The Role of Nerves and Sensibility in Keloids: Functional Sensory Testing and Clinical Correlation

Almost every person develops scars during his or her life, as a result of
dermal injury caused by either trauma, surgery or infection. When the skin is
injured and skin integrity is disrupted, a physiological process, known as the
wound healing cascade, is initiated. This finely orchestrated process involves
several overlapping phases and starts with hemostasis. Dermal injury causes
disruption of the vascular endothelium and exposure of the basal lamina, which
results in platelet activation, initiating the coagulation cascade and the
release of several growth factors and mediators. Immediately following
hemostasis, inflammation takes place to clear debris and bacteria. This phase
lasts 4 to 6 days. Subsequently, the proliferative phase starts, during which
new tissue is formed and the epidermis is restored. Fibroblasts form a new
matrix consisting of type III collagen, glycosaminoglycans and fibronectin.
This matrix is later remodelled during the last phase of wound healing, the
maturation phase which can last to over 1 year. A normal, matured scar then
appears as a thin white line.

Complex interactions between different cell types occur, as does the release of
several growth factors and mediators to finely orchestrate the wound healing
process. Any disturbance of this complex process can lead to problems such as
chronic wounds or excess formation of scar tissue, ranging from hypertrophic to
keloid scars.
Hypertrophic scars are raised, red, firm and thick scars that develop rather
early in the maturation phase (usually several weeks after injury) and tend to
regress spontaneously after a prolonged maturation phase.
Keloid scars are less common and develop sometimes months to even years after
injury and are characterized by raised exophytic growth beyond the borders of
the original wound. As opposed to hypertrophic scars, keloids do not regress
spontaneously and are often refractory to many treatments. These pathologic
scars give rise to a range of aesthetical, psychological and physical symptoms,
impairing both psychological and physical quality of life. A recent study by
Bijlard et al investigated the impact of keloid disease of health-related
quality of life (HRQL) and found that keloid disease was associated with a
considerable impairment of emotional and mental HRQL. Of keloid patients with
substantial pain and itch scores (> 3 on a 10 point scale), 70% had severe
emotional HRQL impairment compared with 16% in keloid patients who had low pain
and itch scores, showing that pain and pruritus are the main indicators of
emotional HRQL impairment. Pruritus has been reported to occur in 86% of
keloids and the prevalence of keloid-related pain has been reported to be 46%.

To date, the questions of why keloid patients experience pain and which are the
underlying mechanisms remain unanswered. Saffari et al explored whether the
keloid-related pain was rather nociceptive or neuropathic, but their study
showed a wide variation of possible pain mechanisms involved and a wide
variation between the pain experiences in individual patients.

Previously, a possible role for nerve fibres was hypothesized in keloid
pathogenesis. Using quantitative sensory testing (QST), thermosensory
thresholds to warmth and cold were assessed in the keloids and a loss of
sensory perception was found, showing abnormalities in small fibre function,
which suggests the presence of small fibre neuropathy. However, both of the
studies that performed QST were explorative and included a very small number of
patients, which limits the generalisability of the conclusions.

Based on the current knowledge, we hypothesize that clinical symptoms of pain
and pruritus in keloids are correlated with nerve fibre function and thus with
functional sensory testing. A better understanding on the role of nerves and
the pathogenesis of keloids can lead to new insights for future therapeutic
options.

The primary objective will be to evaluate the sensation of the keloids as
measured by Semmes-Weinstein monofilaments (SWM), Pressure Specified Sensory
Device (PSSD) and/or Quantitative Sensory Testing (QST), compared between
patients with and patients without substantial clinical symptoms of pain and
pruritus.

Secondarily, each patient will serve as their own control to compare functional
sensibility between keloids and control skin. Furthermore, we will investigate
the association between patient characteristics and sensibility.

This prospective observational study will be conducted at the department of
Plastic, Reconstructive and Hand Surgery of the Maastricht UMC+. Maastricht
UMC+ has a specialized multidisciplinary outpatient clinic for complex scar
management, where patients from all over the region are followed up on a
regular basis. The specialized *scar* clinic focuses mainly on hypertrophic and
keloid scar care. The multidisciplinary team consists of a physiotherapist
specialized in scar treatment, an orthotist, a resident in plastic surgery
and/or a plastic surgeon.
Patients who wish to participate with this study, will undergo functional
sensory testing of their keloids and contralateral unaffected control skin.
Other than functional sensory testing no interventions that aren*t part of
standard care will be performed.

This study doesn*t create specific additional risks, nor does it provide
additional benefits to participants. The participants will undergo sensory
testing in order to investigate the role of nerves in keloids and whether there
is a correlation between clinical symptoms and functional sensibility. The main
burden associated with participation is the time investment for sensory
testing, which is estimated at 20 minutes.