Gil Yosipovitch

The neurobiology of itch

The neurobiology of itch, which is formally known as pruritus, and its interaction with pain have been illustrated by the complexity of specific mediators, itch-related neuronal pathways and the central processing of itch. Scratch-induced pain can abolish itch, and analgesic opioids can generate itch, which indicates an antagonistic interaction. However, recent data suggest that there is a broad overlap between pain- and itch-related peripheral mediators and/or receptors, and there are astonishingly similar mechanisms of neuronal sensitization in the PNS and the CNS. The antagonistic interaction between pain and itch is already exploited in pruritus therapy, and current research concentrates on the identification of common targets for future analgesic and antipruritic therapy.

Prevalence and characterization of uremic pruritus in patients undergoing hemodialysis: uremic pruritus is still a major problem for patients with end-stage renal disease

BACKGROUND Pruritus is a common disabling problem in patients with advanced end-stage renal disease. Few studies have evaluated the clinical characteristics of uremic itch. OBJECTIVES The aim of this multicenter study was to provide a comprehensive description of the prevalence and clinical characteristics of pruritus affecting patients with end-stage renal disease who are undergoing hemodialysis. METHODS A detailed questionnaire recently developed was used to evaluate pruritus in 219 patients undergoing hemodialysis treatment in 3 dialysis units. We examined the relationship of the quality of dialysis and various factors and medical parameters to itch. RESULTS Pruritus was a common symptom in the study population. Approximately 66% of the patients had pruritus at some point, and 48% were affected by it at the time of the study. There was no correlation between the occurrence of pruritus and demographic or medical parameters (type of kidney disease, medical management, dialysis efficacy as expressed by Kt/V) of the patient. The data suggest that uremic pruritus tends to be prolonged, frequent, and intense, and it can impair the patients quality of life including a negative effect on sleep and mood. Major factors found to exacerbate pruritus include rest, heat, dry skin, and sweat. Major factors found to reduce pruritus include activity, sleep, hot and cold shower, and cold. Treatment with angiotensin inhibitors seemed to be more common among those with uremia who had itch (P =.02) whereas furosemide was more commonly used among those who never itched (P =.002). CONCLUSION This study provides a detailed description of uremic pruritus with new data on its characteristics including affective and sensory dimensions and associated symptoms.

Clinical practice. Chronic pruritus

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A Questionnaire for the Assessment of Pruritus: Validation in Uremic Patients

A questionnaire was constructed for the evaluation and measurement of pruritus. The questionnaire, based on the short form of the McGill Pain Questionnaire, was tested in 145 patients suffering from uremic pruritus and currently undergoing hemodialysis treatment in 3 centers. The newly developed questionnaire proved to be reliable and provided valid data on the sensory, affective and overall intensity of uremic pruritus. The data suggest that uremic pruritus tends to be prolonged, frequently intense and a major source of distress to the patient. Dialysis was not found to influence the pruritus. The questionnaire may also be useful in pruritus secondary to other causes.

The Prevalence of Cutaneous Manifestations in IDDM Patients and Their Association With Diabetes Risk Factors and Microvascular Complications

OBJECTIVE The aim of our study was to evaluate the frequency of skin manifestations, including the diabetic hand syndrome, in young IDDM patients. In addition, we studied the relation of the cutaneous manifestations to diabetes duration, glycemic control, and microvascular complications. RESEARCH DESIGN AND METHODS The frequency of skin manifestations, including the diabetic hand syndrome, were examined in 238 IDDM patients (disease duration >5 years) and 122 healthy control subjects in a cross-sectional study. In addition, we studied the relation of the cutaneous manifestations with diabetes duration, glycemic control, BMI, microvascular complications, and stratum corneum hydration using a stepwise logistic regression. RESULTS Diabetic skin manifestations were detected in 168 of 238 (71%) IDDM patients and in 18 of 122 (14%) of the control subjects. Ichthyosiform skin changes of the shins, scleroderma-like skin changes, tinea pedis, and dry scaly palms were detected in 48 vs. 7%, 39 vs. 0%, 32 vs. 7%, and 21 vs. 0.8% of the patients and control subjects, respectively. In the diabetic patients, a significant association was found between ichthyosis of the shins and sclerodermalike skin changes of the hand (P < 0.001) and between scleroderma-like skin changes and the skin dryness of the palms (P < 0.0001). When diabetic risk factors were considered, diabetes duration was significantly associated with scleroderma-like skin changes and ichthyosis of the shins (P < 0.0001). The latter was also found to be related to diabetic retinopathy (P < 0.0001). Keratosis pilaris was present in 21% of the patients versus 9% in control subjects and was found to be exclusively associated with high BMI. CONCLUSIONS Acquired ichthyosis is a common finding and the most prevalent skin manifestation in young IDDM patients. The development of several skin manifestations in insulin-dependent patients seems to be related to duration of diabetes and to development of diabetic microvascular complications.

