Neurobiology of the Scalp in Seborrheic Dermatitis
Condition: Seborrheic Dermatitis
MeSH terms: Dermatitis; Dermatitis, Seborrheic
Study type: Observational

Summary: 
      Seborrheic dermatitis is a common, inflammatory skin condition that causes flaky, white to
      yellowish scales to form on oily areas such as the scalp or inside the ear. These scales can
      occur with or without underlying reddened skin. In addition to causing psychological
      distress, low self esteem, and embarrassment, seborrheic dermatitis is associated with scalp
      pruritus (itch). Treatment modalities exist to control scalp flaking and itch associated with
      seborrheic dermatitis, although such therapies often lose efficacy over time. As seborrheic
      dermatitis is a chronic (life-long) condition, better treatments are needed. The
      investigators propose to better characterize in subjects with seborrheic dermatitis involving
      the scalp versus normal scalp controls: (a) the clinical characteristics of the associated
      itch and (b) the pattern of nerve innervation to the scalp. In this way, the investigators
      hope to get a comprehensive understanding of the factors causing scalp itch with the aim that
      this information will create new candidates to which treatment modalities can be designed. At
      least 12 (up to 20) subjects and similar number of control subjects without disease will have
      one clinic visit including questionnaires, testing of sensation on the scalp, and biopsy of
      the scalp.
    

Detailed description: 
      Seborrheic dermatitis (SD) is a common skin disorder that mainly affects the scalp, causing
      scale, itch, and red skin. Dandruff, a subset of SD, shows scale and itch in the absence of
      associated red skin. Seborrheic dermatitis can occur on many different body areas, including
      the scalp, eyebrows, eyelids, creases of the nose, lips, behind the ears, in the outer ear,
      and middle of the chest. On the scalp, SD is commonly associated with pruritus (itch).
      Multifactorial theories have been proposed regarding the pathogenesis of SD, and these
      include irritation from a skin-based yeast called malessizia, overproduction of sebum by
      sebaceous glands in the affected skin areas, and individual variability. Specifically,
      malassezia produce free fatty acids from sebaceous gland-produced triglycerides, and these
      free fatty acids have an "irritant" (ie, non-immunologic) effect in those patients with a
      "susceptible predisposition." Other factors associated with flares of SD include stress,
      fatigue, weather extremes, infrequent shampoos or skin cleaning, use of lotions that contain
      alcohol, skin disorders (such as acne), obesity, neurologic conditions (including Parkinson's
      disease, stroke, and head injury), and HIV infection. What role, if any, such factors play in
      the etiology of scalp pruritus in patients with SD is not known. Furthermore, itch is
      signaled by specific subsets of nerves in the skin and whether pruritus of SD results from
      alteration of these nerves by the underlying inflammatory state is unknown. Moreover,
      pruritus from the skin can be a result of peripheral sensitization, where skin-derived
      signals activate nerves in the skin to send increased nerve signals into the central nervous
      system. Pruritus sensed in the skin can also be a result of altered central-nervous system
      processing of skin-derived nerve signals, such as when skin-derived touch or pain is
      misperceived as itch by the central nervous system. Whether itch in patients with SD is a
      result of peripheral and/or central sensitization is also not unknown. Understanding this
      distinction has therapeutic implications, in that itch that is a result of misprocessing by
      the central nervous system will not be adequately treated, in the short term, by
      skin-administered topical therapies.

      To better understand the etiology of scalp pruritus in subjects with SD, we will determine
      the clinical characteristics of scalp pruritus in subjects with SD compared with normal
      controls, as well as to determine the relationship between scalp pruritus and changes in
      cutaneous innervation.

      METHODS:

      This exploratory and pilot study has only a single planned visit to the outpatient
      Dermatology clinic in Shapiro center.

