Manual Therapy 18 (2013) 449e457

Contents lists available at ScienceDirect

Manual Therapy
journal homepage: www.elsevier.com/math

Masterclass

Reappraising entrapment neuropathies e Mechanisms, diagnosis

and managementq
Annina B. Schmid a, b, *, Robert J. Nee c, Michel W. Coppieters a, d
a
The University of Queensland, Division of Physiotherapy, School of Health and Rehabilitation Sciences, Brisbane (St Lucia), Australia
b
University of Oxford, Nuffield Department of Clinical Neurosciences, Oxford, United Kingdom
c
Pacific University, School of Physical Therapy, Hillsboro, OR, USA
d
Faculty of Human Movement Sciences, MOVE Research Institute Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: The diagnosis of entrapment neuropathies can be difficult because symptoms and signs often do not
Received 3 June 2013 follow textbook descriptions and vary significantly between patients with the same diagnosis. Signs and
Received in revised form symptoms which spread outside of the innervation territory of the affected nerve or nerve root are
10 July 2013
common. This Masterclass provides insight into relevant mechanisms that may account for this extra-
Accepted 13 July 2013
territorial spread in patients with entrapment neuropathies, with an emphasis on neuroinflammation at
the level of the dorsal root ganglia and spinal cord, as well as changes in subcortical and cortical regions.
Keywords:
Furthermore, we describe how clinical tests and technical investigations may identify these mechanisms
Entrapment neuropathy
Mechanisms
if interpreted in the context of gain or loss of function. The management of neuropathies also remains
Diagnosis challenging. Common treatment strategies such as joint mobilisation, neurodynamic exercises, educa-
Management tion, and medications are discussed in terms of their potential to influence certain mechanisms at the site
of nerve injury or in the central nervous system. The mechanism-oriented approach for this Masterclass
seems warranted given the limitations in the current evidence for the diagnosis and management of
entrapment neuropathies.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction In many neuropathies however, widespread symptoms are the

norm. For example, two thirds of patients with carpal tunnel syn-
The clinical manifestation of entrapment neuropathies is tradi- drome experience pain outside the median nerve territory
tionally considered to be driven by local mechanisms. These local (Caliandro et al., 2006) (Fig. 1). Similarly, only one third of patients
mechanisms may include intraneural ischaemia with subsequent with cervical or lumbar radiculopathy have symptoms in a
breakdown of the bloodenerve-barrier and intraneural oedema dermatomal pattern (Murphy et al., 2009). Motor deficits also occur
formation (Rydevik and Lundborg, 1977), Schwann cell reaction outside the distribution of the affected nerve (Fernandez-de-Las-
and demyelination (Mackinnon, 2002; Gupta and Steward, 2003), Penas et al., 2009). Furthermore, a deficit in left/right recognition
and ectopic impulse generation as a result of an increased density of the affected body part can be present in patients with entrap-
of ion channels at demyelinated sites (Devor, 2006). If the only ment neuropathies (Schmid and Coppieters, 2011).
relevant mechanisms were at the level of the nerve or nerve root, Considering these widespread and variable manifestations, it is
signs and symptoms should follow a clear anatomical pattern understandable that there are no universally accepted diagnostic
limited to the structures innervated by the affected peripheral criteria for entrapment neuropathies (e.g., cervical radiculopathy
nerve, or restricted to the corresponding dermatome, myotome and (Thoomes et al., 2012), lumbar radiculopathy (Genevay et al., 2010),
sclerotome. carpal tunnel syndrome (Bland, 2005)). Also, if the pathological
processes were limited to the entrapment site, it would be expected
that surgical release would yield excellent results, unless the nerve
was irreversibly damaged. However, the mean long-term success
q This work is attributed to the University of Queensland (for address see a).
rate for carpal tunnel syndrome surgery is ‘only’ 75% (Bland, 2007).
* Corresponding author. Nuffield Department of Clinical Neurosciences, Univer-
The outcome of surgical decompression for other neuropathies is
sity of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. Mobile: þ44 079 4765
2403. also suboptimal (e.g., cervical radiculopathy (Nikolaidis et al., 2010),
E-mail address: [email protected] (A.B. Schmid). lumbar radiculopathy (Ronnberg et al., 2007)).

