2

How we may be misdiagnosing peripheral entrapment neuropathies. (Part 1)

The purpose of this blog is to critically review how I and other physiotherapists assess and diagnosis peripheral entrapment neuropathies (PEN) and make the case that there may be inadequacies in the way we do so.

To demonstrate this, we will encounter a fictitious case study with annotated thought processes labelled “Brain” to suggest how our findings from commonly used tests inform our clinical reasoning. I will then isolate each process and critically appraise literature to explain what our clinical tests may be measuring, and how these tests may be inadequate in accurately assessing and diagnosing PEN.

As a learning objective for the reader, I hope by the end of this blog, you may be able to answer the question of why a person may have peripheral entrapment neuropathy even when they have:

1. Symptoms of PEN more than the expected dermatomal pattern
2. Normal neurological testing of sensation, power, and vibration.
3. Negative neurodynamic testing
4. Normal neurophysiological testing

Case Study

Subjective History

Josephine is a 45-year-old typist who complains of a gradual 3-month onset of pins and needles, and numbness in her right hand and fingers.

She reports:

Aggravating factors: Typing for 10 minutes at their work computer

Easing factors: Shaking her hand gets rid of her symptoms

Brain: “Textbook presentation, it’s probably carpal tunnel syndrome (CTS), but just to be sure I’ll do my clinical tests to validate my hypothesis.”

Location and spread of symptoms

Brain: “Hmm..that’s odd, their symptoms are more than that of the median nerve distribution. Must just be an atypical CTS, or it could be coming from the neck.”

On examination:

Neck combined movements, Spurling’s and palpation of the neck: no reproduction of hand symptoms

Brain: Does not seem to be coming from the neck, let’s continue to look more locally.

Neurological examination:

• Sensation to light touch: No sensation loss
• Wrist and Grip strength: No weakness indicated
• C5/C8 Reflex: Normal
• “Special test” (Tinel’s tap and Phalen’s compression): Symptoms not reproduced
• Neurodynamic tension test of Radial/Median/Ulna nerve: Symptoms not reproduced

Brain: “Neurological examination and special tests appear to be normal, but let’s check their nerve conduction study results, that should tell me everything”

Nerve conduction study: 

Negative: No abnormal findings on all tests

Brain:  Not likely CTS, let’s consider other differentials.

What do we know so far?

• Symptoms worse at work, there could be stress related to work
• Their symptoms are widespread and unclear, could be centrally driven
• Their peripheral nerve function appears normal

Brain:  In a case where there are no clear local mechanisms of pathology, with the presence of diffused symptoms, and negative psychological factors, then a diagnosis of central sensitisation should be considered.  

Case Evaluation 

• I followed the American Academy of Orthopaedic Surgeons (2008) clinical practice guidelines in the diagnosis of CTS.
• I systematically reasoned through differential diagnosis and excluded them as I went through my assessment.
• I was able to disprove my initial hypothesis and changed my diagnosis according to my findings.
• If peripheral entrapment neuropathy is excluded, and there are features of diffused pain distributions and potential psychological factors involved, I should consider central sensitisation factors (Adams & Turks 2015).
• I recognised there maybe workplace stress and the patient is worried about their symptoms, there may be central changes in which I should explore and assess.

If you read the case above and found that it was a reasonable assessment with little changes needed, then hopefully this blog will bring food for thought. The main argument of this blog is that what was done in this case study may not be enough to diagnose PEN and lead to misdiagnoses and management.

Pathophysiology of peripheral entrapment neuropathies 

There is no clear definition of PEN in the literature, but the consensus is that it is a group of disorders of the peripheral nerves that are characterized by pain and/or loss of function of the nerves as a result of chronic compression (Hanna 2017). The clinical presentation of PEN is traditionally considered to be driven by local mechanisms. These include a cascade of cellular-level reaction at the injured nerve where demyelination and ectopic firing of the nerve occurs (Schmid et al., 2014).

Sensory nerve morphology and roles

Different nerve fibres exist within a sensory nerve, along with their roles, density and reaction to different types of injuries. A-Beta fibres are large and myelinated and have roles in mechanical detection of touch and vibration. In contrast, A-delta fibres are smaller and myelinated, whilst C fibres are even smaller and unmyelinated; both have roles in thermal and pain detection.

The figure below is interpreted from Erlanger & Gasser (1924) seminal neurophysiological studies.

Distribution

In electron microscopy images of the sciatic nerve in rats, there is a difference in abundance of the large myelinated A-beta fibres and the small A-Delta and C-fibre cells. It is estimated that there is a 20% large fibre density compared to an 80% small fibre density (Schmid et al., 2014).

