Common Neuropathic Itch Syndromes

Common Neuropathic Itch Syndromes

Acta Derm Venereol 2012; 92: 118–125 REVIEW ARTICLE Common Neuropathic Itch Syndromes Anne Louise OAKLANDER Nerve Injury Unit, Departments of Neurology, and Pathology, Massachusetts General Hospital, Boston, USA Patients with chronic itch are diagnosed and treated by neurology textbooks and training curricula, and the dermatologists. However, itch is a neural sensation and visible cutaneous stigmata of neuropathic itch still are some forms of chronic itch are the presenting symptoms unnoticed by most neurologists despite their importance of neurological diseases. Dermatologists need some fami- for localization. Patients with chronic itch should first be liarity with the most common neuropathic itch syndro- evaluated by dermatologists, but if no dermatological or mes to initiate diagnostic testing and to know when to systemic causes are identified, consider the possibility refer to a neurologist. This review summarizes current of neurological causes. knowledge, admittedly incomplete, on neuropathic itch Twycross et al. (3) classified itch according to the ori- caused by diseases of the brain, spinal cord, cranial or gin of the itch-transmitting action potentials. Cutaneous spinal nerve-roots, and peripheral nerves. Key words: or pruritoceptive itch is caused by pruritogens activating itch; pruritus; diagnosis; herpes zoster; radiculopathy; pe- cutaneous nerve endings bearing pruritogenic receptors. ripheral nerve. In contrast, neuropathic itch is defined by diseased or malfunctioning pruritic neurons firing action potentials (Accepted December 24, 2011.) without pruritogenic stimuli (an abnormal stimulus- Acta Derm Venereol 2012; 92: 118–125. response curve). They also recognized neurogenic itch caused by pruritogens acting in the central nervous Anne Louise Oaklander, M.D., Ph.D., Nerve Injury Unit, system (e.g., intrathecal morphine), although it is uncer- Departments of Neurology and Pathology (Neuropatho- tain how often this circumstance otherwise arises. This logy), Massachusetts General Hospital, 275 Charles St./ manuscript summarizes the best known neuropathic itch Warren 310, Boston, MA 02114, USA. E-mail: aoaklan- syndromes to help dermatologists include them in their [email protected] differential diagnoses, initiate appropriate diagnostic evaluations, and know when to refer to a neurologist. The sensation of itch – pruritus in medical terminology – can only be perceived by a few tissues, specifically ANATOMY AND PHYSIOLOGY OF ITCH the skin and superficial mucous membranes such as the conjunctiva. So chronic itch complaints are the province The sensation of pruritus is carried primarily by a of dermatologists, and indeed they most often signal subset of the unmyelinated C-fibers often classified cutaneous injury or inflammation. However, substantial as pain-fibers (nociceptors). Different C-fibers deploy numbers of patients who complain of disabling chronic different receptors and ion-channels to equip them to itch have no apparent cause in the skin. Many of these respond to different sensory stimuli. The C-fibers that patients have systemic or medical causes of itch such as activate after local histamine administration to produce drug reactions, allergic or hypersensitivity syndromes, itch perceptions in the brain are mechanically insensi- metabolic or endocrine disorders, or toxins associated tive afferents (MIAs) with unusually slow conduction with kidney or liver dysfunction. Itch is most likely a velocities and large receptive fields (1). Some also small-fiber-mediated protective (nocifensive) sensation respond to heat stimuli, perhaps explaining why heat like pain. It is hypothesized to have evolved to protect worsens many itch sensations and cooling abrogates against small clinging threats such as insects and plant itch (1). Some laboratories report involvement of the spines that would not be effectively removed by the A-delta thinly myelinated nociceptors in itch sensation withdrawal response associated with sensing pain. A close as well. For clinicians the overlap between itch and pain evolutionary relationship is evident in the considerable neurons means that the same neurological diseases that micro- and macro-anatomical overlap between itch and can cause neuropathic pain can also cause neuropathic pain neurons (1, 2). itch in some patients. However there are differences. There is recent recognition that neurological disorders Most treatments effective for neuropathic pain are not are an additional cause of focal or generalized pruritus. clearly effective for itch. Most notably, opioid pain Dermatologists are increasingly aware of this, but many relievers often cause or worsen itch. neurologists are not and are ill-prepared to treat such The cell bodies of itch neurons are located in the