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SnapshotDx Quiz: June 2018

      Which Treatment is Most Appropriate for This Patient?

      Figure 1
      Figure 1
      Image credit: Brian S. Kim, Washington University School of Medicine.
      Editorial note: Welcome to the Journal of Investigative Dermatology (JID) SnapshotDx Quiz. In this monthly online-only quiz, the first question relates to the clinical image found above, while additional questions concern the findings reported in a JID article by Palkar et al. (https://doi.org/10.1016/j.jid.2017.12.025).
      Detailed answers and a list of relevant references are available following the Quiz Questions below.

      Quiz Questions

      Palkar R, Ongun S, Catich E, Li N, Borad N, Sarkisian A, et al. Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons. J Invest Dermatol 2017.

      QUESTIONS

      • 1.
        Which treatment is most appropriate for this patient?
        • a.
          Recommend hot showers
        • b.
          Non-steroidal anti-inflammatory (NSAID) medications
        • c.
          Diphenhydramine cream
        • d.
          Topical menthol
        • e.
          Terbinafine cream
      • 2.
        What key characteristic differentiates cooling-mediated itch relief from mechanically- mediated itch relief (i.e. scratching)?
        • a.
          Cooling stimuli provide itch relief only after a delay, while mechanical stimuli provide immediate relief from itch sensation.
        • b.
          Cooling provides temporary relief of itch sensation as long as the cooling stimulus is supplied, while mechanical stimulation leads to longer-lasting relief, even after the mechanical stimulus has ceased.
        • c.
          Cooling relieves itch by inhibiting afferent neurons in excitatory itch neurocircuits, while scratching activates separate afferent neurons which activate spinal inhibitory interneurons within the itch circuit.
        • d.
          Cooling-mediated itch relief pathways are distinct from cooling-mediated pain relief pathways, while mechanically-mediated itch relief pathways overlap with mechanically- mediated pain relief pathways.
        • e.
          None of the above
      • 3.
        Which statement is true regarding cold and cold mimetic (e.g. menthol) stimuli?
        • a.
          Both cold and menthol relieve itch through a TRPM8-dependent mechanism, but cold may also relieve itch through additional mechanisms.
        • b.
          Menthol activates TRPM8 channels, while cold does not.
        • c.
          Distinct population of afferent sensory neurons transmit cold and cold-mimetic signals, which converge on spinal interneurons to produce indistinguishable sensations.
        • d.
          Excess cooling produces pain, while cold mimetics do not cause pain or irritation.
        • e.
          Both (a) and (b) are correct
      See following pages for detailed answers.