1356-689X/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.math.2013.07.006
450 A.B. Schmid et al. / Manual Therapy 18 (2013) 449e457

Fig. 1. Frequency of symptoms in median and extramedian territories in patients with carpal tunnel syndrome. Image incorporates data by Nora et al. (2004).

Symptoms outside the innervation area may be referred from lower the firing threshold and induce ectopic activity of both
associated structural lesions, such as the intervertebral disc or facet mechanosensitive and nociceptive neurons (Sorkin et al., 1997;
joints in radiculopathy, or rheumatoid arthritis in carpal tunnel Grossmann et al., 2009).
syndrome. Furthermore, postural changes may strain other Most animal models used to study neuroinflammation cause
musculoskeletal tissues such as the identified forward head posture extensive axonal loss (Basbaum et al., 1991; Hu et al., 2007) and, as
in patients with carpal tunnel syndrome (De la Llave-Rincon et al., mentioned above, are therefore not representative of entrapment
2009). However, these processes cannot account for all widespread neuropathies commonly encountered in the clinic. We have how-
and contralateral symptoms observed in many patients with ever recently shown that even mild nerve compression is sufficient
entrapment neuropathies. Many of these signs and symptoms may to induce intraneural inflammation, which is associated with
be attributed to pathological processes proximal to the lesion site, neuropathic pain behaviour (Schmid et al., 2013). Intraneural
such as, in the dorsal root ganglion (DRG) or central nervous sys- inflammation is therefore a plausible explanation for the presence
tem. The following section will discuss recent discoveries in this of hyperalgesia, both locally and in the affected nerve territory.
area to better understand the clinical presentation of patients with However, local neuroinflammation may not explain most extra-
entrapment neuropathies. territorial symptoms.

2. Mechanisms e recent discoveries explaining spread of 2.2. Neuroinflammation in the dorsal root ganglia and spinal cord
symptoms
Following peripheral nerve injury, there is an invasion and
Many mechanisms which explain spread of symptoms have activation of macrophages, T-lymphocytes and satellite glial cells in
been identified in animal models of severe nerve injury (for review the DRG (Hu and McLachlan, 2002; Hu et al., 2007; Schmid et al.,
see Woolf, 2004). These severe nerve injuries are however not 2013) (Fig. 4). Inflammatory mediators released from these im-
representative for many commonly encountered human entrap- mune cells may result in ectopic activity of DRG neurones (Schafers
ment neuropathies, and extrapolations should be made cautiously. et al., 2008; Schmid et al., 2013). Given the close proximity of cell
Here, we will focus mainly on those mechanisms identified in pa- bodies from different peripheral nerves within a DRG, neuro-
tients with neuropathies or in animal models that more closely inflammation around affected DRG neurons may also alter the firing
mimic human entrapment neuropathies (Fig. 2). threshold of adjacent intact neurones originating from different
sites. Therefore, neuroinflammation in the dorsal root ganglia
2.1. Local mechanisms (DRGs) is a plausible explanation for the clinically observed spread
of symptoms to extraterritorial areas. For example, tarsal tunnel
In the last decade, neuroinflammation has gained considerable syndrome may induce neuroinflammation in the L4 DRG, which
interest in the field of neuropathic pain (for review see Moalem and may lower the firing threshold not only of tibial nerve neurones, but
Tracey, 2006; Thacker et al., 2007). There is ample evidence from also of the fibular and femoral nerve neurones. As a consequence,
animal models of peripheral nerve injuries that immune cells, such symptoms and hypersensitivity may occur in other areas than those
as macrophages and T-lymphocytes, are recruited to the injury site innervated by the entrapped tibial nerve at the ankle.
(Mueller et al., 2003; Moalem et al., 2004) (Table 1, Fig. 3). These Neuroinflammation after severe peripheral nerve injury also
cells release inflammatory mediators, such as cytokines, which occurs at the level of the spinal cord. T-lymphocytes and glial cells
 A.B. Schmid et al. / Manual Therapy 18 (2013) 449e457 451