      Subjects who carry the diagnosis of seborrheic dermatitis and scalp itch, or controls who
      don't, (either internally referred through routine visits to outpatient Dermatology clinics
      at BMC or externally referred from outside providers or who respond to recruitment
      techniques) will undergo an initial phone screening to review inclusion and exclusion
      criteria. This screening will involve anonymous screening questions without collection of
      personal health information. Subjects/controls that meet the criteria to be eligible for the
      study will then be asked if they are willing to come to BMC for the single study visit. Those
      subjects/controls that then agree to be scheduled will next be told that we are seeking
      informed consent by phone for the following minimal risk procedures in preparation for the
      study visit:

        1. to place a unique patient code identifier on the screening form and

        2. if they are willing to stop using any topical scalp treatments for seborrheic
           dermatitis/dandruff as well as (c) to stop any prn or elective use of prescribed or
           over-the counter antihistamines for at least 3 weeks before their scheduled visit.

      (d) if they are willing not to wash their hair for at least 48 hours prior to the visit.

      The consent process will include highlighting that the individual can stop the "washout" at
      anytime. Those subjects/controls, after undergoing informed consent process read to them over
      the phone, that agree to (a) and (b) and (c) above, will then be scheduled for a one hour
      visit at the outpatient Dermatology floor during a non-clinic time.

      At this visit, all subjects/controls will first undergo the following:

        1. Visual and non-invasive inspection of the scalp

        2. Completion by the patient of a visual analogue scale (VAS) score to measure degree of
           scalp pruritus over the past week. This VAS form will have no identifiable health
           information.

        3. Review of the inclusion/exclusion criteria answers they provided over the phone, that
           after informed consent by phone at the time they gave those answers, they agreed to
           allow us to store with a unique subject/control identifying code.

      The above 3 minimal risk procedures (one of which the patients have already provided informed
      consent for), will happen before "study visit screening" (described in detail in Screening
      Section 20.0 below) and the second informed consent process is performed. This order is to
      respect the patient's time. If they no longer meet inclusion/exclusion criteria based on the
      above minimal risk screening, they will not be eligible for the study and so would then have
      unnecessarily undergone additional screening as well as an informed consent process.

      After obtaining written informed consent to participate in the study, the following will
      occur:

        1. Female subjects of child-bearing potential will take a urine pregnancy test.

        2. Subjects/controls will fill-out a questionnaire for pruritus and a questionnaire that
           contains additional targeted questions related to their scalp itch and hair care
           practices

        3. Investigators will assess scalp to identify involved, pruritic sites along EEG lead axis
           T3-O1 or, secondarily, along EEG lead axis C3 to Pz. EEG testing is a standard
           non-invasive neurologic test in which scalp electrodes are placed in well-defined and
           specified positions on the scalp. We will not be doing an EEG or using electrodes. We
           are simply using the anatomic landmarks specified for EEG placement to allow uniform
           selection of scalp areas to test and biopsy.

        4. Digital photographs of the patient's head, focusing on the scalp will be taken.

        5. At the selected scalp site, an investigator will perform the following tests for central
           sensitization, at the selected scalp site (see below for methods for these tests):

             -  Warm heat (methods section below explains this procedure) to assess it is or is not
                felt as itch using 3 mm diameter metal probe

             -  Alloknesis (brush to itch: if possible on scalp with hair)

             -  Hyperknesis (enhanced sensation of itch to pinprick)

             -  Duration of itch elicited by insertion of a cowhage spicule into the scalp (if
                possible on scalp with hair). This procedure is described in detail below.

        6. The investigator will then perform a single scalp biopsy procedure at the site of
           central sensitization testing, according to standard of care practices. The 2mm specimen
           will be placed into formalin for routine paraffin-embedding. The 3mm specimen will be
           placed into a special fixative that optimizes immunohistochemistry on frozen sections to
           detect antigens expressed by nerves. These specimens will be labeled with the
           subjects/control's unique identifying code only and without personal health information.

      This one visit completes the subjects/control's entire participation in the study. No
      additional visits will be scheduled (unless the individual has opted for suture option and
      removal of these sutures at BMC) but the subject/control will be provided the contact
      information of the investigator in the rare event that the subject/control requires further
      care as a complication of the biopsy procedure, such as bleeding, persistent pain, infection,
      and/or failure to heal.

