Skin biopsy as diagnostic tool in anterior cutaneous nerve entrapment syndrome (ACNES): A Pilot Study

The abdominal wall is an underrecognized cause of abdominal pain. Chronic
abdominal pain originating in the abdominal wall is termed Chronic Abdominal
Wall Pain (CAWP). A CAWP syndrome is often due to the anterior cutaneous nerve
entrapment syndrome (ACNES). This is caused by unknown triggering of the
anterior and lateral cutaneous branches of anterior rami of thoracic
intercostal nerves 7th-12th in the rectus abdominis muscle. These nerves
provide both motor innervation of the rectus abdominis muscle and sensory
innervation of the abdominal wall.

The diagnosis ACNES is based on clinical findings. Comprising a combination of
patient*s history, physical examination and pain relief after trigger point
injection (TPI) with a local anaesthetic. Most distinctive is a continuous,
localized pain of the abdomen which can be located with a fingertip. Specific
findings during physical examination are altered sensibility (hypo-,
hyperesthesia or allodynia) of the skin surrounding the painful spot, altered
cold perception, a disproportionate pain while pinching the skin (hyperalgesia)
and a positive Carnett sign at the trigger point.

To date, no truly objective diagnostic modality is available to confirm the
diagnosis. The end branches of the anterior cutaneous nerve are too small to be
identified on imaging tests. Most patients had an extensive diagnostic
evaluation, such as laboratory test and (multiple) abdominal imaging without
abnormalities and therefore lacking an explanation for the abdominal pain.

In the ongoing search for diagnostic modalities to confirm or support the
diagnosis ACNES, we looked at other neuropathic pain conditions. Patients with
Small-Fibre Neuropathy (SFN) have similar sensory abnormalities (altered
sensation for pain and temperature) as seen in patients with ACNES. In SFN, it
is known that Aδ- and C-fibres are affected. Myelinated Aδ-fibres and
unmyelinated C-fibres regulate temperature sensitivity and pain sensation of
the skin. These intraepidermal nerve fibres (IENF) can be quantified by skin
biopsy, defined as intraepidermal nerve fibre density (IENFD). In SFN, the
intraepidermal nerve endings are degenerating, resulting in a reduced IENFD.

Although there is a resemblance in sensory symptoms, it must be realized that
SFN is, in contrast to ACNES, a generalized polyneuropathy. However, skin
biopsies also have been performed in single nerve entrapment neuropathies like
carpal tunnel syndrome (median nerve) and meralgia paresthetica (lateral
cutaneous femoral nerve). In both disorders, skin biopsies have been taken from
the skin innervated by the affected nerve and compared with healthy controls or
an unaffected region of the skin in the same patient. These biopsies showed a
significantly reduced IENFD in the affected skin of both patient groups with
carpal tunnel syndrome and meralgia paresthetica.

A reduced IENFD has also been demonstrated in different neuropathic pain
conditions, but has never been examined in patients with ACNES. Therefore, we
want to measure IENFD in patients with ACNES. A 3-mm punch skin biopsy will be
taken from the affected skin of the abdominal wall. Skin biopsy and
quantification of the IENF will be done in accordance to the guideline of the
European Federation of Neurological Societies for skin biopsy in SFN. The
guideline is predominantly written for skin biopsy in the diagnosis for SFN.
For this indication skin biopsy is performed at the distal leg. At the distal
leg, normative reference values of IENFD are known. Unfortunately, those
reference values cannot be applied to IENFD for other parts of the skin, as
there is a proximal to distal gradient in IENFD. The guideline recommends to
take a control biopsy of the contralateral non-affected side, when measuring
IENF in unilateral neuropathic pain conditions at sides other than the distal
leg. Therefore, we will perform a second skin biopsy at the contralateral
non-affected side of the abdominal wall.

We hypothesize that patients with ACNES will have a reduced IENFD of the
affected skin compared to the contralateral non-affected skin. This will
potentially demonstrate measurements of IENFD as the first objective diagnostic
technique supporting the diagnosis ACNES. Moreover, it will give further
insight in the pathophysiology of ACNES. This can possibly result in exploiting
new, more effective, treatment options.

Our primary objective is to determine if there is a reduced IENFD in patients
with ACNES. We hypothesize there will be a reduced IENFD of the affected skin
(side of the pain) in comparison to the non-affected side.

Our secondary objectives are to see if there are any correlations between
reduction of IENFD and;
- Duration of pain (months)
- Average pain score on numeric pain rating scale (NRS) before start of
treatment
- Treatment response

A mono-center, prospective cohort study.

Skin biopsies are a well known and often used diagnostic tool. The only
reported complications are mild wound infection and bleeding. Complications are
estimated at 1.9:1000 skin biopsies. Local treatment is sufficient to treat the
complications.
Wound will not need sutures.
Therefore, we believe that the minimal risks of a 3-mm skin biopsy are
negligible in contrast to the potential benefits (first diagnostic test in
ACNES and a potential better understanding of the pathofysiology).