pe- patients. Neuropathic itch remains unmentioned in most ripheral nervous system (PNS) just outside the central Acta Derm Venereol 92 © 2012 The Authors. doi: 10.2340/00015555-1318 Journal Compilation © 2012 Acta Dermato-Venereologica. ISSN 0001-5555 Neuropathic itch syndromes 119 nervous system (CNS), for instance in the trigeminal lack of benefit of antihistamines (9). Serotonin is an- (Gasserian) ganglion that subserves facial sensation, other mast-cell product implicated in itch signaling. and in the dorsal root ganglia of spinal nerves. These Several pruriceptors on primary afferent neurons are ganglia also send central axons inwards into the spinal G-protein coupled receptors (GPCRs) including not cord or brain to trigger the central itch-processing only the histamine and non-histamine receptors PAR2 neurons that lead to conscious and unconscious itch and serotonin receptors (10), but also the chloroquine perceptions, and the emotions, actions and decisions that receptor, Mrgpr (11). Neither antihistamines nor anti- these evoke. Nociceptive afferent neurons have other inflammatories treat most types of neuropathic itch, functions besides pain. These evolutionarily primitive likely because the causative neuronal action potentials nerve cells have a larger goal – maintaining homeostasis have become ectopic – uncoupled from their usual and optimal functioning of tissues and organs. Pain and peripheral stimuli. Many sensory receptors are over- itch sensations, which protect against actual or threate- expressed on the ends of regenerating axons, a potential ned danger, merely serve that larger goal. These same cause of the itching that often accompanies scar forma- peripheral neurons, known collectively as “small-fibers” tion. They may also be over-expressed in the bulbous also have important efferent and trophic activities. They neuromas that can form at the distal ends of transected innervate and influence all of the body’s organs and tis- nerves to contribute to phantom itch perceived in an sues, except hair and nails, innervating and regulating amputated limb or other missing body part. the small blood vessels, the internal organs, and the immune response. In the past such regulatory functions Transmission of itch signals into and within the central were attributed to the subset of small-fibers whose cell nervous system bodies are in the autonomic rather than somatic gang- lia, but multiple lines of evidence increasingly blur the Once transduced, it is not entirely clear how the action distinction between autonomic and somatic afferent potentials of pruritoceptive neurons travel from the neurons. Many structures including blood vessels and skin towards the CNS. Current experimental evidence sweat glands have overlapping innervation by somatic supports both the existence of distinct itch neurons that as well as autonomic neurons (4). Small-fiber mediated are insensitive to pain (labeled-line theory) (1) and also vasomotor and efferent functions likely also contribute of neurons that can signal either itch or pain by using to itch, for instance by antidromic release of neuropepti- different firing patterns (signal-selectivity theory). des such as calcitonin gene-related peptide (CGRP) and Furthermore, several lines of evidence demonstrate that substance P (SP) (5). These have wide spread effects on itch and pain neurons intersect or intercommunicate. nearby non-neural tissues, including those that augment For instance, pain often inhibits itch and opioid pain- inflammation and worsen itch. relievers can cause pruritus. And noxious temperature changes, both cold and hot, modulate itch perception (for better and for worse, respectively) (12). In the Neuronal and non-neuronal itch receptors dorsal horn, the first sensory relay within the CNS – or Itch is the least understood among the somatic senses the equivalent spinal nucleus of the trigeminal nerve and the neural circuits that transduce, transmit, and – spinothalamic-tract neurons receive incoming action modulate it are incompletely identified (6). It is not potentials from the central axon of primary afferent even fully known how pruritogens trigger neuronal itch-transducing neurons (2). They transmit itch signals firing in healthy let alone diseased neurons. Itch signal rostrally towards the brain, but there is considerable sig- transduction involves non-neuronal cells as well as nal modulation before that happens. Murine knock-out sensory neurons. Keratinocytes express the heat-sen- studies of the atonal-related transcription factor Bhlhb5 sing vanilloid type 3 (TRPV3) receptor (7), and several have identified dorsal-horn inhibitory interneurons that neuronal sodium channels (8), so they may contribute to tonically inhibit itch signals (13). Spinal cord lesions

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