Background: Accumulating experimental and clinical evidence supports the hypothesis
that complex regional pain syndrome type I (CRPS-I) may be a small fiber neuropathy.
Objectives: To evaluate the use of commercially available standard biopsy methods to
detect intradermal axon pathology in CRPS-I, and to ascertain if these structural changes
can explain quantitative sensory testing (QST) findings in CRPS-I.
Study Design: Retrospective review of charts and laboratory data.
Setting: Outpatient clinic
Methods: Skin biopsies from 43 patients with CRPS-I were stained with PGP 9.5,
and epidermal nerve fiber density, sweat gland nerve fiber density and morphological
abnormalities were evaluated. Thirty-five patients had quantitative sensory testing.
Results: Alterations in skin innervation were seen in approximately 20% of CRPS-I
patients with commercial processing. There were no patient characteristics, including
duration of disease, that predicted a decreased epidermal nerve fiber density (ENFD). There
was no consistent relationship between QST changes and ENFD measured by standard
commercial skin biopsy evaluation procedures.
Limitations: Commercial processing of tissue does not utilize stereologic quantitative
analysis of nerve fiber density. Biopsy material is utilized from a proximal and distal source
only, and differences in denervation of a partial nerve territory may be missed. The
functional attributes of small fibers cannot be assessed.
Conclusions: The negative results indicate that CRPS-I may be associated with changes
in the ultramicroscopic small fiber structure that cannot be visualized with commercially
available techniques. Alternatively, functional rather than structural alterations of small
fibers or pathological changes at a more proximal site such as the spinal cord or brain may
be responsible for the syndrome.
Key words: Complex Regional Pain Syndrome, CRPS-1, CRPS, skin biopsy, epidermal
nerve fiber density, sweat gland nerve fiber density, quantitative sensory testing.
Significant difference between three observers in the assessment of intraepidermal nerve fiber density in skin biopsy