Fig. 2. Mechanisms that may account for widespread signs and symptoms in entrapment neuropathies. (A) Changes in peripheral musculoskeletal structures that contribute to or
are initiated by peripheral entrapment neuropathies. Examples are structural changes of facet joints associated with radiculopathies or ischaemic changes in muscles associated
with postural changes. (B) Changes at the level of the dorsal root ganglia. These may include proliferation of satellite glial cells, apparent by the formation of multilayer rings around
sensory nerve cell bodies. Furthermore, immune cells such as macrophages may become activated and increase in numbers. (C) Changes at the level of the spinal cord. These may
include activation of microglial cells apparent by their phenotypic change into larger cell bodies with shortened and thickened processes. (D) Changes in cortical areas. These may
include reorganisation of the somatosensory cortex such as the identified shift of finger representation in patients with carpal tunnel syndrome (Napadow et al., 2006).

start to release various inflammatory mediators (for review see inflammatory response in the spinal cord may lower the firing
Watkins and Maier, 2002). Since incoming primary afferents ascend thresholds of sensory fibres in a multi-segmental manner.
or descend several segments when entering the spinal cord before Interestingly, neuroinflammation after severe unilateral pe-
they synapse in the dorsal horn (Cervero et al., 1979), an ripheral nerve injury also occurs in the DRGs and spinal cord on the
452 A.B. Schmid et al. / Manual Therapy 18 (2013) 449e457

Table 1
Overview of the role of the most common immune cells and immune competent cells after peripheral nerve injury.

Cell type Role after peripheral nerve injury

Neutrophils Leukocytes Acute local immune response. Phagocytic function and secretion of
inflammatory mediators (e.g., TNF, IL-1b, IL-2 and IL-6) that attract other immune cells.
Mast cells Acute local immune response. Secretion of mediators, which sensitise nociceptors (e.g. histamine,
TNF) or directly activate them (e.g. serotonin). Recruitment of other immune cells.
Macrophages Leukocytes Acute and chronic immune response. Phagocytosis and antigen presentation to other immune cells.
Secretion of mediators that sensitise nociceptors or attract other immune cells (e.g., prostaglandins,
IL1b, IL-6, IL12, TNF and reactive oxygen species).
T-lymphocytes Leukocytes Acute and chronic immune response. Destruction of pathogens or cells directly or by secreting cytokines
(e.g. IL-1b, IL-2 and TNF or IL-4, IL-5, IL-10). Activation of other immune cells (e.g., B-cells, macrophages
and other leukocytes).
Schwann cells Glial cells of Secretion of nerve growth factors, proinflammatory cytokines (e.g. IL-1, IL-6, IL-8) as well as prostaglandins
the peripheral and ATP which can directly sensitise nociceptors. Recruitment of other immune cells and presentation of antigens.
nervous system
Satellite glial cells Glial cells in the DRGs Secretion of cytokines and chemokines (e.g. IL-1b, TNF) that increase ectopic firing of neurones
Astrocytes Glial cells in the central Release of substances (ATP, nitric oxide, IL-1b, TNF and IL-6), which modulate the firing threshold of neurons.
nervous system Facilitation of synaptic transmission and communication with other immune cells.
Microglia Glial cells in the central Tissue repair by phagocytosing cellular debris and pathogens. Communication with neurones and immune cells,
nervous system release of several neuro-active mediators including cytokines, chemokines and growth factors.

