Understanding entrapment neuropathies

Entrapment neuropathies are a common group of conditions that affect small nerves as they pass through narrow anatomical spaces. 

Examples include carpal tunnel syndrome, cubital tunnel syndrome, cervical and lumbar radiculopathies and Morton’s neuroma in the foot. 

Professor Annina Schmid, who is Professor of Pain Neurosciences and a Specialist Musculoskeletal Physiotherapist (in the UK system) at the Nuffield Department of Clinical Neurosciences at the University of Oxford, uses a translational, interdisciplinary approach to study the pathophysiology of neuromusculoskeletal conditions, with the goal of improving their management. 

Her research into neuropathic pain stretches back to her PhD and postdoctoral studies at the University of Queensland. Annina gave three presentations at the Australian Pain Society conference, with a focus on the role played in neuropathic pain by neuroinflammation. 

In early research conducted with Australian neuroscientist Professor Elspeth McLachlan, Annina developed an animal model for entrapment neuropathy by wrapping a silicone tube around the sciatic nerve of young rats. 

In this model, as the nerve grows it slowly becomes compressed by the tube, causing a compression neuropathy with an associated neuroinflammatory response occurring not just at the site of the compression but also further away, at the dorsal ganglia. 

‘This suggests there is neuroinflammation happening, even if the compression of the nerve is very mild,’ Annina said in her presentation. 

Using human nerves in her current research, she and her research team have identified some of the immune system cells and markers that appear to be involved in the neuroinflammation present in people with entrapment neuropathies. 

In nerves removed from patients with Morton’s neuroma, they found that a higher level of immune cells – in particular, macrophages – in the affected nerves correlated with higher levels of paroxysmal pain. 

They are currently using human stem cells reprogrammed into sensory nerves to examine whether specific types of macrophages can indeed increase the excitability of human sensory neurons.

Annina noted that while this work is ongoing, it strongly suggests that neuroinflammation is playing a role in the neuropathic pain experienced by these patients. 

‘These are patients who on average have had about 2.5 years of pain already. 

‘We are not talking here about an acute inflammatory response; this is a very chronic, low-grade, nonresolving inflammatory response.’ 

Annina also talked about studies she did with Australian hand therapist Karina Lewis on people with carpal tunnel syndrome, which showed that in a cohort of patients waiting for surgery, an intervention of education, night splinting and neurodynamic exercises reduced the need for surgery by a not insignificant 21 per cent. 

Annina’s team has since used MRI images to examine the nerves of patients with mild-to-moderate carpal tunnel syndrome, looking at changes to the nerve structure and function and potential correlation to clinical outcomes. 

They compared patients who did neurodynamic exercises without splinting (the intervention group), received a steroid injection (positive control) or received advice on management (negative control). 

Results showed that the patients in the exercise and injection groups had self-reported improvements in symptoms and function compared to the advice group but the researchers were not able to identify any changes to nerve structure or function across the cohort. 

‘While exercise seems to be a powerful intervention to improve patient outcomes in animal models and humans, the exact mechanism in humans still remains to be confirmed,’ Annina said. 

Sciatica was the topic of Annina’s second presentation, during a topical session on the condition, which has recently been renamed as spine-related leg pain or spine-related limb pain, encompassing somatic referred pain, radicular pain and radiculopathy with or without pain. 

Annina and her team have recently finished collecting data for the FORECAST study, a longitudinal study looking at the transition from acute to persistent leg pain in a deeply phenotyped cohort of patients who had been diagnosed with spine-related leg pain. 

The aim of the study is to identify ‘mechanism-based’ predictors like inflammatory markers, nerve sensitivity and psychosocial factors that explain why some patients develop persistent pain while others recover. 

While the team is yet to publish most of their results, Annina presented some of the early findings, including differences in pain experiences across the cohort.

‘Patients with painful radiculopathy have more pain than patients with somatic heightened nerve mechanosensitivity. 

‘They also have more disability and in fact the radicular pain group represents an intermediate phenotype in terms of disability here. 

‘So people with painful radiculopathy are more disabled than people with somatic nerve mechanosensitivity.’ 

She noted that the delineation into different clinical groups could have an impact on treatment choice and that many studies looking at treatments did not do a good job of matching the treatment appropriately to the pain type. 

‘Spine-related leg pain groups are clinically distinct… and they might react differentially to interventions. 

‘We definitely need trials that use more specific case definitions or at least give the case definition very carefully. 

‘We should probably think about that in clinics, too, as well as when we design our next study.’ 

In her final plenary presentation, Annina discussed the potential role of neuropathic pain in whiplash-associated disorders. 

Her research stems from her own clinical observations that many people with a whiplash injury had symptoms of neuropathic pain but a lot of the time, this was not specifically identified or diagnosed. 

She was interested in whether the neuropathic symptoms were appearing early on, during the acute phase of the injury, or only in people with chronic pain from a whiplash injury. 

In a study that looked at patients within one month of a whiplash injury and then followed them up for about six months, the researchers did a very comprehensive neurological examination encompassing muscle testing, reflex testing and sensory tests including light touch to pinprick testing and thermal testing. 

Other testing included tests for immune dysregulation and inflammation, skin biopsies to look at dermal innervation and specialised magnetic resonance imaging to see what was happening in different parts of the nervous system including in the brachial plexus, the dorsal root ganglia and the nerve roots. 

The results of the study strongly suggest that neuropathic pain is involved in a subgroup of people with whiplash-associated disorders. 

‘Two-thirds of patients with acute whiplash grade 2, which is traditionally considered to not have a nerve problem, in fact have neuropathic pain. 

‘There is objective evidence for structural and functional nerve injury in a subgroup of patients but not in all of them. 

‘This was apparent at bedside [when] doing a careful neurological examination, which I think is important for us clinicians. 

‘It was also partially apparent on skin biopsy but not so clearly, definitely in the blood and certainly on MRI scanning, including the microstructural scans that are changed in these patients,’ Annina said, noting that the nerve pathology, although not as a single marker, might be able to weakly predict chronicity. 

Annina highlighted a trial being conducted by Australian Specialist Research Physiotherapist (as awarded by the Australian College of Physiotherapists in 2009) Professor Michele Sterling FACP and her team at the RECOVER Injury Research Centre at the University of Queensland, which is testing whether pregabalin, a drug used to treat neuropathic pain, might prevent central sensitisation from developing. 

‘I’m wondering whether this intervention quite likely might have a beneficial effect on the more neuropathic characteristics of these patients as well.’