      In all biopsies, the density and distribution of different subsets of cutaneous nerve fibers
      will be determined by immunohistochemistry in the frozen-fixed tissue and the presence or
      absence of histopathologic features of seborrheic dermatitis will be evaluated in the
      paraffin-embedded tissue. Left over tissue from either the frozen and/or the
      paraffin-embedded tissue will be saved in a repository if the individual consents, and the
      storage of these tissues and safeguards are described in detail in the tissue banking section
      of the BMC approved IRB protocol.

      Estimated Duration of Enrollment (how long will it take to recruit the required sample size):
      One year.

      Estimated Duration of Entire Study (estimated duration from initial IRB approval through data
      analysis to close of study): Two years Sample Size- Total=60 patients with scalp itch and
      seborrheic dermatitis =30

        -  consent and/or fully participate in study = 20

        -  expected drop outs withdrawal and terminations = 5

        -  screened and not enrolled = 5 patients without scalp itch and without seborrheic
           dermatitis =30

        -  consent and/or fully participate in study = 20

        -  expected drop outs withdrawal and terminations = 5

        -  screened and not enrolled = 5

      Sample Size Justification:

      Although the proposed study is exploratory in intent and does not require a formal power
      statement, we can nonetheless estimate power for the primary outcome of no central
      sensitization in patients with seborrheic dermatitis versus controls for the planned sample
      size of 20 subjects. The expected average mean score for a patient with central sensitization
      is 3 out of 10 and for a control patient 1 out of 10 with a standard deviation of 1.
      Therefore, for there to be no difference between both groups, we would expect both groups to
      have a mean score of 1 with a standard deviation of 1. In this case, if there is truly no
      difference between the control and experimental group (ie, no central sensitization), then 36
      total patients (18 per group) are required to be 80% sure, 40 total patients (20 per group)
      are required to be 85% sure, and 44 total patients (22 per group) are required to be 90%
      sure, that the 90% two-sided confidence interval will exclude a difference in means of more
      than 1. We feel that in this instance, certainty over 80% will be clinically meaningful and
      have opted for 40 instead of 36 to better ensure the date achieves at least 80% certainty.

      For the total number per cohort, some number of patients will contact us and undergo
      anonymous screening questions without collection of personal health information. This number
      is difficult to predict, and those patients that do not meet eligibility criteria based on
      the answers to these anonymous screening questions, are not included in either cohort as
      there is no risk to them, again because no personal health information is being collected.

      Data Analysis:

      The proposed study design is one in which for each one of the three specific aims described
      above, there is one dependent variable (outcome) and 1 independent variable (2 independent
      populations: subjects with seborrheic dermatitis and scalp itch and controls without scalp
      itch or seborrheic dermatitis). For non-normal data, we intend to use a non-parametric test,
      such as the Mann Whitney or Wilcoxon rank sum test to assess for statistical differences
      between the medians between these populations. In addition, we will use non-parametric
      analysis, such as the Spearman correlation to correlate results of the skin testing with
      results of the immunohistochemical counts of nerves. If in fact distributional assumptions
      are met to allow parameteric analysis, we will use a 2 independent sample t-test to assess
      for statistical differences between the means.
    

Intervention name(s): Biopsy
Intervention type(s): Procedure
Intervention description(s): 1 scalp biopsy will be done at the site of central sensitization testing, according to standard of care practices. First, the site will be anesthetized and within this area, 2 immediately adjacent (ie contiguous) punch biopsies will be taken-2mm & 3mm. Both will be closed simultaneously using either (i) non fast-absorbing gut sutures, requiring a 10-14 day follow-up visit for suture removal; (ii) fast absorbing gut sutures that will not require a subsequent suture removal visit, or (iii) gel foam without stitches that also does not require a suture removal visit. Wound care instruction will be discussed with patient. The patient will be instructed to apply petroleum jelly at least 3 times per day to the biopsy site, reflecting standard of care clinical care at BMC.
Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Dermatology clinic patients
      
Biospecimen description: 
      Scalp biopsy
    
Keywords: pruritus; itch; skin; scalp; seborrheic dermatitis