Which nerves are affected in peripheral entrapment neuropathies?

PEN usually is as a result of chronic constriction and differs from acute neuropathies where acute trauma or lesion has occurred. This seems to influence which sensory nerves are affected and may be important in how we assess patients with these two different mechanisms of injury.

In acute and traumatic crush nerve injuries, it has been well established that the nerve goes through the phases of Wallerian degeneration where progressive axonal changes occur. This mechanism indiscriminately affects both the large fibres and the small fibres sensory nerves (Ding & Hammarlund, 2019). However, in gradual constrictive injuries, evidence suggests small fibre dysfunction is more likely to occur whilst large fibres are spared (Menorca et al., 2013).

Gupta and Steward et al. (2003, 2004) studied the nerve morphology of rats subjected to chronic nerve constriction injuries using constriction tubes and evaluated the results using electron microscopy.  What they found were processes associated with neuroinflammation and nerve degeneration including cell apoptosis and demyelination. They also found there were no detectable changes to nerve conduction in neurophysiological studies. This may suggest that there is a preservation of axonal function despite ongoing nerve injury and may mean that large sensory fibres are spared in PEN.

However, the main limitation of using animal models in peripheral nerve research is that we are unable to directly generalise data from animal studies to humans. This is due to the physiological differences in peripheral nerve morphology in animals and humans. In the literature comparing nerve morphology of rats, cats, primates and humans, there are differences of ranges of densities and counts of myelinated axons, axon diameter and myelin thickness across species Furthermore, the procedures were performed on very young animals who are free of co-morbidities. Induced nerve injuries are artificial and do not mimic injuries occurred in nature which may include stretch, lacerations, neuroma formation or a combination of all these modes of injury seen in clinical settings.  Nevertheless, the replication of nerve ligation and constriction injuries may produce irreversible nerve damage and hence the process is not performed in humans (Mohanty et al., 2019).

When possible, human tissue can be used for anatomical investigation, although several problems arise with the lack of perfusion and subsequent degradation of myelin sheaths (Saliani et al., 2017).   Schmid et al. (2014) studied the histology of sensory nerves fibres by taking skin biopsies from participants with CTS and used staining techniques to assess the large and small fibre changes to chronic constrictive nerve injuries. Findings are suggestive that there is a greater loss of small nerve fibres compared to that of large nerve fibres which remain largely intact. This was further validated with quantitative sensory testing, a clinically valid tool in the assessment of sensory nerve function and found a greater dysfunction in small nerve fibre function compared to large nerve fibre function.

However, the difficulty of interpreting this study and its novel methods in the assessment of nerve morphology is that in the wider research, there is no agreed standardised assessment of nerve morphology due to the varied parameters used by researchers. It is therefore difficult to draw a consensus from the literature-based as there are issues with inter-rater reliability of nerve morphology studies.

These studies provide an insight into the possible pathophysiological mechanisms in people presenting with constriction type PEN and suggest that there are greater small fibre degradation and minimal large fibre changes. This is important as the majority of PEN that we see clinical are likely as a result of chronic constriction and therefore the emphasis on small fibre nerve testing should be made. However, due to the limitations of animal studies, efficacy studies in humans, and varied research approaches, the noteworthy results of these studies must be interpreted with limitations in mind.

Why do some people with peripheral entrapment neuropathy have symptoms outside their expected dermatomal distribution? 

Brain: “Hmm..that’s odd. Their symptoms are more than that of the median nerve distribution – must just be an atypical CTS or it could be coming from the neck.”

Typically, we are taught that injuries to a specific nerve site will only bring on symptoms at the dermatomal distribution of where that nerve innervates. However, the literature suggests that this may not be true and that many common neuropathies present with symptoms outside their expected territorial distribution.

A study completed by Caliandro et al. (2006) demonstrated that different severity of CTS as classified by neurophysiology studies, influence the distribution of symptoms in the hand. Participants with mild to moderate nerve dysfunction presented with a “Glove distribution” (70%), compared to those who had severe nerve dysfunction presented with a median nerve distribution (30%).

A noticeable flaw in this study is that participants were limited in choosing from onlytwo distinctive options of  “glove”, which included symptoms of the whole hand, or, “median”, defined as the presence of paraesthesia at the first three fingers with or without the involvement of the lateral region of the IV finger and the palmer region of the hand.

The main problem with set dermatome mapping in research is that there is an inconsistent and conflicting agreement of what constitutes normal dermatome mapping in the literature. This is due to the different methodological parameters used and individual differences in researching dermatomes (Downs, 2011).

