ARTICLE IN BRIEF
The article discusses ongoing basic and clinical research that seeks to clarify the neuronal pathways and neurological causes of itch (pruritus).
“Neurologists have not traditionally thought about itch as a neurological problem,” said Anne Louise Oaklander, MD, PhD, associate professor of neurology at Harvard Medical School and Massachusetts General Hospital, and a member of the Neurology Today editorial advisory board. But that may be changing, she said, as new basic and clinical research clarifies the neuronal pathways and neurological causes of itch (pruritus).
Last October, the NIH National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) invited Dr. Oaklander and others to an invitation-only roundtable of experts to explore the underlying mechanisms of chronic itch, including its connections to the CNS. In an interview with Neurology Today, Dr. Oaklander highlighted key findings from the meeting.
While short-term itch — from mosquito bites or allergy, for example — is a minor clinical problem, Dr. Oaklander said there is increasing medical awareness that chronic intractable itch causes suffering and disability on par with chronic pain. The NIH roundtable was a significant step forward in recognizing the neurological aspects of itch, she said, and the first NIH meeting devoted to the topic.
Participants identified areas of progress in identifying neural pathways and mediators of itch — some of which comes from neuroscientists also studying pain, a more developed field with considerable overlap. Itch has become a robust area of neuroscience research, although this is not yet reflected in clinical neurology practice, according to Dr. Oaklander.
CATEGORIES OF ITCH
Workshop participants — specialists in neuroscience, dermatology, immunology, anesthesiology, pharmacology and psychiatry – agreed on the three major categories of chronic itch. These include not only skin diseases such as atopic dermatitis, but also organ diseases of the liver, kidney, and blood, where abnormal metabolites stimulate itch neurons. However, it is increasingly evident that some patients with chronic itch have neurological causes that require a neurologist's attention for diagnosis and treatment. Also discussed were psychiatric conditions that can cause excess scratching, notably obsessive-compulsive disorder and delusional parasitosis. Additional study was recommended, as these too might have a neurological basis.
Neuropathic itch can be triggered by any neurological condition that damages portions of the neuronal pathways that mediate itch. One cause is post-herpetic itch (PHI) after shingles, a common neurological illness. PHI and other forms of neuropathic itch can be dangerous when unremitting itch is accompanied by reduced protective pain sensation — this normally limits scratching to brief bouts.
In patients whose condition is caused by severe nerve damage, their continued scratching becomes painful and some scratch to the point of self-injury. A stroke syndrome, lateral medullary infarction, also known as Wallenberg syndrome, is another cause of facial self-injury from neuropathic itch, said Dr. Oaklander, who described the condition in a 2009 paper in Neurology.
Workshop participants discussed theories about itch perception. One theory suggests that itch sensation is transmitted by subsets of small-fibers that may or may not also transmit pain. Signals are transmitted from the skin along unmyelinated and thinly myelinated small-fibers (C- and A-delta axons) to the dorsal-horn of the spinal cord, up the spinothalamic tract to the brain. Secretions of other cells including mast cells and keratinocytes influence whether or not itch-neurons fire.
Itch is thought to have evolved to protect against threats best removed by scratching, small, clinging stimuli such as insects. The earliest itch mediator found was histamine, and antihistamines are often prescribed for itch. However, recent advances demonstrate more diverse molecular mediators including the protease-activated receptor 2 (PAR2); the serotonin 5-HT2 receptor; and MRGD (mas-related G-protein coupled receptor member D). This explains why antihistamines are ineffective for many patients, including those with neuropathic itch.
In a 2007 report in Nature, researchers at Washington University in St. Louis led by Zhou-Feng Chen, PhD, identified in mice an itch-specific spinal synapse mediated by gastrin-releasing peptide (GRP). Neuronal itch responses are likely influenced by genetic polymorphisms in these receptors and their expression likely changes in various illnesses and even during aging, Dr. Oaklander said.
In a 2010 study in Acta Dermato Venereologica, an international journal on dermatology, Gil Yosipovitch, MD, professor of dermatology, neurobiology and anatomy, and regenerative medicine at Wake Forest University, and colleagues reported associations between ethnicity and different forms of chronic itch. They found, for example, that cutaneous amyloidosis, a type of pruritic dermatosis, is common in Asians and rare in whites and Americans, and speculated that this may relate to a genetic polymorphism in the interleukin-31 receptor.
As with pain, constant, low-level spinal/CNS activation (central sensitization) can create a hypersensitive system that sends itch messages to the brain with little or no stimulation; this may be the basis for chronic itch in some patients. And inhibitory spinal inter-neurons are likely play a critical “dampening-down” role, as they do in pain. In a March 2010 paper in Neuron, Sarah E. Ross, PhD, and colleagues at Harvard Medical School reported that in mice the “atonal-related transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord and seems to play a role in the inhibition and regulation of pruritic (itch) circuits.” They offered evidence that the loss of inhibitory synaptic input resulted in abnormal itch in Bhlhb5-mutant mice.
NEW TREATMENTS FOR ITCH
Despite similarities to pain pathways, the ineffectiveness of most pain medications for itch attests to the existence of distinct mediators, Dr. Oaklander said. In fact, itch is a common side effect of morphine and similar pain-relievers. The experts agreed that new treatments for chronic itch are urgently needed, and the pharmaceutical industry has also taken note.
A new oral kappa-opioid receptor agonist, nalfurafine, is in clinical trials for pruritus from chronic liver and kidney disease, Dr. Oaklander said. Other potential therapeutic targets include cholecystokinin, PAR2, and GRPR antagonists. The roundtable participants noted that developing large-animal models of itch would speed drug development. They urged multidisciplinary research collaborations and use of brain imaging (such as functional MRI) as well as molecular and cellular analysis of skin biopsies, along with continued research on the psychosocial and behavioral aspects of itch and its comorbidities.
As this goes forward, Dr. Oaklander offers a simple message for her colleagues in practice. “Neurologists need to ask their patients about itch, and to pay attention to signs of excess scratching,” she said, citing as an example a condition dermatologists know as brachioradial pruritus, where patients have itchy patches on their arms or torso. This was recently shown to be caused by radiculopathy that may require neurosurgical decompression, Dr. Oaklander said. When itch is caused by neurological disease, then “we can't really be sending these patients to dermatologists,” she said. “What we're talking about is neurological management.”
A summary of the NIAMS workshop is available online: http://bit.ly/hiU65R.
Ross SE, Mardinly AR, Greenberg ME, et al. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in BHlhb5 mutant mice. Neuron 2010; 65:886-898.
Sun YG, Chen ZF.A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 2007;448(7154):700-703.
Oaklander AL, Cohen SP, Raju SVY. Intractable postherpetic itch and cutaneous deafferentation after facial shingles. Pain
Schmelz M. A neural pathway for itch. Nature 2001; 4:9-10.
Tey HL, Yosipovitch G. Review Article: Itch in ethnic populations. Acta Derm Venereol
Davidson S, Zhang X, Giesler GL Jr., et al. Relief of itch by scratching: State dependent inhibition of primate spinothalamic tract neurons. Nat Neurosci 2009; E-pub 2009 April 6.
Oaklander AL, Seo W-K, Park MH. Neuropathic pruritus following Wallenberg syndrome. Neurology