TNF: tumour necrosis factor; IL: interleukins; ATP: adenosine triphosphate.

contralateral side (Koltzenburg et al., 1999; Jancalek et al., 2010). explored whether inflammatory changes are present at these
This may be one of several factors explaining bilateral symptoms in higher levels in mild nerve compression.
patients with a unilateral entrapment neuropathy such as carpal Functional changes at cortical or subcortical levels have already
tunnel syndrome. However, substantial axonal loss seems neces- been demonstrated in patients with entrapment neuropathies. For
sary to induce such changes (Schmid et al., 2013). instance, left/right recognition of the affected body part is impaired
in patients with carpal tunnel syndrome (Schmid and Coppieters,
2.3. Mechanisms at subcortical and cortical levels 2011) and possibly cervical radiculopathy (Coslett et al., 2010).
Since this task activates similar brain areas as imagined and
There is preliminary evidence that severe peripheral nerve in- executed movements (Michelon et al., 2006), accurate performance
juries induce a glial cell reaction in higher pain centres, such as in is thought to depend on the integrity of the body’s representation
the midbrain (Mor et al., 2010) or the thalamus (LeBlanc et al., in cortical and subcortical areas (Schwoebel et al., 2002). Further-
2011). Changes at these sensory relay centres could explain wide- more, there is emerging evidence for reorganisation of the so-
spread symptoms, even in another quadrant. It remains to be matosensory cortex in patients with entrapment neuropathies. In

Fig. 3. Activation of immune and inflammatory cells at the site of a peripheral nerve injury. A peripheral nerve lesion leads to an early activation of mast cells and neutrophils,
which release chemicals that activate resident macrophages. The macrophages phagocytose axonal or myelin debris and secrete proinflammatory substances that sensitise axons or
attract other immune cells. A breakdown of the blood nerve barrier by physical damage or substances released by immune cells leads to an additional influx of blood-borne immune
cells. Schwann cells also ingest myelin and subsequently release proinflammatory chemicals. Both Schwann cells and macrophages signal T-cells, some of which will also secrete
inflammatory chemicals. This complex cascade with activation of the innate and adaptive immune system leads to a local inflammatory environment that lowers the firing
threshold of axons and contributes to neuropathic pain. TNF: tumour necrosis factor; PGE: prostaglandin; IL: interleukin; NGF: nerve growth factor; ATP: adenosine triphosphate.
 A.B. Schmid et al. / Manual Therapy 18 (2013) 449e457 453

Fig. 4. Neuroinflammation at the level of the dorsal root ganglia (DRGs) in a rat model of mild nerve compression. Longitudinal section through an intact, non-operated (left) DRG at
the level L5 and a DRG that receives afferents from a mildly compressed sciatic nerve (right). Satellite glial cells are stained with glial fibrillary acid protein (GFAP) in green. A higher
staining intensity and the formation of some GFAPþ rings around some neurone cell bodies are visible after mild nerve compression. This indicates activation of satellite glial cells.
Macrophages are stained in red with a CD68 antibody. A slight upregulation in numbers of positively stained macrophages is visible in the DRG after mild nerve compression.
Calibration applies throughout. Image incorporates findings from Schmid et al. (2013).

