This blog summarises the available evidence on the influence of entrapment neuropathies on the anatomical and physiological features of the peripheral nervous system that have previously been discussed. Let’s get started!

Entrapment Neuropathies and Ischaemia

Entrapment neuropathies are hypothesised to disrupt intraneural blood flow by reversing the pressure gradient required for optimal blood supply. Extraneural pressures as low as 20–30 mmHg interrupt intraneural venous circulation, while pressures as high as 40–50 mmHg decrease arteriolar and capillary blood flow (Rydevik B. et al. 1981).

Extraneural pressure is higher in patients with entrapment neuropathies. Pressures above 50 mmHg were measured around the afflicted nerve roots in patients with lumbar disc herniations, with some patients exhibiting pressures as high as 250 mmHg (Takahashi K. et al. 1999). Such increased pressures, especially if present for an extended period of time, will be sufficient to reverse the usual pressure gradient, creating venous return obstruction with subsequent intraneural circulation slowing and oedema formation (Sunderland S. 1976).

Patients with entrapment neuropathies frequently have transient ischaemia. It not only explains the traditional position-dependent paraesthesia, but it can also help reproduce symptoms during provocative exercises. Whereas real neurological abnormalities are usually persistent, fluctuations with positional changes, for example, have been observed (Hough AD et al., 2007; Sabbahi MA; Ovak-Bittar F., 2018). Such fluctuations may be due to ischemic conduction block rather than demyelinating conduction block.

Ischemia can also cause the normal nighttime aggravation of symptoms that subsides with modest movement. The physiological nightly decline in blood pressure and associated dip in intraneural blood flow (Low PA, Tuck RR. 1984) can reverse the pressure gradient, resulting in ischaemia, alterations in metabolic activity, and ectopic firing. Venous distension can potentially contribute to pain by stimulating venous afferents (Sumikawa K. et al. 2001). Ischemia may be seen in mild entrapment neuropathies in the absence of structural abnormalities. This is demonstrated by the quick alleviation of symptoms in certain patients following surgery (Werner RA; Andary M. 2002). Enlargement of the compressed nerves (Nakamichi KI, Tachibana S. 2000; Yoon JS, et al. 2010) and increases in signal intensity on specialised magnetic resonance sequences (Cudlip SA, et al. 2002; Sirvanci M, et al. 2009; Lewis AM, et al. 2010) are clinical signs of oedema in entrapment neuropathies.

Oedema can eventually lead to intraneural and extraneural fibrotic alterations affecting connective and adipose tissues if left untreated (Mackinnon SE, 2002). Neural fibrosis has been reported in both radiculopathies (Ido K., Urushidani H. 2001) and peripheral nerve trunk entrapments (e.g., cubital and carpal tunnel syndrome) (Abzug JM et al. 2012).

Extraneural fibrotic alterations may be responsible for compressed nerves’ reduced gliding ability in relation to their surrounding tissues. However, such biomechanical changes are unlikely to be the only mechanism underlying signs of increased nerve sensitivity during neurodynamic testing (for example, provocation of symptoms, change in symptoms by moving joints away from the symptomatic area [structural differentiation], and potentially reduced range of motion). Positive neurodynamic tests in individuals with entrapment neuropathies may instead be explained by a variety of neurophysiological alterations leading to greater neural mechanosensitivity.

Entrapment Neuropathies Cause Demyelination

Focal demyelination is thought to be a defining feature of nerve entrapments (Mackinnon SE, 2002). Demyelination is a common side effect of prolonged ischaemia, which causes Schwann cell failure (Nukada H, et al. 1993), but it can also be linked to mechanical deformation (Lin MY, et al. 2012) or a cytotoxic environment caused by processes such as inflammation.