So in this study, participants who presented with a larger than expected median nerve distribution, but less than a glove distribution, may pick the latter due to its bigger catchment area. Therefore the 70% glove distribution may be an over-representation of participants who may just have a wider spreading median nerve distribution.

A different study which looked at people presenting with cervical and lumbar nerve root compression found that only 30% of participants presented with symptoms associated with the specific nerve root. This was done by comparing self-reported body maps to accepted dermatomal patterns in the literature (Murphy et al., 2009).

Although the presence of nerve root impingement was confirmed by MRI, CT or neurophysiological studies, the authors placed high importance of the use of neurodynamic tests as a means to structurally identify specific nerve root pathology. This has its limitations as neurodynamic tests are not shown to be reliable in identifying nerve root pathology (Schmid et al., 2018). Therefore, In the context of this study, the validity of the identification of a specific nerve root could be questioned and may explain why some participants presented symptoms outside the expected distribution.

However, these studies raise the awareness that there are differences in dermatome patterns amongst individuals with PEN. Furthermore, these patterns do not usually fit the typical patterns found in textbooks. We cannot, therefore, accurately diagnose PEN by site and spread of location alone, and that multi-segment distribution are to be expected in most people we see clinically.

Why people with normal bedside neurological assessment may still have peripheral entrapment neuropathy? 

Brain: “Textbook presentation, it’s probably CTS, but just to be sure I’ll do my clinical tests to validate my hypothesis.”

Bedside neurological testing

The case study followed clinical practice guidelines in the assessment of CTS and recommends using sensation, power and vibration testing (AAOS, 2008).If we were to follow the Erlanger and Gasser (1924) classification of nerve roles, these tests exclusively assess for large A-beta fibre functions.

This means, from what we can infer from the electron microscopy studies (Schmid et al., 2014), we may only be testing 20% of the sensory nerve and neglecting the 80% of small A-delta and C-fibres due to the absence of thermal or pain detection testing. This is significant because interpreting from the animal studies, constriction type nerve injuries are more likely to affect the small fibres whilst large fibres morphology and function are spared. (Gupta & Steward et al., 2003,2004)

This may explain why a person with significant small fibre loss, could have normal bedside neurology findings because large fibres function remains unaffected. Therefore clinically, a normal bedside neurology assessment may not be sensitive in identifying people with PEN.

Why people with normal neurodynamic tension tests may still have peripheral entrapment neuropathy? 

Neurodynamic tension tests are commonly used clinically as a symptom provocation tests to identify the presence of nerve dysfunction (Gifford & Butler, 1997). The rationale behind these tests is that compression and tension stimulate mechanoreceptors of the nerve and reproduces a nociceptive reaction (Hall and Elvey, 1999).

There are, however, inconsistencies in what is considered a positive neurodynamic test with some literature suggesting a positive test to be a combination of pain provocation, patient symptoms reproduction, and reduced range of movement. Whilst others suggesting partial reproduction with structural differentiation is important. At this time neurodynamics is not used consistently by researcher and clinicians alike which has implications on the reliability and validity when interpreting from research (Schmid et al., 2018).

Intuitively, it seems plausible that people with PEN should have a positive neurodynamic test, due to our understanding of the local mechanisms that occur from a peripheral injury, i.e. the increase of mechanosensitivity from the process of neuroinflammation, reduced threshold potential, and ectopic firing.

However, if the nociceptive mechanisms were to be dysfunctional within a sensory nerve, then arguably a nerve may not be mechanosensitive to stress and strains induced by a neurodynamic test. This phenomenon does not seem to be unusual, and there is evidence that people who suffer from conditions which predominantly affect small nerve fibres, for example, diabetes-related peripheral neuropathy may have reduced mechanosensitivity to neurodynamic tests (Boyd et al., 2010).

It may not be surprising then that neurodynamic tests are not shown to be a valid tool in the specific identification of PEN, and were not considered helpful for either making or ruling out a diagnosis of CTS (Nee et al., 2012).  A good example of this is Balselgia et al’s. (2016) study which demonstrated that only 55% of their 53 participants with CTS had a positive neurodynamic test. A differentiating feature in the 45% of participants with negative neurodynamic tests demonstrated a reduced ability in warm detection which is thought to be linked to small fibre dysfunction. Paradoxically, this suggests patients with greater small fibre dysfunction were more likely to have a negative neurodynamic test, potentially supporting the hypothesis of reduced mechanosensitivity due to greater small fibre loss.

