Implications of mild peripheral nerve compression beyond the lesion site Mechanisms and interventions

Symptoms in mild compression neuropathies such as carpal tunnel syndrome (CTS) are commonly considered to be driven by peripheral mechanisms. This view concurs with the classical localisation of symptoms in the median nerve territory. However, the majority of patients with CTS present with symptoms and sensory changes outside the median nerve distribution area. Patients with CTS also have a high prevalence of secondary nerve disorders, but controversy surrounds the proposed underlying mechanisms. Most mechanisms have been formulated over a decade ago and have since then not been updated despite substantial advances in neuroscience. Widespread symptoms and a high prevalence of coexisting disorders are commonly observed in patients with severe neuropathic pain conditions and are attributed to central mechanisms. Among other factors, immune-inflammation at the lesion site as well as in dorsal root ganglia (DRG) and the spinal cord are proposed to be responsible for this widespread hypersensitivity. The immune-inflammatory contribution is based on studies using animal models that involve substantial axonal loss. This does not reflect mild nerve compression, which is characterised by demyelination and minimal axonal loss. It therefore remains unclear whether mild nerve compression is sufficient to induce local or remote inflammatory changes. Besides the limited understanding of the mechanisms involved in mild nerve compressions, appropriate conservative treatment strategies for CTS remain elusive. Nerve and tendon gliding exercises are commonly administered and there is reasonable evidence for their effectiveness for CTS. It has been hypothesised that the beneficial effect may be due to a reduction in carpal tunnel pressure with subsequent improvement in blood circulation and dispersal of oedema. The exact therapeutic mechanism remains however to be investigated. The studies included in this thesis aimed to advance our understanding of the neuropathological mechanisms involved in mild peripheral nerve compression, and to determine potential therapeutic mechanisms of commonly used conservative treatment modalities. Most studies that demonstrated widespread sensory changes in CTS did not exclude comorbidities such as neck or shoulder/arm pain. In Study I, we therefore used a comprehensive quantitative sensory testing protocol to investigate whether widespread hypersensitivity in patients with CTS could be substantiated in the absence of coexisting disorders. Whereas sensory changes outside the affected hand could not be replicated, pain during thermal pain testing was rated significantly higher, even at sites distant to the affected hand. This was interpreted as an early indication of the involvement of central mechanisms. Impaired left/right judgement of the affected body part is consistently observed in patients with severe neuropathic pain states where the presence of central mechanisms is commonly accepted. To further investigate the potential involvement of central changes in CTS, Study II used a left/right judgement task for hands, feet, neck and objects. This study revealed a selective impairment in recognition accuracy limited to the affected quadrant, further supporting the presence of central involvement in CTS. Study III used a Delphi design to update views on potential mechanisms underlying dual nerve disorders. An international panel of experts listed 22 mechanisms. The wide range of mechanisms indicated that previous theories may be insufficient to explain the high prevalence of dual nerve disorders. Among the newly suggested mechanisms, immune inflammation was considered a highly plausible mechanism. For Study IV, an animal model was refined which closely mimics mild peripheral nerve compression in humans. The findings demonstrated that mild nerve compression without overt axonal loss is sufficient to induce an inflammatory reaction not only at the lesion site, but also in associated DRG. Therapeutic mechanisms of nerve and tendon gliding exercises and splinting were evaluated in Study V. Intraneural oedema quantified from magnetic resonance images was evaluated. A decrease in signal intensity of the median nerve was apparent following one week of splinting or exercise, whereas signal intensity remained unchanged in patients who received no intervention. Carpal ligament bowing, an indirect measure of carpal tunnel pressure, did not improve after either intervention. To further clarify the findings of Study V, direct measurements of carpal tunnel pressure were made to examine the therapeutic mechanisms of nerve and tendon gliding exercises. Although statistical analysis did not reveal a significant effect of exercise compared to no-treatment, individual changes suggested that a substantial proportion of patients responded to exercise with a reduction in pressure beyond measurement error. The studies included in this thesis provide insight into the pathological mechanisms involved in symptoms following mild nerve compression. The involvement of central mechanisms is further strengthened and the evidence from the animal study proposes immune-inflammation as a neuropathological mechanism. Furthermore, therapeutic mechanisms of nerve and tendon gliding exercises and splinting are elucidated, suggesting that these may be capable of reducing intraneural oedema, and possibly carpal tunnel pressure in a subgroup of patients with CTS. The reduction in intraneural oedema and nerve compression may limit the inflammatory responses observed in the animal study