Diagnosing small fiber neuropathy in sarcoidosis patients using corneal confocal microscopy

Recently, it is recognized that small fibre neuropathy (SFN) occurs in many
patients suffering from sarcoidosis and may be the
underlying cause of the poor HRQL. The precise prevalence of SFN in patients
with chronic sarcoidosis remains unknown, but
some studies suggests it might be as high as approximately 75%. SFN only
affects the small myelinated A* and unmyelinated
C-fibres, also known as small somatic and autonomic fibres respectively. With
common nerve conduction tests, only large
myelinated nerves are investigated. As consequence, SFN is complicated to
diagnose following the regular procedures.
Currently, the diagnosis of SFN is highly underestimated due to lack of a gold
standard and awareness among clinical
physicians. The most commonly available diagnostic tools for SFN are nerve
conduction studies and electromyography, in order
to exclude polyneuropathy, skin wrinkling test, skin biopsy and quantitative
sudomotor axon reflex testing (QSART). Skin biopsies
show a decreased intra-epidermal nerve fibre density (IENFD) in patients with
SFN. Corneal confocal microscopy (CCM) is a
relative new technique. As well as skin biopsies, it measures the amount of
small nerve fibres. Although CCM and IENFD show
comparable sensitivity and specificity, CCM has some major advantages. It is a
quick, non-invasive technique, it shows higher
reproducibility and allows multiple replicates in both cross-sectional and
longitudinal studies. Moreover, it can be evaluated manually,
semi-automatically, and automatically. Additionally, it is even suggested that
corneal nerve fibre density is inversely related to
symptoms in patients with painful sarcoidosis related neuropathy. The
translation of CCM from research domain to clinical
diagnosis has been limited by lack of normative reference values, the
requirement of specific training and limited clinical question. In
order to support the diagnostic value of CCM, additional research is required.
Introduction of phenotyping SFN, might explain the great variety between
different outcome measures, from different diagnostic methods. Additionally,
sudoscan and blood pressure measurements will be performed. Those can measure 2
types of autonomic small fiber functions. This way, all phenotypes can be
measured with corresponding diagnostic methods. Consequently, it can be
confirmed whether or not phenotypes can be distuighuised.

Primairy objective:
Validating of nerve fiber length, nerve fiber density, nerve fiber branches and
tortuosity of a healthy control group, sarcoidosis patients with small fiber
neuroapthy and sarcoidosis patients without small fiber neuropathy.

Secondary objectives:
- Validating skin wrinkling grade: grade 0-4
- Validating Electrochemical skin conductance
- Validating BP to postural change
- SFNSL-score: <11 no SFN, >48 SFN confirmed
- Phenotypes: SFSCD, SFMNP, SFMWP and SFMAD

This is a prospective observational study with all sarcoidosis patients
admitted in one year to the ILD-department of the St. Antonius hospital.

The participants have to answer the SFN-scoring list (SFNSL) with 21 multiple
choice questions, give a VAS-score, CFQ-score and FAS-score and perform the
skin wrinkling test. Nerve conduction studies (NCS) and electromyography (EMG)
measurement are performed to exclude polyneuropathy. Blood pressure to postural
change measures the autonomic function of small never fibers. Except for the
questionnaires, those tests are all part of standard care. With the temperature
threshold test, a thermode is used to apply different temperatures at the
thenar eminence of digit 1 and at the foot. The thermode does not apply
harmfull temperatures. The sudoscan measures skin conductance between two
electrodes. Blood pressure measurements are routine measures, which can be
performed within 10 min and do not show any detrimental effects. Skin biopsy is
a safe and easy procedure and part of standard care for dermatologists. Serious
or major adverse events are not expected and the risk of an increase in
morbidity or mortality is considered negligible. Detrimental effects may be:
bleedings, bruises, allergic reaction on anesthaetics and scars. For the CCM
measurements, ophthalmic anaesthetics are applied on the eyes of interest. The
CCM measurements takes 2 minutes. Serious or major adverse events are not
expected and the risk of an increase in morbidity or mortality is considered
negligible. Possible negative effects of the CCM are infection and abrasion.
The lens will be carefully disinfected to minimize the risk. Patients with
epithelial defects, ulcers and corneal epithelial or basement dystrophies, may
be at higher risk of corneal abrasion. The obtained information has a great
value for the diagnosis to SFN in patients suffering from sarcoidosis. It is
expected that CCM is a reliable, non-invasive and quick method to diagnose SFN.