Manual Therapy 16 (2011) 557e562

Contents lists available at ScienceDirect

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

Original article

The double crush syndrome revisited - A Delphi study to reveal current expert
views on mechanisms underlying dual nerve disorders
Annina B. Schmid, Michel W. Coppieters*
Centre of Clinical Research Excellence in Spinal Pain, Injury and Health, Division of Physiotherapy, School of Health and Rehabilitation Sciences, The University of Queensland, QLD
4072, St Lucia, Brisbane, Australia

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

Article history: A high prevalence of dual nerve disorders is frequently reported. How a secondary nerve disorder may
Received 7 January 2011 develop following a primary nerve disorder remains largely unknown. Although still frequently cited,
Received in revised form most explanatory theories were formulated many years ago. Considering recent advances in neurosci-
7 April 2011
ence, it is uncertain whether these theories still reflect current expert opinion. A Delphi study was
Accepted 9 May 2011
conducted to update views on potential mechanisms underlying dual nerve disorders. In three rounds,
seventeen international experts in the field of peripheral nerve disorders were asked to list possible
Keywords:
mechanisms and rate their plausibility. Mechanisms with a median plausibility rating of
7 out of 10
Double crush syndrome
Nerve compression syndromes
were considered highly plausible. The experts identified fourteen mechanisms associated with a first
Neuropathic pain nerve disorder that may predispose to the development of another nerve disorder. Of these fourteen
Delphi study mechanisms, nine have not previously been linked to double crush. Four mechanisms were considered
highly plausible (impaired axonal transport, ion channel up or downregulation, inflammation in the
dorsal root ganglia and neuroma-in-continuity). Eight additional mechanisms were listed which are not
triggered by a primary nerve disorder, but may render the nervous system more vulnerable to multiple
nerve disorders, such as systemic diseases and neurotoxic medication. Even though many mechanisms
were classified as plausible or highly plausible, overall plausibility ratings varied widely. Experts indi-
cated that a wide range of mechanisms has to be considered to better understand dual nerve disorders.
Previously listed theories cannot be discarded, but may be insufficient to explain the high prevalence of
dual nerve disorders.
Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction
The double crush hypothesis was first formulated in 1973 and
states that axons that have been compressed at one site become
especially susceptible to damage at another site (Upton and
McComas, 1973). The basis for this hypothesis was the high prev-
alence of cervical radiculopathy observed in patients with carpal
tunnel syndrome (CTS) (Table 1). All studies reported a much
higher prevalence of cervical radiculopathy in patients with CTS
compared to the prevalence of cervical radiculopathy in the general
population (<1%) (Radhakrishnan et al., 1994; Salemi et al., 1996).
Even though these epidemiological studies suggest that dual
nerve disorders are a clinical entity, controversy still surrounds the
double crush hypothesis. A recent international online survey in
528 clinicians revealed that 58% supported the double crush
* Corresponding author. Tel.: þ61 7 3365 1644; fax: þ61 7 3365 1622.
E-mail address: m.coppieters@uq.edu.au (M.W. Coppieters).
hypothesis; 21% remained undecided and 21% did not support it.
The level of acceptance of the hypothesis varied between profes-
sions. The majority of physiotherapists (85%) agreed with the
double crush hypothesis, half of the hand surgeons (51%) and
a minority of neurologists (24%) agreed (Schmid and Coppieters,
2010).
In addition to the controversy on the existence of the double
crush syndrome, there is debate on underlying mechanisms. The
main point of debate is whether a primary nerve disorder can indeed
predispose the nervous system to further injury, or whether the
frequent coexistence of nerve disorders is caused by an underlying
pathology, such as diabetes or thyroid disease (Wilbourn and
Gilliatt, 1997; Morgan and Wilbourn, 1998). Proposed mechanisms
associated with a primary nerve disorder which may predispose the
nervous system to a secondary nerve disorder are impaired axonal
transport (Upton and McComas, 1973; Dahlin, 1991), reduced
intraneural microcirculation (Lundborg and Dahlin, 1992;
Mackinnon, 1992) and altered nerve elasticity (Osterman, 1991).
Axonal transport and intraneural microcirculation have been shown

