The relationship of nerve fibre pathology to sensory function in entrapment neuropathy

Annina B Schmid, Jeremy D P Bland, Manzoor A Bhat, David L H Bennett, Annina B Schmid, Jeremy D P Bland, Manzoor A Bhat, David L H Bennett

Abstract

Surprisingly little is known about the impact of entrapment neuropathy on target innervation and the relationship of nerve fibre pathology to sensory symptoms and signs. Carpal tunnel syndrome is the most common entrapment neuropathy; the aim of this study was to investigate its effect on the morphology of small unmyelinated as well as myelinated sensory axons and relate such changes to somatosensory function and clinical symptoms. Thirty patients with a clinical and electrophysiological diagnosis of carpal tunnel syndrome [17 females, mean age (standard deviation) 56.4 (15.3)] and 26 age and gender matched healthy volunteers [18 females, mean age (standard deviation) 51.0 (17.3)] participated in the study. Small and large fibre function was examined with quantitative sensory testing in the median nerve territory of the hand. Vibration and mechanical detection thresholds were significantly elevated in patients with carpal tunnel syndrome (P<0.007) confirming large fibre dysfunction and patients also presented with increased thermal detection thresholds (P<0.0001) indicative of C and Aδ-fibre dysfunction. Mechanical and thermal pain thresholds were comparable between groups (P>0.13). A skin biopsy was taken from a median nerve innervated area of the proximal phalanx of the index finger. Immunohistochemical staining for protein gene product 9.5 and myelin basic protein was used to evaluate morphological features of unmyelinated and myelinated axons. Evaluation of intraepidermal nerve fibre density showed a striking loss in patients (P<0.0001) confirming a significant compromise of small fibres. The extent of Meissner corpuscles and dermal nerve bundles were comparable between groups (P>0.07). However, patients displayed a significant increase in the percentage of elongated nodes (P<0.0001), with altered architecture of voltage-gated sodium channel distribution. Whereas neither neurophysiology nor quantitative sensory testing correlated with patients' symptoms or function deficits, the presence of elongated nodes was inversely correlated with a number of functional and symptom related scores (P<0.023). Our findings suggest that carpal tunnel syndrome does not exclusively affect large fibres but is associated with loss of function in modalities mediated by both unmyelinated and myelinated sensory axons. We also document for the first time that entrapment neuropathies lead to a clear reduction in intraepidermal nerve fibre density, which was independent of electrodiagnostic test severity. The presence of elongated nodes in the target tissue further suggests that entrapment neuropathies affect nodal structure/myelin well beyond the focal compression site. Interestingly, nodal lengthening may be an adaptive phenomenon as it inversely correlates with symptom severity.

Keywords: carpal tunnel syndrome; entrapment neuropathy; nodes of Ranvier; quantitative sensory testing; skin biopsy; small fibres.

© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Figure 1
Figure 1
Somatosensory profiles determined with quantitative sensory testing in the median nerve territory (A and C) and the radial nerve territory (B and D) of patients with carpal tunnel syndrome (orange) and age and gender matched control subjects (green). Data are expressed as mean Z-scores with standard deviations and the grey area indicates the normal range of ± 2SD of the control subjects. (A) Patients with carpal tunnel syndrome have a significant loss of function in all detection thresholds measured in the median nerve territory compared to control subjects. (B) In the radial nerve territory, patients with carpal tunnel syndrome have loss of function in cold (CDT), warm (WDT) and mechanical detection thresholds (MDT) but not vibration detection (VDT). Patients also have a reduced ability to differentiate temperature changes (e.g. thermal sensory limen, TSL). No changes were apparent for any of the pain thresholds measured both in the median nerve territory (C) and the radial territory (D). This indicates that patients with carpal tunnel syndrome overall had a pattern of hypoaesthesia but not hyperalgesia. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. CDT = cold detection threshold; WDT = warm detection threshold; TSL = thermal sensory limen; MDT = mechanical detection threshold; VDT = vibration detection threshold; CPT = cold pain threshold; HPT = heat pain threshold; MPS = mechanical pain sensitivity; MPT = mechanical pain threshold; PPT = pressure pain threshold; WUR = wind-up ratio; CTS = carpal tunnel syndrome.
Figure 2
Figure 2
Patients with carpal tunnel syndrome have a reduced intraepidermal nerve fibre density. Images in (A) show representative skin biopsy sections from an age matched control participant (left) and a patient with carpal tunnel syndrome (CTS, right). Whereas there is an abundance of axons (red, protein gene product, PGP9.5) in the subepidermal plexus (arrow heads), the papillae (asterisks) and the epidermis (arrows) in the control skin, the skin of the patient with carpal tunnel syndrome shows a reduced density of axons in the subepidermal plexus and a clear reduction of axons piercing into the epidermis. Scale bar = 100 µm. The graph in B shows the mean intraepidermal nerve fibre density expressed as fibres per mm epidermis as well as single data points. Patients with carpal tunnel syndrome have a significantly lower intraepidermal nerve fibre density than the matched control group. This reduction was independent of electrodiagnostic test severity (colour coded according to the bar below). ****P < 0.0001.
Figure 3
Figure 3
Representative images of dermal histology in 50 µm thick immuno-stained sections. (A) A Meissner corpuscle located in the dermal papilla. The characteristic winding-like structure of the Meissner corpuscle is formed by axons (red, protein gene product, PGP9.5) and it is innervated by a myelinated fibre (green, myelin basic protein, MBP). Nuclei are stained in blue (DAPI). (B) Example of a Merkel cell complex (red, PGP9.5) located at the base of the epidermis and innervated from fibres originating from the subepidermal plexus (bottom). (C) Representative images of the quantified dermal axon bundles containing more than five axons (red, PGP9.5) in the same section. Whereas the bundle on the top only contains unmyelinated fibres, on the bottom is an example of a dermal nerve bundle that contains two myelinated fibres (green, MBP). Calibration of 50 µm applies throughout. (D) Graph shows a comparable amount of Meissner corpuscles per mm epidermis in patients with carpal tunnel syndrome and controls participants. Data are shown as mean and single data points, P = 0.28. (E) Graph shows comparable percentage of dermal PGP bundles containing MBP-positive fibres between patients with carpal tunnel syndrome and control participants. Plot depicts median and single data points, P = 0.38.
Figure 4
Figure 4
Patients with carpal tunnel syndrome have a higher proportion of elongated nodes. (A) A myelinated fibre (red, protein gene product, PGP9.5; green, myelin basic protein, MBP) with two nodes (arrow heads). The filled arrowhead points towards a clearly elongated node whereas the black arrowhead shows a normal nodal length. Scale bar = 20 µm. (B) The graph shows the percentage frequency histogram of nodal lengths in patients with carpal tunnel syndrome (grey) and control participants (white). There is a shift towards longer node lengths in patients with carpal tunnel syndrome (Kolmogorov-Smirnov P < 0.0001). (C) The graph confirms that the proportion of elongated nodes >6.1 µm is higher in patients with carpal tunnel syndrome compared to control participants (P < 0.0001) and is independent of electrodiagnostic test severity (colour-coded according to bar below).
Figure 5
Figure 5
Elongated nodes are characterized by lengthening of the paranodal gap and dispersion of voltage gated sodium channels. (A) Merged images (first row) of nodes of Ranvier triple stained with MBP (green, second row), Caspr (red, third row) and pNav (blue, fourth row) of a control participant (a) and patients with carpal tunnel syndrome (b–d). Panel (a) depicts a normal node of a control participant with clear demarcation of Caspr staining in the paranodes as well as a short band of pNav staining; and (b) shows an elongated node with separation of caspr staining and dispersion of VGSCs within the nodal gap. This was the most frequently identified pattern. We also found occasional elongated nodes with a separation of Caspr staining and absent pNav staining (c). We also identified some heminodes (d), characterized by pNav staining adjacent to the paranodes with a pNav negative gap in the middle of the node. The calibration of 5 µm applies throughout. (B) shows the mean length of the Caspr gap in patients with carpal tunnel syndrome (orange) and control participants (green). This gap was significantly elongated in patients with carpal tunnel syndrome (P = 0.021). (C) The mean length of nodal pNav staining was significantly higher in patients with carpal tunnel syndrome compared to control participants (P = 0.026).

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