Peripheral nerve pathology in patients with severely affected complex regional pain syndrome type I

Abstract

Complex regional pain syndrome type I (CRPS-I) is a chronic pain syndrome with no clinical evidence of nerve injury; however, recently, changes in muscle tissue have been found in case of CRPS-I. Our aim was to search for histological changes in peripheral nerves of amputated limbs from patients with therapy-resistant CRPS-I that could justify muscle tissue changes. Fifteen patients with CRPS-I (duration >1 year) were included. Multiple nerve samples were taken from upper (n=4) and lower (n=11) amputated limbs. Histological changes (signs of nerve fiber loss and regeneration), fiber diameters, fiber diameter distribution, and fiber density were studied through microscopy and morphometry. Samples from three healthy sural nerves were used as control data as well as data from the literature. All patients (93% of tissue samples) showed histological signs of nerve fiber loss and fiber regeneration, varying in severity. No specific preference was found for any nerve or the location within the nerve. Sural nerves showed loss of especially larger nerve fibers (>12 μm) in comparison with control data. Sympathectomy did not influence this finding. The morphometric results of the other nerves are more difficult to interpret because of the absence of good-quality control data from the literature. However, the percentages of nerve fibers greater than 12 μm seem to lie within the normal range. Besides the known pathology of thin nerve fibers innervating the skin or blood vessels in CRPS-I, this study also shows pathological changes more proximal in the nerves, especially in the sural nerve.

Transcranial magnetic stimulation of the brain

“… 71 Neuropathic pain syndromes are reported to benefit most from rTMS of the motor cortex, 58 but some chronic pain syndromes labeled as “nonneuropathic” 58 include conditions such as CRPS I and fibromyalgia (FM) that have been associated with nerve injury. 7 , 38 , 84 – 86 Focal lesions with defined onset, for instance from shingles or trauma, have the advantage of known localization and time of onset, but early cases often improve spontaneously, which complicates the outcome; therefore, established cases, for instance of more than a year's duration, are preferable.…”

Selective Fiber Degeneration in the Peripheral Nerve of a Patient With Severe Complex Regional Pain Syndrome

“…Figure 2 depicts an entire nerve fascicle, with evidence of myelinated nerve fibers. Myelinated nerve fiber densities were calculated and compared to other CRPS affected nerves from the literature (Geertzen et al, 2015 ; Table 3 ). In addition, radial myelinated nerve fiber density was compared to healthy nerves from the literature (O'Sullivan and Swallow, 1968 ; Table 3 ); the medians of radial nerves in our study and healthy radial nerves in O'Sullivan and Swallow were similar.…”

“…Concerning peripheral nerves, a decrease in myelinated nerve fiber density has previously been demonstrated (van der Laan et al, 1998 ), and an animal model has suggested it affects primarily large fibers (Guilbaud et al, 1993 ). Another human study has also shown histological evidence of nerve fiber loss and regeneration in CRPS nerves, with specific large nerve fiber loss when compared to controls (Geertzen et al, 2015 ). Several hypotheses for peripheral nerve damage in CRPS have been proposed: local pressure from oedema (Guilbaud et al, 1993 ), microvascular ischemia from oxidative stress(Coderre and Bennett, 2008 ), retrograde degeneration (Geertzen et al, 2015 ), neurogenic inflammation(Weber et al, 2001 ), and decreased metallothionein (oxidative stress) (Oki et al, 2012 ).…”

“…The pathophysiology of CRPS remains elusive, and consequently treatment options are still inadequate. Several pathophysiological hypotheses have been suggested: Central nervous system (CNS) reorganization (Maihöfner et al, 2007 ; Lebel et al, 2008 ; Cohen et al, 2013 ), inflammation (Huygen et al, 2004 ; Parkitny et al, 2013 ), neurogenic inflammation from neuropeptides (Birklein et al, 2001 ), peripheral nerve pathology (van der Laan et al, 1998 ; Geertzen et al, 2015 ), capillary dysfunction (Schattschneider et al, 2006 ; Tan et al, 2012 ), and autoimmunity (Blaes et al, 2004 ; Kohr et al, 2009 ; Dirckx et al, 2015 ). Concerning peripheral nerves, a decrease in myelinated nerve fiber density has previously been demonstrated (van der Laan et al, 1998 ), and an animal model has suggested it affects primarily large fibers (Guilbaud et al, 1993 ).…”

The role of peripheral nerve injections in the diagnosis and treatment of CRPS

“…Geertzen et al [17] in a case-control study, found that 79.2% of patients with CRPS were able to relate a major stressful event at least 3 months prior to the disease versus 21.4% of the control group. Dilek et al [18] also showed that high anxiety was correlated with a higher incidence of CRPS after distal radial fracture.…”