Lower extremity lymphedema: Update: Pathophysiology, diagnosis, and treatment guidelines

Lower extremity lymphedema is an important medical issue which causes morbidity and is frequently seen by dermatologists. The subject has not been adequately addressed in dermatologic literature for many years. Primary lymphedema is caused by an inherent malfunction of the lymph-carrying channel, in which no direct outside cause can be found. Secondary lymphedema is caused by an outside force, such as tumors, scar tissue after radiation, or removal of lymph nodes, which results in dysfunction of the lymph-carrying channels. Treatment is based on rerouting the lymph fluid through remaining functional lymph vessels. This is accomplished through elevation, exercises, compression garments/devices, manual lymph drainage, and treatment is combined with good skin care practices.

Effect of topically applied menthol on thermal, pain and itch sensations and biophysical properties of the skin.

The effect of menthol and alcohol as its vehicle on thermal sensations, pain, experimental itch and irritation were studied in 18 subjects, using a computerized thermal sensory analyzer, laser Doppler flowmetry and an evaporimeter for transepidermal water loss (TEWL). Menthol had a subjective cooling effect lasting up to 70 min in 12/18 subjects; however, it did not affect cold and heat threshold, nor did it affect cold and heat pain threshold. Alcohol produced an immediate cold sensation lasting up to 5 min in 4/18 subjects and lowered the sensitivity of cold sensation threshold (P<0.05). Histamine injection did not change thermal and pain thresholds. Menthol did not alleviate histamine-induced itch magnitude, nor its duration. Following histamine injection, cold sensation median threshold decreased by 1.2°C from (29.9°C to 28.7°C) on the site treated with menthol (P<0.01) with similar changes in thresholds at the alcohol-treated site (P<0.05). Warm sensation and pain threshold in subjects receiving histamine injections, measured after menthol and alcohol application, did not differ from their baseline values with histamine alone. TEWL at the site treated with menthol was significantly higher (P<0.05) than at the alcohol-treated and the control site (P<0.01), suggesting that menthol has a higher skin irritating effect, or at least alters the stratum corneum water permeability. Our results suggest that menthol fulfills the definition of a counterirritant, but does not affect histamine-induced itch, nor does it affect pain sensation.

Neuropathic and psychogenic itch

ABSTRACT:  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.

A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch

Previous PET and fMRI brain imaging studies targeting neural networks processing itch sensation have used histamine as the sole itch inducer. In contrast with histamine, cowhage-induced itch is mediated via proteinase activated receptors PAR2 and is transmitted through a separate spinothalamic pathway, therefore imaging the brain activation evoked by cowhage could provide further insight into central processing of itch. We report for the first time a functional MRI Arterial Spin Labeling (ASL) study of neuronal processing of itch induced by cowhage, analyzed in contrast with histamine-induced itch. We also explored the brain responses induced by histamine and cowhage combined in a tight sequence. The results of our analyses obtained in a group of 15 healthy volunteers suggested that cowhage and histamine co-activated a core group of brain structures, while also revealing notable differences. Core areas activated by both stimuli were found in the thalamus, primary and secondary somatosensory cortices, posterior parietal cortex, superior and middle temporal cortices, PCC, ACC, precuneus and cuneus. Cowhage induced a notably distinct and more extensive involvement of the insular cortex, claustrum, basal ganglia, putamen, thalamic nuclei and pulvinar. The differences observed between these two itch modalities were investigated to determine the impact of quantitative versus qualitative factors, and correlations between itch intensity and the patterns in brain activation were explored. Our analysis revealed that the most significant differences between cowhage and histamine itch were not affected by stimulus intensity, although a subset of regions displayed activations which were intensity-dependent. The combined application of cowhage and histamine highlighted the role of insula and claustrum in the processing of both itch modalities in the same time. The present results suggest the existence of overlapping but also distinct neuronal networks processing these two different types of itch.

Ipilimumab in patients with cancer and the management of dermatologic adverse events

Ipilimumab is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor T-cell responses. Phase III studies have demonstrated survival benefit in both previously treated and treatment-naïve patients with metastatic melanoma. In clinical trials, adverse events (AEs) related to treatment with ipilimumab were mostly grade 1/2 (as per Common Terminology Criteria for AEs, Version 4.02), and mostly reversible with appropriate management. Distinct immune-related AEs that may reflect the mechanism of action of ipilimumab have been identified, and occur commonly in the skin, typically presenting as a maculopapular rash, which can be accompanied by pruritus, pruritus with no skin lesions, alopecia, and vitiligo. Histologic analyses have revealed epidermal spongiosis, and perivascular CD4(+) T-cell infiltrates with some eosinophils in areas of rash. Timely implementation of toxicity-specific treatment guidelines that emphasize vigilance and early intervention allows mitigation of dermatologic AEs. Adherence to guidelines is necessary to maintain quality of life, ensure consistent dosing, and obtain the best possible clinical outcome.