a disturbing itch in the same distribution as her pain. The patient had significant reduction in the frequency and intensity of the lancinating attacks after placement of a thoracic epidural catheter with continuous infusion of 1 μg/mL clonidine and 0.05% bupivacaine. The itching resolved completely as well. Conclusion: High thoracic epidural infusion of bupivacaine and clonidine was beneficial in relieving neuropathic itch in a patient with acute herpes zoster-related pain in the distribution of the trigeminal nerve.

Herpes zoster itch: preliminary epidemiologic data

The best-known complication of shingles (herpes zoster) is postherpetic neuralgia (PHN). PHN is commonly studied to investigate causes of and treatments for neuropathic pain. However, many patients with shingles experience neuropathic itch accompanying, or instead of, pain. Some report severe disabling postherpetic itch (PHI), and though it is rare, some patients injure themselves by scratching itchy skin that has lost protective sensation. To date, there is virtually no mention of PHI in the medical literature; neither epidemiologic, anatomic, physiologic, nor treatment studies. We analyzed 3 independent existing sets of data from 586 adults with shingles or PHN to glean epidemiologic information about pruritus during and after shingles. All data refer to itch localized to shingles-affected areas and initiated by shingles. They indicate that pruritus, usually mild or moderate, commonly accompanies both acute zoster and PHN. There was no significant difference in age between subjects with and without PHI. In one group, but not in another, there was an increased number of women with PHI. Subjects whose shingles affected the head, face, and neck were more likely to experience PHI than those whose shingles affected the torso. These findings indicate a need for research on zoster-associated itch, including prospective studies on frequency, impact, and treatment.

Itch associated with skin disease: advances in pathophysiology and emerging therapies.

Itch, also known as pruritus, is the major symptom in skin diseases with a variety of etiologies and pathophysiologies. Significant progress has been achieved in understanding the pathophysiology of itch in the last 5 years. Neurophysiological experiments in humans and animals have revealed that itch is carried by specific C nerve fibers. Recent studies have demonstrated that peripheral mediators other than histamine are involved in induction of itch. Mast cell tryptase seems to be an important mediator in itch by its activation of proteinase activated receptor 2 in the sensory nerves. Opioids have central and peripheral itch producing activity. Neuropeptides, such as substance P, induce itch by their effect on mast cells. Based upon our improved understanding of the neurophysiology of itch a clinical classification of itch has been proposed. The classification highlights differences between peripheral pruritoceptive itch, neuropathic itch (itch related to damage to afferent nerve fibers) and neurogenic itch (itch originating in the central nervous system without any evidence of nerve damage). Emerging therapies based on these findings include topical vanilloid receptor antagonists, topical antihistamines, and topical arachidonic acid inhibitors, as well as inhibitors of non-histamine inflammatory mediators, immunomodulators and strontium salts. Systemic therapies include thalidomide, opioid antagonists, phototherapy with narrow band UVB and experimental treatments with cutaneous field stimulation and vagal nerve stimulation. With the new information it seems we will be able to better help our dermatologic patients who have itch, however we are not closer to identifying a single agent specifically targetable to this symptom.

Intractable postherpetic itch and cutaneous deafferentation after facial shingles

Some patients develop chronic itch from neurological injuries, and shingles may be a common cause. Neuropathic itch can lead to self-injury from scratching desensate skin. A 39-year-old woman experienced severe postherpetic itch, but no postherpetic neuralgia, after ophthalmic zoster. Within 1 year, she had painlessly scratched through her frontal skull into her brain. Sensory testing and skin biopsies were performed on itchy and normal scalp to generate preliminary hypotheses about mechanisms of neuropathic itch. Quantitation of epidermal neurites in PGP9.5-immunolabeled skin biopsies demonstrated loss of 96% of epidermal innervation in the itchy area. Quantitative sensory testing indicated severe damage to most sensory modalities except itch. These data indicate that in this patient, severe postherpetic itch was associated with loss of peripheral sensory neurons. Possible mechanisms include electrical hyperactivity of hypo-afferented central itch-specific neurons, selective preservation of peripheral itch-fibers from neighboring unaffected dermatomes, and/or imbalance between excitation and inhibition of second-order sensory neurons.

Excitatory amino acid receptor subtypes in postmortem schizophrenic hippocampi : R.W. Kerwin and S. Patel Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK

Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self-injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At-level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis-related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation.This study suggests that intramedullary injection of quisqualic acid in rats causes death of at-level peripheral as well as central neurons. Self-injurious dermatomal scratching that develops in spinal-injured rats may reflect neuropathic itch and loss of protective pain sensations.

Physiological changes in sympathetic ganglia infected with pseudorabies virus.