carpal tunnel syndrome for instance, both a more extended rep- testing for instance provides important information on loss of
resentation of the fingers innervated by the median nerve function in large myelinated motor neurons and Ab fibres. Whereas
(Napadow et al., 2006, 2007), as well as a decreased representation these are believed to be primarily affected in entrapment neurop-
(Druschky et al., 2000) have been reported. Potentially, a differen- athies (Mackinnon, 2002), recent evidence suggests that small axon
tial effect of paraesthesia and pain on cortical reorganisation may loss is common (e.g., cervical (Chien et al., 2008) and lumbar rad-
explain these conflicting findings (Tecchio et al., 2002). Although iculopathy (Nygaard and Mellgren, 1998) and carpal tunnel syn-
further research into the effect of entrapment neuropathies on drome (Lang et al., 1995; Wilder-Smith et al., 2003; Schmid et al.,
cortical and subcortical areas is needed, such changes may 2012b) and may occur even before dysfunction of large axons be-
contribute to extraterritorial or contralateral spread of symptoms. comes apparent (Tsuboya et al., 2007; Tamburin et al., 2010;
Schmid et al., 2013)) (Fig. 5). Clinical reliance on electrodiagnostic
3. Diagnosis testing in isolation may however not only be insufficient since it
does not provide any information about the integrity of the thinly
Considering the various mechanisms mentioned above and that myelinated or unmyelinated fibres (e.g., Ad and C-fibres) (Mallik
the dominant mechanism is likely to vary between patients, it is and Weir, 2005) but also since it only tests loss of function.
logical that there are no universally accepted criteria (or gold) Quantitative sensory testing (QST) protocols are designed to
standards to diagnose neuropathies. Diagnostic accuracy studies for assess both loss and gain of function, in small and large diameter
neuropathies therefore reflect the strength of the correlation be- nerve fibres. Commonly performed protocols include tests to
tween a test and an imperfect criterion standard, rather than the determine a deterioration in thermal and mechanical detection
test’s true ability to detect a neuropathy. Consequently, providing thresholds (loss of function) or lowered pain thresholds (gain of
an overview of the sensitivity, specificity, and likelihood ratios for function) (Rolke et al., 2006). Certain loss of function tests may
tests to diagnose entrapment neuropathies is not within the scope indicate which type of nerve fibre might be involved. For instance,
of this Masterclass. Detailed overviews can be found elsewhere elevated vibration and von Frey monofilament detection thresholds
(e.g., carpal tunnel syndrome (MacDermid and Wessel, 2004), suggest demyelination or dysfunction of the Ab fibres. Altered cold
cervical radiculopathy (Rubinstein et al., 2007), lumbar radiculop- and warm detection thresholds may indicate Ad and C-fibre
athy (van der Windt et al., 2010). Rather, this section will focus on dysfunction, respectively (Rolke et al., 2006). In contrast, the
how different diagnostic tests may inform a clinician about po- presence of gain of function (lowered pain thresholds) indicates
tential mechanisms involved in an individual patient. neuronal hyperexcitability. Extraterritorial gain of function (Chien
Symptoms and signs in neuropathies can be classified as gain or et al., 2008; Schmid et al., 2012b), allodynia upon stimulation
loss of function. Gain of function, such as paraesthesia, spontaneous with a brush or cotton wool tip (Treede et al., 2004), paradoxical
pain, hyperalgesia and allodynia, reflects abnormal excitability or heat sensations and pain exacerbation following repetitive stimuli
reduced inhibition in the nervous system. Loss of function, such as as compared to a single stimulus (wind-up like pain) (Rolke et al.,
hypoesthesia or anaesthesia, indicates reduced impulse conduction 2006) are indicative of central mechanisms.
along the nervous system (Woolf, 2004). Mechanisms already QST has merit in identifying nerve fibre function, but its appli-
mentioned above that may result in loss of function are axonal loss cability to individual patients is still limited to those body areas
or demyelination (e.g., numbness). However, demyelination may with available reference values (Rolke et al., 2006). QST is often
also induce gain of function (e.g., paraesthesia). Neuroinflammation considered too time consuming to be integrated in routine clinical
at various levels in the nervous system is mainly associated with evaluations and the expensive equipment is not widely available to
hypersensitivity of neurones, resulting in gain of function. clinicians. Certain tests of the standardised QST battery may how-
Interpretation of clinical tests and technical investigations for ever be performed by clinicians without costly equipment. Hyper-
neuropathies in the context of gain and loss of function may assist sensitivity to mechanical pin prick (without quantification) and
in the identification of underlying mechanisms. Electrodiagnostic wind-up can be evaluated with a tooth pick. Tests for allodynia
454 A.B. Schmid et al. / Manual Therapy 18 (2013) 449e457

Fig. 5. Preferential small axon damage after mild peripheral nerve compression in rats. The figure shows longitudinal sections through rat L5 DRG. Neuronal cell bodies are stained
with neuronal nuclei stain (red). Cell bodies with damaged axons are stained with activating transcription factor 3 (ATF3, green), a marker for axotomised neurones. Whereas no
damaged neurones are present in a non-operated control DRG (left), the marker for damaged neurones is preferentially found in neurones with small diameter, most likely
representing unmyelinated C-fibres or small myelinated Ad fibres. Calibration applies throughout. Image incorporates findings from Schmid et al. (2013).