      Detailed Answers

      QUESTIONS

      • 1.
        Which treatment is most appropriate for this patient?
      ANSWER:
      • d.
        Topical menthol
      The patient pictured has excoriations resulting from chronic pruritus. Pruritus is a common manifestation of numerous dermatologic conditions, including atopic dermatitis and psoriasis, as well as systemic diseases, such as those resulting in renal, hepatic, and thyroid dysfunction. Frequently, no specific cause can be identified. While no single therapeutic intervention is successful in all patients, general skin care measures such as frequent use of emollients and avoidance of overbathing, wool and other rough fabrics can be helpful. Topical cooling agents, such as menthol, can provide immediate symptomatic relief, interrupting the itch-scratch cycle. Oral antihistamines at bedtime may reduce sleep disturbance. If an underlying etiology can be identified, the resulting pruritus may resolve with appropriate treatment. For this patient with excoriations and without evidence identifying the cause of her pruritus, topical menthol ointment is the most appropriate choice, along with gentile skin care recommendations (
      • Patel T.
      • Ishiuji Y.
      • Yosipovitch G.
      Menthol: a refreshing look at this ancient compound.
      ,
      • Yosipovitch G.
      • Bernhard J.D.
      Clinical practice.
      ).
      Discussion of incorrect answers
      • a.
        Recommend hot showers
      Xerosis is among the most common contributors to chronic pruritus. Excess bathing with hot water decreases skin moisture retention, worsening xerosis. Therefore, appropriate bathing recommendations for patients with chronic pruritus include using lukewarm water, as well as limiting bathing frequency and length.
      • b.
        Non-steroidal anti-inflammatory (NSAID) medications
      Many medications have been reported to cause pruritus, including NSAIDs. Increased synthesis of leukotrienes is the most likely mechanism, with 1–7% of patients affected (
      • Reich A.
      • Stander S.
      • Szepietowski J.C.
      Drug-induced pruritus: a review.
      ). A careful medication review is an important part of the evaluation of patients presenting with chronic pruritus.
      • c.
        Diphenhydramine cream
      While topical antihistamine preparations may provide short-term itch relief, there is a significant risk of contact sensitization (
      • Heine A.
      Diphenhydramine: a forgotten allergen?.
      ). Therefore, these agents are not recommended.
      • d.
        Terbinafine cream
      Terbinafine is an allylamine antifungal medication used for the treatment of cutaneous superficial mycoses such as tinea corporis. While pruritus is a common feature of fungal infections, the patient pictured lacks findings suggestive of this diagnosis, such as scaly erythematous annular plaques with central clearing. Therefore, a topical antifungal medication is not the most appropriate choice.
      • 2.
        What key characteristic differentiates cooling-mediated itch relief from mechanically- mediated itch relief (i.e. scratching)?
      ANSWER:
      • b.
        Cooling provides temporary relief of itch sensation as long as the cooling stimulus is supplied, while mechanical stimulation leads to longer-lasting relief, even after the mechanical stimulus has ceased.
      Palkar et al find that cooling-mediated itch relief is temporary, lasting only as long as the cooling stimulus is supplied. Placing mice on a cooled surface merely served to delay licking and biting behaviors, which returned as soon as the surface was warmed (Figure 3 A and C). In contrast, mice exposed to a pruritic stimulus without cooling developed itching and scratching behavior which attenuated over several minutes, indicating more long-lasting relief. Notably, licking and biting behavior returned after suppressing with a cooling stimulus that was maintained for longer than the licking and biting bouts themselves, indicating that attenuation of licking and biting behavior did not occur simply due to time-dependent decrease in the itch stimulus. Studies in humans have demonstrated a similar effect (
      • Fruhstorfer H.
      • Hermanns M.
      • Latzke L.
      The effects of thermal stimulation on clinical and experimental itch.
      ), although the mechanism is unclear.
      Discussion of incorrect answers
      • a.
        Cooling stimuli provide itch relief only after a delay, while mechanical stimuli provide immediate relief from itch sensation.
      Palkar et al found that cooling stimuli suppressed licking and biting behavior as soon as mice regained consciousness after injection with the pruritogen, within 30 seconds. If a cooling stimulus was not applied, mice developed licking and scratching behaviors within minutes, and these persisted for approximately 20 minutes. This finding, consistent with other animal and human studies (
      • Fruhstorfer H.
      • Hermanns M.
      • Latzke L.
      The effects of thermal stimulation on clinical and experimental itch.
      ,
      • LaMotte R.H.
      • Shimada S.G.
      • Sikand P.
      Mouse models of acute, chemical itch and pain in humans.
      ), suggests that itch relief from mechanical stimuli is delayed, while itch relief from cooling stimuli is immediate.
      • c.
        Cooling relieves itch by inhibiting afferent neurons in excitatory itch neurocircuits, while scratching activates separate afferent neurons which activate spinal inhibitory interneurons within the itch circuit.
      Palkar et al identify TRPM8-expressing afferent neurons as key mediators of cooling-mediated itch suppression. While prolonged cold might theoretically decrease itch sensation by decreasing nerve conduction in itch-mediating pathways, that is not the key mechanism here. TRPM8-expressing neurons are distinct from neurons previously implicated in itch neurocircuits, including gastrin-related peptide receptor expressing projection neurons and testicular orphan factor 4-dependent excitatory interneurons (
      • Bautista D.M.
      • Wilson S.R.
      • Hoon M.A.
      Why we scratch an itch: the molecules, cells and circuits of itch.
      ,
      • Sun Y.G.
      • Chen Z.F.
      A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
      ,
      • Wang X.
      • Zhang J.
      • Eberhart D.
      • Urban R.
      • Meda K.
      • Solorzano C.
      • et al.
      Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch.
      ). Ablation of TRPM8- expressing neurons did not prevent pruritogen-induced itch behavior, confirming that these neurons may inhibit itch sensation, but they do not propagate itch themselves. Spinal inhibitory interneurons dependent on the transcription factor bHLHb5 have been implicated in itch inhibition, but the afferent neurons mediating this signal were not identified (