1356-689X/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.math.2011.05.005
558 A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562
Table 1
Prevalence of cervical radiculopathy in patients with carpal tunnel syndrome as
reported by different authors.
Publication Prevalence
Morgan and Wilbourn, 1998 5%
Kuntzer, 1994 6%
Yu et al., 1979 11%
Cassvan et al., 1986 14%
Pierre-Jerome and Bekkelund, 2003 16e53%
Osterman, 1988 18%
Moghtaderi and Izadi, 2008 24%
Herczeg et al., 1997 33%
Liveson, 1991 48%
Upton and McComas, 1973 76%
Golovchinsky, 1995 94%
The publications are ranked based on prevalence (low to high). Due to a lack of
a gold standard to diagnose cervical radiculopathy and carpal tunnel syndrome,
different diagnostic methods have been employed which may be responsible
for the variation in prevalence values.
to be impaired at the site of nerve compression (Lundborg, 1970;
Rydevik et al., 1980; Lundborg et al., 1983; Dahlin et al., 1984).
However, to what extent these impairments influence the nerve
proximal and distal to the site of compression remains largely
unknown.
Despite the controversy surrounding the double crush hypoth-
esis, it is still frequently cited to explain the phenomenon of dual
nerve disorders (e.g., Moghtaderi and Izadi, 2008; Smith et al.,
2008; Fitzpatrick, 2010). Numerous reviews have summarised the
sparse available evidence for potential mechanisms (e.g., Osterman,
1988; Mackinnon, 1992; Simpson and Fern, 1996; Wilbourn and
Gilliatt, 1997). These mechanisms have however all been formu-
lated more than 10 years ago. Since then, they have neither been
updated nor revised despite substantial advances in neuroscience.
Rather than continuing to review potentially outdated mecha-
nisms, other study designs are needed to reveal which mechanisms
are currently considered important for the double crush hypoth-
esis, taking into consideration recent advances in neuroscience. A
Delphi study was therefore conducted with the following two main
aims: (1) to determine whether experts agree that a nerve disorder
can be a predisposition for the development of a secondary nerve
disorder, and (2) to compile an up-to-date list of plausible mech-
anisms to explain the occurrence of dual nerve disorders.
2. Methods
A three-round Delphi survey was conducted in a panel of
international experts in the field of peripheral nerve disorders. The
‘classical Delphi’ method is used to reach consensus on a contro-
versial topic (Dalkey, 1967). As reaching consensus was not the aim
of this study, a ‘policy Delphi’ was conducted. A ‘policy Delphi’
specifically intends to develop alternatives to already existing
theories and to examine their acceptability rather than aiming to
reach consensus (Turoff, 1970; Loo, 2002). This modification of the
Delphi design is therefore a well-suited method to address the aims
of this study.
2.1. Expert panel
Fifty experts were invited by mail and email to participate in this
study. Invited experts were either clinical researchers who pub-
lished at least 2 articles specifically on the double crush hypothesis
(n ¼ 12), basic scientists with at least 15 articles in the field of
peripheral nerve injuries published in international peer-reviewed
journals identified via ISI Web of Knowledge (n ¼ 32), and
university lecturers with an international reputation in peripheral
nerve disorders and neuropathic pain (at least 5 peer-reviewed
publications, 1 book chapter and presenting international work-
shops on neuropathic pain) (n ¼ 6). These a-priori established
selection criteria and the number of contacted experts varied
among the three subgroups in order to attract the top segment of
each category and to correct for the anticipated differences in
response rates. All experts remained anonymous towards each
other. The institutional ethics committee granted ethical approval.
2.2. Procedure
In the first round, experts rated their level of agreement
regarding the statement that a nerve disorder in the upper limb or
neck is a predisposition for the development of a secondary nerve
disorder in the upper limb or neck. The example which was given
was the occurrence of CTS following cervical radiculopathy. A
5-point Likert scale ranging from ‘strongly disagree’ to ‘strongly
agree’ was used. In addition, the experts were asked in an open
question to list possible mechanisms which may explain the
occurrence of a second nerve disorder following a primary nerve
disorder. Upon receipt of the completed first-round questionnaires,
responses were anonymised and two investigators composed a list
of mechanisms incorporating every suggestion of the panel. Each
mechanism was summarised with a short title followed by a para-
graph detailing the proposition. If several experts mentioned the
same mechanism, the answers were merged. Since the wording
therefore differed from the original answers, all experts were
contacted in a second round to verify that their suggestions were
still represented in the newly compiled list of mechanisms. (No
modification was requested.) In addition, they were given the
chance to propose additional mechanisms should they have felt
that the list was not complete. (One additional mechanism was
added.) The online appendix contains the complete list of mecha-
nisms as compiled in the second round.
In the third round, every expert rated the plausibility of each
mechanism on a 10-point Likert scale ranging from 1 (‘not at all