Therefore, clinically, the presence or absence of neuro tension tests during our assessment may not be able to help us accurately diagnosis peripheral entrapment neuropathy.  However, current literature around the reliability of neurodynamic tests in the presence of peripheral neuropathy is mainly done in the upper limb and more specifically in CTS.  A generalisation cannot be made to other types of PEN such as those in the lower limb or the nerve root.

Why people with normal neurophysiology tests may still have peripheral entrapment neuropathy? 

Brain: “But let’s check their nerve conduction study results, that should tell me everything”

Conventional nerve conduction studies and nerve biopsy explore only large nerve fibres (Lefaucheur et al., 2015). In pure small nerve fibre dysfunction, conventional nerve conduction studies will be normal and therefore their purpose is to exclude an associated large fibre component. (Themistocleous et al., 2014).

Similarly, to the aforementioned points, clinically neurophysiology studies may only tell us the function of large nerve fibres, and not the 80% of small nerve fibres dysfunction which we are beginning to understand are most affected with PEN. Therefore, reliance on nerve conduction studies to diagnosis PEN is limited and should not be used as a sole method clinically.

Reflection

If we look at how as clinicians we came to learn about the assessment of PEN, It is easy to see why I had not changed my practice considering the emerging evidence. Our current methods are plausible, which has been informed by perceived confident sources of academia, colleagues, and clinical practice guidelines. Anecdotally I had positive results and experiences with using current assessments, and there have not been any significant negative drivers to challenge my practice.

However, in light of developing research, if I don’t reflect on a case where a person with PEN presents without positive findings to our current clinical tests, I cannot confidently say I have excluded PEN as a diagnosis, since current approaches may not be sensitive enough, and risk misdiagnoses and management.

Conclusion 

• The mechanism of injury to chronic constrictive related PEN affects small nerve fibre cells over large cell fibres.

• Large and small fibres sensory nerves have distinctively different roles: (Sensation and vibration vs pain and thermal detection) and different distributions within a sensory nerve (20% vs 80%) respectively.

• Clinically we may be misdiagnosing and neglecting patients with peripheral entrapment neuropathy because of current guidelines and accepted practice in the general profession.

• The traditional view that peripheral nerve injuries present itself in a predictable dermatomal presentation is may only be true for around 30% of the time.

• The current clinical tests including bedside neurological examination, neurodynamic tests, and neurophysiology studies are biased in the assessment of large nerve fibres and neglect small fibre function

References

AAOS, Academy, A., Board, O. S., & September, D. (2008). CLINICAL PRACTICE GUIDELINE ON THE TREATMENT OF CARPAL TUNNEL SYNDROME Adopted by the American Academy of Orthopaedic Surgeons Board of Directors, (September), 10–22.

Adams, L., & Turk, D. (2015). Psychosocial Factors and Central Sensitivity Syndromes. Current Rheumatology Reviews, 11(2), 96–108. https://doi.org/10.2174/1573397111666150619095330

Baselgia, L. T., Bennett, D. L., Silbiger, R. M., & Schmid, A. B. (2017). Negative Neurodynamic Tests Do Not Exclude Neural Dysfunction in Patients With Entrapment Neuropathies. Archives of Physical Medicine and Rehabilitation, 98(3), 480–486. https://doi.org/10.1016/j.apmr.2016.06.019

Boyd, B. S., Wanek, L., Gray, A. T., & Topp, K. S. (2010). Mechanosensitivity during lower extremity neurodynamic testing is diminished in individuals with Type 2 Diabetes Mellitus and peripheral neuropathy : a cross sectional study, 5–8.

Caliandro, P., La, G., Aprile, I., Pazzaglia, C., Commodari, I., Tonali, P., & Padua, L. (2006). Distribution of paresthesias in Carpal Tunnel Syndrome reflects the degree of nerve damage atwrist *, 117, 228–231. https://doi.org/10.1016/j.clinph.2005.09.001

Ding, C., & Hammarlund, M. (2019). Mechanisms of injury-induced axon degeneration. Current Opinion in Neurobiology, 57, 171–178. https://doi.org/10.1016/j.conb.2019.03.006

Downs, M. B. (2011). Conflicting Dermatome Maps: Educational and Clinical Implications, 41(6), 427–434. https://doi.org/10.2519/jospt.2011.3506

Erlanger J, Gasser HS, Bishop GH. The compound nature of the action current

of nerve as disclosed by the cathode ray oscillograph. Am J Physiol 1924;70:624-666.