      • Ross S.E.
      • Mardinly A.R.
      • McCord A.E.
      • Zurawski J.
      • Cohen S.
      • Jung C.
      • et al.
      Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice.
      ). TRPM8-expressing neurons are candidates for that role.
      • d.
        Cooling-mediated itch relief pathways are distinct from cooling-mediated pain relief pathways, while mechanically-mediated itch relief pathways overlap with mechanically-mediated pain relief pathways.
      Itch- and pain-mediating pathways partially overlap (
      • Ma Q.
      Labeled lines meet and talk: population coding of somatic sensations.
      ); the same appears to be the case for itch- and pain-relief pathways. Palkar et al identify TRPM8-expressing neurons as key mediators of cooling-induced itch relief, and prior works have implicated these neurons in cooling-induced pain relief as well (
      • Knowlton W.M.
      • Palkar R.
      • Lippoldt E.K.
      • McCoy D.D.
      • Baluch F.
      • Chen J.
      • et al.
      A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling- mediated analgesia.
      ,
      • Proudfoot C.J.
      • Garry E.M.
      • Cottrell D.F.
      • Rosie R.
      • Anderson H.
      • Robertson D.C.
      • et al.
      Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain.
      ). The mechanisms by which mechanical stimulation relieves itch have yet to be fully elucidated.
      • e.
        None of the above
      • 3.
        Which statement is true regarding cold and cold mimetic (e.g. menthol) stimuli?
      ANSWER:
      • a.
        Both cold and menthol relieve itch through a TRPM8-dependent mechanism, but cold may also relieve itch through additional mechanisms.
      Knockout of TRPM8 in mice abrogated itch relief from both menthol and cooling to 20°C (Figures 4 and 5). However, TRPM8-/- mice still experienced itch relief with cooling to 17°C, suggesting the involvement of non-TRPM8-dependent mechanisms. However, those mechanisms must still involve TRPM8- expressing neurons, as ablation of these neurons by genetically targeted expression of the diphtheria toxin receptor prevented itch relief at both 17°C and 20°C. This is consistent with prior studies, which identified greater attenuation of avoidance responses to noxious cold temperatures in TRPM8-ablated mice than in TRPM8-/- mice (
      • Knowlton W.M.
      • Palkar R.
      • Lippoldt E.K.
      • McCoy D.D.
      • Baluch F.
      • Chen J.
      • et al.
      A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling- mediated analgesia.
      ,
      • Pogorzala L.A.
      • Mishra S.K.
      • Hoon M.A.
      The cellular code for mammalian thermosensation.
      ). Less specific effects of noxious cold temperatures, such as slowed neuronal conduction or altered vascular tone cannot fully explain this result.
      Discussion of incorrect answers
      • b.
        Menthol activates TRPM8 channels, while cold does not.
      Both cold and cold mimetics such as menthol have been shown to activate TRPM8 channels in sensory neurons (
      • McKemy D.D.
      • Neuhausser W.M.
      • Julius D.
      Identification of a cold receptor reveals a general role for TRP channels in thermosensation.
      ,
      • Peier A.M.
      • Moqrich A.
      • Hergarden A.C.
      • Reeve A.J.
      • Andersson D.A.
      • Story G.M.
      • et al.
      A TRP channel that senses cold stimuli and menthol.
      ). Furthermore, both cold and cold mimetics induce pain relief in a TRPM8-dependent manner (
      • Knowlton W.M.
      • Palkar R.
      • Lippoldt E.K.
      • McCoy D.D.
      • Baluch F.
      • Chen J.
      • et al.
      A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling- mediated analgesia.
      ,
      • Liu B.
      • Fan L.
      • Balakrishna S.
      • Sui A.
      • Morris J.B.
      • Jordt S.E.
      TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.
      ,
      • Proudfoot C.J.
      • Garry E.M.
      • Cottrell D.F.
      • Rosie R.
      • Anderson H.
      • Robertson D.C.
      • et al.
      Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain.
      ). However, as discussed for answer a, TRPM8 expression is not always required for itch relief, as TRPM8-/- mice still experienced itch relief with cooling to 17°C (Figure 4). Cooling can activate TRPM8 channels, but it can also relieve itch through alternate mechanism which requires TRPM8-expressing neurons, but not the TRPM8 channel itself.
      • c.
        Distinct populations of afferent sensory neurons transmit cold and cold-mimetic signals, which converge on spinal interneurons to produce indistinguishable sensations.
      Much evidence indicates that cold and cold-mimetic signals are transmitted through the same afferent pathways, and often activate the same ion channels (
      • Jordt S.E.
      • McKemy D.D.
      • Julius D.
      Lessons from peppers and peppermint: the molecular logic of thermosensation.
      ). This is the case with TRPM8, which is activated both by cold and menthol (
      • McKemy D.D.
      • Neuhausser W.M.
      • Julius D.
      Identification of a cold receptor reveals a general role for TRP channels in thermosensation.
      ,
      • Peier A.M.
      • Moqrich A.
      • Hergarden A.C.
      • Reeve A.J.
      • Andersson D.A.
      • Story G.M.
      • et al.
      A TRP channel that senses cold stimuli and menthol.
      ), and TRPM8- expressing sensory afferent neurons, which mediate behavioral responses to both cold and menthol (
      • Bautista D.M.
      • Siemens J.
      • Glazer J.M.
      • Tsuruda P.R.
      • Basbaum A.I.
      • Stucky C.L.
      • et al.
      The menthol receptor TRPM8 is the principal detector of environmental cold.
      ). While multiple cohorts of sensory neurons determine the overall perception of temperature, sensory pathways for cold and cold-mimetic signals closely overlap.
      • d.
        Excess cooling produces pain, while cold mimetics do not cause pain or irritation.
      Cold mimetics such as menthol can produce significant local irritation (
      • Liu B.
      • Fan L.
      • Balakrishna S.
      • Sui A.
      • Morris J.B.
      • Jordt S.E.
      TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain.
      ). Interestingly, this effect is at least partly TRPM8 dependent. Palkar et al demonstrate that the irritant response to menthol application, cheek wipes, is partially attenuated in TRPM8-/- mice (Figure 5).
      • e.
        Both (a) and (b) are correct
      Answer b is incorrect

      Supplementary Material

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