plausible’) to 10 (‘highly plausible’) (Brunner et al., 2008). For each
mechanism, the authors were given the option to abstain from
rating if they felt they did not have sufficient knowledge in that
particular field. This option was incorporated to increase the val-
idity of the actual ratings. The questionnaires of each round were
trialled in a small sample of researchers and clinicians to increase
the chance of correct implementation before they were sent to the
participating experts.
2.3. Statistical evaluation
Plausibility ratings were analysed in SPSS Version 15.0 (SPSS Inc,
Chicago, Illinois) by calculating the median and the corresponding
interquartile ranges (IQR) for each mechanism. Plausibility ratings
were classified according to their median ranking into highly
plausible (
7), plausible (>4 to <7) and implausible (4). A Krus-
kalleWallis test was performed on the agreement ratings and the
plausibility ratings of each mechanism to evaluate potential
differences between the three subgroups of experts.
3. Results
Seventeen experts from seven countries (Australia (n ¼ 4),
Canada (n ¼ 1), Denmark (n ¼ 1), Israel (n ¼ 1), Sweden (n ¼ 1),
United Kingdom (n ¼ 1) and United States of America (n ¼ 8))
completed the first round of the study. Sixteen experts completed
the entire study. The panel consisted of six clinical researchers, six
basic scientists and five university lecturers.
 A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562
Fifty-nine percent of the experts either agreed or strongly
agreed that the presence of a nerve disorder is a predisposition for
the development of a secondary nerve disorder in the same
quadrant; 12% remained undecided and 29% disagreed. None of the
experts strongly disagreed. There was no difference in agreement
ratings between expert subgroups (KruskalleWallis p ¼ 0.61).
The experts listed 22 potential mechanisms to explain the
occurrence of dual nerve disorders (Figs. 1 and 2). Fourteen
mechanisms explained the occurrence of a secondary nerve
disorder following a primary nerve disorder (Fig. 1). Of these
mechanisms, nine have not previously been suggested in relation to
dual nerve disorders. Four mechanisms reached a median of
7 and
were therefore considered highly plausible (impaired axonal
transport, ion channel up or downregulation, inflammation in the
dorsal root ganglia and neuroma-in-continuity). Seven mecha-
nisms were categorised as plausible (median >4 to <7), whereas
three mechanisms were considered implausible (median 4)
(Fig. 1).
The remaining eight mechanisms (Fig. 2) could be regarded as
underlying common drivers. These mechanisms by themselves
may predispose to multiple nerve disorders in contrast to processes
that are associated with a first nerve disorder subsequently leading
to a secondary nerve disorder. Five of these mechanisms were
considered highly plausible (systemic factors, neurotoxic medica-
tion, age, lifestyle and the fact that these disorders are common).
The remaining three mechanisms were considered plausible
(Fig. 2).
The experts pointed out that mechanisms are likely to occur
together. A combination of mechanisms was rated as highly plau-
sible (median ¼ 9.5; IQR ¼ 1.8). For most of the other mechanisms
there was a large variability in plausibility ratings between experts
as evidenced by the relatively large interquartile ranges.
The experts could abstain from rating when they felt a particular
mechanism was outside of their area of expertise, but on average,
there were only 1.5 abstentions per mechanism. There was no
Fig. 1. Suggested mechanisms associated with a nerve disorder that may predispose to the generation of a secondary nerve disorder. Median and interquartile ranges (IQR) of the
plausibility ratings, the number of experts who abstained from rating and whether mechanisms have previously been linked to the double crush hypothesis are listed for each
mechanism. DRG: dorsal root ganglia.
559
difference in plausibility ratings among the three subgroups of
experts for any mechanism (KruskalleWallis all p > 0.05).
4. Discussion
Fifty-nine percent of the experts either agreed or strongly
agreed that the presence of a nerve disorder is a predisposition for
the development of a secondary nerve disorder in the same
quadrant. Although the majority of experts supported this view, the
fact that 29% of experts disagreed indicates that controversy still
surrounds the double crush hypothesis. Interestingly, the level of
agreement among experts was comparable with the agreement
among clinicians (Schmid and Coppieters, 2010).
Experts who did not support the statement that a primary nerve
disorder predisposes to a secondary nerve disorder were not
excluded from continuing in the study. One reason for this was that
when asked to list mechanisms to explain dual nerve disorders,
experts could also list mechanisms which may cause dual or
multiple nerve disorders, such as systemic diseases. In other words,
mechanisms associated with underlying pathologies that can cause
multiple nerve injuries could be listed in addition to mechanisms
associated with a primary nerve disorder that lead to a secondary
nerve disorder.
Eight mechanisms which could be regarded as common drivers
for dual or multiple nerve injuries were listed. There is high level
evidence that systemic factors such as diabetes or thyroid disease
(Briemberg, 2009), and neurotoxic medication such as cancer drugs
(Peltier and Russell, 2006) lead to polyneuropathies. These mech-