can be mimicked with a paint brush or cotton wool tip. Although delineating the variety of mechanisms involved in a particular
not tested in entrapment neuropathies as yet, the pain intensity neuropathy. Preliminary attempts have been made to identify signs
during ice pack application can identify cold hyperalgesia in pa- and symptoms suggestive of peripheral neuropathic pain and
tients with whiplash associated disorders (Maxwell and Sterling, central sensitisation (Smart et al., 2010). It is unknown however
2012). whether these characteristics accurately reflect the underlying
Traditional clinical tests can also be interpreted in terms of gain pathobiological mechanisms or simply represent a consensus
and loss of function (see Table 2). Loss of function is detected during adopted by clinicians.
the bedside neurological examination (reduced power, reflexes or
sensation). Typical signs for gain of function are the provocation of 4. Management
paraesthesia or pain during Tinel’s sign (ectopic activity), palpation,
neurodynamic tests or Spurling’s test. As gain of function is often Several recent reviews summarised the effects of conservative
widespread, clinicians should consider using these tests in extra- treatments for carpal tunnel syndrome (e.g., Page et al., 2012),
territorial areas. cervical radiculopathy (e.g., Thoomes et al., 2013), and lumbar
Whereas the tests above focus on the function of the nervous radiculopathy (e.g., Chou et al., 2009). The lack of high-level evi-
system, its structure can also be examined using standard imaging dence means that no strong treatment recommendations can be
methods (e.g., ultrasound, magnetic resonance imaging (MRI)) or made. In line with the approach of this Masterclass, rather than
skin biopsies to quantify nerve fibre density (Myers and Peltier, summarising recommendations based on relatively weak evidence,
2013). Skin biopsies are a valuable technique which can provide a this section will discuss how various treatments may influence
unique insight into the structural integrity of both unmyelinated some of the above-mentioned mechanisms involved in entrapment
and myelinated nerve fibres, but is also not yet routinely available neuropathies. Treatments evaluated in patients with neuropathies
clinically and is (minimally) invasive. or in animal models of neuropathic pain will be emphasised.
A combination of clinical presentation, clinical tests and tech- Obviously, the ability to influence pathological processes alone
nical investigations is typically considered the optimal diagnostic does not prove clinical efficacy. However, considering the wide
approach (Rempel et al., 1998). However, currently identified test variety of treatments suggested for neuropathies and the high cost
clusters (Wainner et al., 2003, 2005) need to be validated and new of clinical trials, an appraisal of how treatments may influence
clusters need to be developed that incorporate items capable of specific mechanisms seems warranted.

Table 2
Clinical tests and technical investigations commonly used in entrapment neuropathies and their main findings in the context of loss and gain of function.

Gain of function Loss of function Structure

Electrodiagnostic tests Conduction slowing, increased

latencies, decreased amplitudes
Bedside neurological examination Hyperreflexia, muscle spasm, dystonia, Weaker/absent reflexes,
clonus, allodynia, hyperalgesia muscle weakness, reduced sensation
Quantitative sensory tests Lowered pain thresholds: hyperalgesia, Elevated detection thresholds:
wind up, allodynia hypoaesthesia, anaesthesia
Neurodynamic tests Increased neural mechanosensitivity and
ectopic impulse generation
Palpation (neural and non-neural Increased mechanosensitivity Tissue condition
structures) (e.g., swelling, thickening)
Tinel’s sign Increased neural mechanosensitivity and
ectopic impulse generation
Neural compression tests Increased neural mechanosensitivity and
(e.g., Spurling’s, Phalens test) ectopic impulse generation
Imaging methods (ultrasound, MRI, etc) E.g., increased nerve signal
intensity, increased cross
sectional area, nerve flattening
 A.B. Schmid et al. / Manual Therapy 18 (2013) 449e457 455