Histological data from animal models of mild nerve compression (O’Brien JP, et al. 1987; Schmid AB, et al. 2012; Gupta R, et al. 2004) and from patients with entrapment neuropathies (Foix C, Marie P. 1913; Neary D. 1975; Mackinnon SE, et al. 1986) confirm focal demyelination and remyelination with intra-fascicular fibrosis and connective tissue thickening. Similar histological results have been found in asymptomatic people at common entrapment locations (Jefferson D., Eames RA. 1979; Neary D., et al. 1975). This shows that such focal histological changes may not always result in symptoms. Myelin alterations spread beyond the lesion site in addition to focal demyelination. Demyelination of the tibial nerve following focal mild nerve compression of the sciatic nerve in rats (Schmid AB, et al. 2013) and the presence of elongated nodes of Ranvier in skin biopsies taken more than 9 cm beyond the compression site in patients with carpal tunnel syndrome (Schmid AB, et al. 2012) support this.

Because ion channels can be more easily inserted into the membrane at demyelinated regions and the neuronal cell body, changes in ion channel configuration are more common at these sites (Liu X, et al., 2001; Jiang YQ, et al., 2008; Drummond PD, 2014; England JD, et al., 1994).

These ion channel alterations have been linked to spontaneous ectopic action potential production (Amir R. et al., 1999; Chen Y., Devor M., 1998). Because action potentials are normally relayed but do not originate along the axon or cell body, these sites are referred to as aberrant impulse-producing sites.

Changes in the configuration of ion channels in entrapment neuropathies may not only underpin ectopic activity (e.g., paraesthesia, Tinel’s sign, nerve mechanosensitivity upon palpation), but may also impair normal saltatory impulse conduction, resulting in the characteristic slowing or block of nerve conduction during electrodiagnostic testing (Mallik A., Weir AI., 2005; Kiernan MC, et al., 1999).

Entrapment Neuropathies Affect Both Large- and Small-Diameter Nerve Fibres

In an animal model of mild nerve compression (Schmid AB, et al. 2013), a predominant compromise of small axons with structural sparing of large axons (apart from demyelination) was observed, contrary to common beliefs that small fibres are relatively resistant to compression (Dahlin LB, et al. 1989).

Most studies using quantitative sensory testing suggest loss of function of small myelinated and unmyelinated fibres (deficit in cold and warm detection) in both lumbar and cervical radiculopathy as well as CTS (Schmid AB, et al. 2014; Witt JC, et al. 2004; Tamburin S, et al. 2010; Chien A, et al. 2008; Tampin B, et al. 2012; Samuelsson L, Lundin A. 2002).

Several studies find significant alterations of sympathetic axon function in patients with CTS and radiculopathy (Wilder-Smith EP, et al. 2003; Kiylioglu N., 2007; Kuwabara S, et al. 2008; Kiylioglu N, et al. 2005; Reddeppa S, et al. 2000; Erdem Tilki H, et al. 2014), and laser-evoked brain potentials (mediated by A and C fibres) are reduced in patients with CTS (Arendt-Nielsen L, et al. 1991).

In patients with entrapment neuropathies, tiny fibres are damaged not only in function but also in structural integrity (Schmid AB et al. 2014; Ramieri G et al. 1995). This is evidenced by a significant loss of epidermal nerve fibres in the skin of CTS sufferers.

The effect of the detected loss of tiny fibres on the diagnosis and management of entrapment neuropathies has to be investigated further. Interestingly, preliminary studies in patients with CTS symptoms but normal neurophysiology imply that alterations in electrodiagnostic testing may precede changes in small axon dysfunction or loss (Schmid AB et al., 2024; Tamburin S et al., 2010). These findings suggest that tests for small fibre function should be included in the early diagnosis of entrapment neuropathies. Simple bedside neurological tests (e.g., pin prick sensitivity, cold and warm detection), as well as more equipment-intensive examinations such as quantitative sensory testing, sympathetic reflex testing, laser or heat-evoked brain potentials, or skin biopsies, are examples of clinical small fibre tests.

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