Gifford, L. S., & Butler, D. S. (1997). The integration of pain sciences into clinical practice. Journal of Hand Therapy, 10(2), 86–95. https://doi.org/10.1016/S0894-1130(97)80063-4

Gupta, R., & Steward, O. (2003). Chronic nerve compression induces concurrent apoptosis and proliferation of Schwann cells. Journal of Comparative Neurology, 461(2), 174–186. https://doi.org/10.1002/cne.10692

Gupta, R., Rowshan, K., Chao, T., Mozaffar, T., & Steward, O. (2004). Chronic nerve compression induces local demyelination and remyelination in a rat model of carpal tunnel syndrome, 187, 500–508. https://doi.org/10.1016/j.expneurol.2004.02.009

Gupta, R., Rummler, L. S., Palispis, W., Truong, L., Chao, T., Rowshan, K., … Steward, O. (2006). Local down-regulation of myelin-associated glycoprotein permits axonal sprouting with chronic nerve compression injury. Experimental Neurology, 200(2), 418–429. https://doi.org/10.1016/j.expneurol.2006.02.134

Gupta, R., Nassiri, N., Hazel, A., Bathen, M., & Mozaffar, T. (2012). Chronic nerve compression alters schwann cell myelin architecture in a murine model. Muscle and Nerve, 45(2), 231–241. https://doi.org/10.1002/mus.22276

Hall, T. M., & Elvey, R. L. (1999). Nerve trunk pain: Physical diagnosis and treatment. Manual Therapy. https://doi.org/10.1054/math.1999.0172

Hanna, A. (2017). Nerve Entrapment Syndromes: Practice Essentials, Etiology, Pathophysiology. [online] Emedicine.medscape.com. Available at: https://emedicine.medscape.com/article/249784-overview [Accessed 12 Feb. 2020].

Lefaucheur, J. P., Wahab, A., Planté-Bordeneuve, V., Sène, D., Ménard-Lefaucheur, I., Rouie, D., … Ng Wing Tin, S. (2015). Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests. Neurophysiologie Clinique, 45(6), 445–455. https://doi.org/10.1016/j.neucli.2015.09.012

Luis Quintero. (2019) [ONLINE]. Available at: https://unsplash.com/photos/qKspdY9XUzs/info [Accessed 16 February 2020].

Saliani, A., Perraud, B., Duval, T., Stikov, N., Rossignol, S., & Cohen-Adad, J. (2017). Axon and myelin morphology in animal and human spinal cord. Frontiers in Neuroanatomy, 11(December), 1–19. https://doi.org/10.3389/fnana.2017.00129

Schmid, A. B., Nee, R. J., & Coppieters, M. W. (2013). Reappraising entrapment neuropathies-Mechanisms, diagnosis and management. Manual Therapy, 18(6), 449–457. https://doi.org/10.1016/j.math.2013.07.006

Schmid, A. B., Bland, J. D. P., Bhat, M. A., & Bennett, D. L. H. (2014). The relationship of nerve fibre pathology to sensory function in entrapment neuropathy. Brain, 137(12), 3186–3199. https://doi.org/10.1093/brain/awu288

Schmid, A. B., Hailey, L., & Tampin, B. (2018). Entrapment Neuropathies: Challenging Common Beliefs With Novel Evidence. Journal of Orthopaedic and Sports Physical Therapy, 48(2), 58–62. https://doi.org/10.2519/jospt.2018.0603

Themistocleous, A. C., Ramirez, J. D., Serra, J., & Bennett, D. L. H. (2014, December 1). The clinical approach to small fiber neuropathy and painful channelopathy. Practical Neurology. BMJ Publishing Group. https://doi.org/10.1136/practneurol-2013-000758

Menorca, R. M. G., Fussell, T. S., & Elfar, J. C. (2013). Peripheral Nerve Trauma : Mechanisms of Injury and Recovery. Hand Clin, 29(3), 317–330. https://doi.org/10.1016/j.hcl.2013.04.002.Peripheral

Mohanty CB, Bhat DI, Devi B I. Use of animal models in peripheral nerve surgery and research. Neurol India 2019;67, Suppl S1:100-5

Murphy, D. R., Hurwitz, E. L., Gerrard, J. K., & Clary, R. (2009). Chiropractic & Osteopathy Pain patterns and descriptions in patients with radicular pain : Does the pain necessarily follow a specific dermatome ?, 9, 1–9. https://doi.org/10.1186/1746-1340-17-9

Nee, R. J., Jull, G. A., Vicenzino, B., & Coppieters, M. W. (2012). The validity of upper-limb neurodynamic tests for detecting peripheral neuropathic pain. Journal of Orthopaedic and Sports Physical Therapy, 42(5), 413–424. https://doi.org/10.2519/jospt.2012.3988