Various central nervous system processes, including sensitisa- Table 4

tion through neuroinflammation, are triggered by aberrant pe- Most frequently employed modalities by musculoskeletal physiotherapists in the
management of cervical radiculopathy (ROM: range of motion).
ripheral input (Devor, 2009; Suter et al., 2009). Furthermore,
considering the immediate e albeit short term e relief following a Explanation and advice
local cortisone injection in w70% of patients with carpal tunnel Exercise (motor control, muscle strength & endurance, ROM)
Passive mobilisation (but not manipulation)
syndrome (Bland, 2007), attenuation of ongoing peripheral input Nerve gliding exercises
into the central nervous system is an important goal in the man- Stretching (neck and shoulder musculature)
agement of entrapment neuropathies in order to prevent or Taping (neck and shoulder)
diminish central modulation. Recent practice surveys (Coppieters More heat than cold
Manual traction (but not mechanical or ‘home’ traction)
and Soon, 2013; Nee et al., 2013) revealed the most common mo-
Prescription of home exercise program
dalities used by hand therapists and musculoskeletal physiother-
apists to manage carpal tunnel syndrome (Table 3) and cervical
radiculopathy (Table 4), respectively. Typical management strate- with carpal tunnel syndrome (Bialosky et al., 2009b). Additionally, a
gies include explanation and education, postural and ergonomic recent study in rats with a severe peripheral nerve injury showed
advice, joint mobilisation, soft tissue techniques, neural mobi- that passive neurodynamic exercises are capable of reducing
lisation and exercise. nociceptive behaviour in combination with a normalisation of the
Accessory and physiological joint mobilisations and manipula- satellite glial cell response in the DRGs and astrocyte response in
tions are commonly performed in patients with neuropathies the spinal cord (Santos et al., 2012).
(Coppieters and Soon, 2013; Nee et al., 2013). These techniques may Although not identified as a common treatment modality in
facilitate the descending pain inhibitory system (for review see recent physiotherapy practice surveys, animal research suggests
Vicenzino et al., 2007; Bialosky et al., 2009a). At a peripheral level, that aerobic physical exercise may positively influence neuropathic
mobilisation may disperse and therefore dilute the concentration of pain processes. Swimming and treadmill exercise decreased the
chemical mediators that trigger ectopic firing. Following the in- overproduction of pro-inflammatory cytokines (tumour necrosis
jection of inflammatory mediators around the L5 DRG in rats, Song factor (TNF) and interleukin 1b (IL-1b)) (Chen et al., 2012), and
et al. (2006) demonstrated that spinal manipulation reduced reduced mechanical and cold allodynia, and thermal hyperalgesia
inflammation and hyperexcitibility of the DRG neurons, which was (Kuphal et al., 2007; Shen et al., 2013) in rats with a partial pe-
accompanied by a reduction of thermal and mechanical hyper- ripheral nerve injury or a constricted sciatic nerve. Future studies
algesia. Similarly, peripheral joint mobilisation in rats produced an are required, but progressive exercise may prove to be a safe and
anti-hyperalgesic effect in conjunction with a normalisation of glia cost-effective therapy in a variety of neuropathic pain states (Shen
activation in the dorsal horn of the spinal cord (Martins et al., 2011). et al., 2013).
Neurodynamic mobilisations (or nerve gliding exercises) are When the clinical reasoning process suggests the predominant
also frequently applied in various neuropathies (Coppieters and involvement of important central processes, many other treatment
Soon, 2013). A recent MRI study in patients with carpal tunnel strategies may be worthwhile to consider. The central mechanisms
syndrome revealed a decrease of intraneural oedema (a clinical mentioned above are not unique to patients with entrapment
correlate of neuroinflammation) following one week of nerve and neuropathies. Sensory discrimination training, graded motor im-
tendon gliding exercises, which was not observed in a control group agery (GMI), neuroscience education, and cognitive behavioural
who received advice to remain active (Schmid et al., 2012a). This therapy (CBT) have been proven beneficial to primarily influence
study illustrates that gentle mobilisation of a nerve and sur- these central mechanisms in other diagnoses and may be plausible
rounding structures does not aggravate the inflammatory process, interventions for patients with entrapment neuropathies.
but rather reduces oedema. Although the oedema reduction was Sensory discrimination training can reduce pain in patients with
not superior to splinting, considering the other benefits of move- phantom limb pain (Flor et al., 2001) and complex regional pain
ment, there are various situations when gentle exercises aimed at syndrome (Moseley et al., 2008), and this hypoalgesia is also
mobilisation of the nerve and surrounding structures may be associated with reductions in cortical reorganisation (Flor et al.,
preferred over partial immobilisation. Nerve and tendon gliding 2001; Maihofner et al., 2004).
exercises also resulted in an immediate and substantial reduction in GMI involves the specific sequence of left/right discrimination
carpal tunnel pressure in a subgroup of patients with carpal tunnel training, motor imagery exercises and mirror therapy (Moseley and
syndrome (Coppieters, 2012; Schmid, 2013). Flor, 2012) and appears to be effective for patients with phantom
There is also preliminary evidence that neurodynamic exercises limb pain and complex regional pain syndrome (Bowering et al.,
have an effect on central mechanisms. Movements of the wrist in 2013).
an arm position that elongate the length of the median nerve The goals of neuroscience education (i.e., education about the
bedding reduced temporal summation (a clinical correlate of neurophysiological mechanisms related to a patient’s pain experi-
increased excitability of spinal dorsal horn neurones) in patients ence) and CBT are to help the individual gain a sense of control over
pain and initiate behaviours that can improve function (Waters
et al., 2007; Moseley and Flor, 2012). Theoretically, a better un-
Table 3 derstanding of pain mechanisms and the use of pain-related coping
Most frequently employed modalities by hand therapists in the management of strategies and appropriate pacing to gradually increase activity
carpal tunnel syndrome.
levels without flare-ups can reduce the threat value of the pain
Explanation and advice experience and reduce the hypersensitivity of the central nervous
Splinting system (Moseley, 2003). Neuroscience education (Louw et al., 2011)
Ergonomic and postural advice
and CBT (Linton and Ryberg, 2001; Sveinsdottir et al., 2012;
Nerve gliding exercises
Tendon gliding exercises Williams et al., 2012) can be effective for persistent pain condi-
Active exercises for wrist and fingers tions that are associated with central sensitisation.
Stretching of the forearm muscles Since neuroinflammation seems to be triggered and depen-
Strengthening exercises for the hand muscles dent on the extent of the compression, it may be beneficial to
Prescription of home exercise program
combine interventions that prevent compression and restore
456 A.B. Schmid et al. / Manual Therapy 18 (2013) 449e457