ArticlePhysiological Changes in Sympathetic Ganglia Infected With Pseudorabies VirusJohn Dempsher, Martin G. Larrabee, Frederik B. Bang, and David BodianJohn DempsherFrom the Jenkins Laboratories of Biophysics and the Departments of Medicine and of Epidemiology, Johns Hopkins University and Hospital, Baltimore, Maryland, Martin G. LarrabeeFrom the Jenkins Laboratories of Biophysics and the Departments of Medicine and of Epidemiology, Johns Hopkins University and Hospital, Baltimore, Maryland, Frederik B. BangFrom the Jenkins Laboratories of Biophysics and the Departments of Medicine and of Epidemiology, Johns Hopkins University and Hospital, Baltimore, Maryland, and David BodianFrom the Jenkins Laboratories of Biophysics and the Departments of Medicine and of Epidemiology, Johns Hopkins University and Hospital, Baltimore, MarylandPublished Online:01 Jul 1955https://doi.org/10.1152/ajplegacy.1955.182.1.203MoreSectionsPDF (3 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByComparative Pathology of Pseudorabies in Different Naturally and Experimentally Infected Species—A Review4 August 2020 | Pathogens, Vol. 9, No. 8The Neuropathic Itch Caused by Pseudorabies Virus31 March 2020 | Pathogens, Vol. 9, No. 4Cell-cell fusion in the nervous system: Alternative mechanisms of development, injury, and repairSeminars in Cell & Developmental Biology, Vol. 60Cell-fusion events induced by α-herpesvirusesFuture Virology, Vol. 10, No. 2In vivo imaging of alphaherpesvirus infection reveals synchronized activity dependent on axonal sorting of viral proteins26 August 2013 | Proceedings of the National Academy of Sciences, Vol. 110, No. 37Alphaherpesvirus Infection Disrupts Mitochondrial Transport in NeuronsCell Host & Microbe, Vol. 11, No. 5A New General Concept of the Neurohumoral Functions of Acetylcholine and Acetylcholinesterase12 April 2011 | Journal of Pharmacy and Pharmacology, Vol. 14, No. 1Pseudorabies Virus Infection Alters Neuronal Activity and Connectivity In Vitro30 October 2009 | PLoS Pathogens, Vol. 5, No. 10Martin G. LarrabeeInfection and Spread of Alphaherpesviruses in the Nervous SystemIon channels involved in the presynaptic hyperexcitability induced by herpes virus suis in rat superior cervical ganglionNeuroscience, Vol. 41, No. 2-3Early Evidence of Presynaptic ReceptorsAnnals of the New York Academy of Sciences, Vol. 604, No. 1 Presynaptic RTransmembrane Channels and DiseaseAutonomic Ganglia and Their BiochemistryRegulation of Acetylcholine synthesis in normal and neurotropic viral infected sympathetic gangliaBrain Research, Vol. 242, No. 2Alteration of the electrophysiological activity in symphathetic ganglia infected with a neurotropic virus. I. Presynaptic origin of the spontaneous bioelectric activityBrain Research, Vol. 240, No. 1Stimulus-sensitive spinal myoclonus.Journal of Neurology, Neurosurgery & Psychiatry, Vol. 44, No. 10Tyrosine hydroxylase activity in the superior cervical ganglion during herpes simplex virus infection: Correlation with viral titers and viral antigenBrain Research, Vol. 214, No. 2A neurobiological approach to neurotropic virusesTrends in Neurosciences, Vol. 3, No. 6Synaptic function in the nervous system: A theory and its application11 June 2016 | Acta Biotheoretica, Vol. 28, No. 2Normal and pseudorabies virus infected primary nerve cell cultures in scanning electron microscopyMedical Microbiology and Immunology, Vol. 167, No. 2Evidence on the periodic mechanism in herpes simplex encephalitisElectroencephalography and Clinical Neurophysiology, Vol. 46, No. 3Ultrastructure and function in sympathetic ganglia isolated from rats infected with pseudorabies virusBrain Research, Vol. 140, No. 1Presynaptic origin of penicillin afterdischarges at mammalian nerve terminalsBrain Research, Vol. 138, No. 1Viral infections of the autonomic nervous system and its target organs: Pathogenetic mechanicsmsMedical Hypotheses, Vol. 3, No. 1Cellular Pharmacology of Ganglionic TransmissionLatent infection of the peripheral ANS with herpes simplex virusNature, Vol. 257, No. 5528Ganglionic TransmissionThe EEG of kuruElectroencephalography and Clinical Neurophysiology, Vol. 34, No. 4Acetylcholine depolarization of bullfrog sympathetic preganglionic nerve terminalsLife Sciences, Vol. 6, No. 11Pharmacologic, Toxicologic, and Therapeutic Properties of Anticholinesterase AgentsREFERENCESAn analysis of the role of presynaptic and postsynaptic slow potentials in sympathetic gangliaInternational Journal of Neuropharmacology, Vol. 1, No. 4The role of acetylcholine and cholinesterase in sympathetic gangliaInternational Journal of Neuropharmacology, Vol. 1, No. 4OXYGEN CONSUMPTION OF EXCISED SYMPATHETIC GANGLIA AT REST AND IN ACTIVITYJournal of Neurochemistry, Vol. 2, No. 2-3 More from this issue > Volume 182Issue 1July 1955Pages 203-216 Copyright & PermissionsCopyright © 1955 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1955.182.1.203PubMed13248967History Received 28 December 1954 Published online 1 July 1955 Published in print 1 July 1955 Metrics