1. 2012;15;255-266Skin Biopsy in Complex Regional Pain Syndrome: Case Series and Literature Review
   Retrospective Review
   Siddharth Kharkar, MD, Yedatore S. Venkatesh, MD, John R. Grothusen, PhD, Luisa Rojas, MD, and Robert J. Schwartzman, MD.

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.