normal movement with anti-inflammatory treatments. However, Chou R, Atlas SJ, Stanos SP, Rosenquist RW. Nonsurgical interventional therapies for
low back pain: a review of the evidence for an American Pain Society clinical
the evidence for drug treatment in patients with entrapment
practice guideline. Spine (Phila Pa 1976) 2009;34:1078e93.
syndromes is sparse. Whereas corticosteroids and oral or topi- Cohen SP, Bogduk N, Dragovich A, Buckenmaier 3rd CC, Griffith S, Kurihara C, et al.
cally applied non-steroidal anti-inflammatory drugs have a Randomized, double-blind, placebo-controlled, doseeresponse, and preclinical
beneficial short term effect in neuropathies, there is no evidence safety study of transforaminal epidural etanercept for the treatment of sciatica.
Anesthesiology 2009;110:1116e26.
for a superior effect over placebo in the long term (Marshall et al., Coppieters MW. Physiotherapy management of nerve-related neck and arm pain.
2007; Benoist et al., 2012). Unfortunately, there is evidence for In: Second Brazilian conference of manipulative and musculoskeletal physio-
inefficacy or only slight effectiveness for drugs commonly used to therapy (II COBRAFIMM) 2012. Sao Paulo, Brazil.
Coppieters MW, Soon BTC. Non-surgical management of carpal tunnel syndrome. A
treat neuropathic pain, such as anticonvulsants (e.g. pregabalin), national practice survey among Australian hand therapists; 2013 [submitted for
tricyclic antidepressants, opioids and their combination in pa- publication].
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Larger scale trials are needed to confirm beneficial effects of
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