anisms are however independent of a primary nerve disorder and
do therefore not reflect the initially described double crush
hypothesis where one nerve disorder predisposes the nervous
system to the development of a secondary nerve disorder (Upton
and McComas, 1973). In this discussion, we will therefore focus
on the mechanisms associated with a first nerve disorder which
may trigger a secondary nerve disorder.
560 A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562
Fig. 2. Suggested mechanisms that can be considered a common driver to the generation of multiple nerve disorders. Median and interquartile ranges (IQR) of the plausibility
ratings and the number of experts who abstained from rating are listed for each mechanism.
All mechanisms previously linked to the double crush hypoth-
esis were still listed, indicating that these mechanisms cannot be
dismissed. The nine newly proposed mechanisms suggest however
that the traditionally advocated mechanisms may be insufficient to
explain how a nerve disorder may render the nervous system more
vulnerable for the development of a secondary nerve disorder.
To prevent the introduction of bias, all experts were invited to
rate each mechanism regardless of their level of agreement with
the double crush hypothesis. Although approximately one third
of the experts disagreed with the double crush hypothesis and had
the choice to rate the mechanisms related to a primary nerve
disorder as ‘not at all plausible’, only 3 mechanisms were consid-
ered implausible. Considering the low abstention rate (1.5 experts
per mechanism) experts were reluctant to dismiss the suggested
mechanisms. Below we will briefly discuss the mechanisms that
were rated as highly plausible or plausible.
4.1. Highly plausible mechanisms
4.1.1. Axonal transport
Animal studies revealed that axonal transport is impaired at
pressure levels commonly observed in patients (Dahlin and
Lundborg, 1990; Rempel et al., 1997). Chemical blockage of axonal
transport increases the mechanosensitivity of axons locally and just
proximal to the blocking site, but not distally (Dilley and Bove,
2008). It has however been proposed that the peripheral nerve
and the dorsal root have separate axonal transport systems
(Morgan and Wilbourn, 1998), suggesting that impaired axonal
transport in one system may be insufficient to explain the coexis-
tence of cervical radiculopathy and CTS. Similarly, impaired axonal
transport by itself cannot explain the combination of CTS and ulnar
neuropathy as different nerves have separate transport systems
(Morgan and Wilbourn, 1998). It remains to be investigated
whether compromised axonal transport due to mechanical
compression is sufficient to render the nerve more vulnerable at
remote sites.
4.1.2. Ion channel up or downregulation
Ion channel upregulation (e.g., sodium-channels) and down-
regulation (e.g., potassium-channels) distal as well as proximal to
the primary nerve injury may lower the firing threshold of neurons.
There is growing evidence for upregulation of specific sodium-
channels locally as well as in the dorsal root ganglia, dorsal horn
and the thalamus (Dib-Hajj et al., 1999; Hains et al., 2004; Zhao
et al., 2006). These sodium-channels rapidly recover from inacti-
vation and are excitable by depolarisations below the action
potential threshold (Waxman et al., 2000). This characteristic
allows action potential generation at higher frequencies which has
been associated with the development and maintenance of
neuropathic pain (Waxman et al., 2000; Hains et al., 2004).
However, these experiments use nerve injury models which
involve major axonal loss. There is one recent study that demon-
strated sodium-channel upregulation in Schwann cells at the site of
injury in mild nerve compression injuries (Frieboes et al., 2010).
Future studies need to investigate whether such changes are
present at distant sites to the injury.
4.1.3. Immune-inflammation of the dorsal root ganglia
Animal studies demonstrated an invasion of immune cells in
the dorsal root ganglia (DRG) following peripheral nerve injury
(Hu et al., 2007). Excitatory cytokines released by these immune
cells may lower the firing threshold of sensory neurones
(Moalem and Tracey, 2006). Since cell bodies of intact and
injured neurones lie in very close proximity in the DRG,
immune-inflammation at this site may affect intact axons orig-
inating from a site distant to the injury. Even though there is
growing evidence for such immune-inflammation, a limitation is
that these experiments were carried out in the chronic
constriction injury model (Bennett and Xie, 1988). This model
leads to extensive axonal loss (Hu et al., 2007) and may not
reflect human neuropathies, often characterised by minimal
fibre loss (Mackinnon and Dellon, 1986).
4.1.4. Neuroma-in-continuity
If the epineurium remains intact after peripheral nerve injury,
regenerating axons sprout along the nerve trunk. These axonal
sprouts may fail to reach their peripheral targets, forming so called
neuroma-in-continuity (Mavrogenis et al., 2008). Regenerating
axons are more sensitive to mechanical and thermal stimuli (Jänig
et al., 2009) and exhibit ectopic activity (Gorodetskaya et al., 2003).
The experts suggested that otherwise pain free stimuli such as
movement may now be sufficient to excite these regenerating
axons even at distant sites from the injury.
4.2. Plausible mechanisms
4.2.1. Central sensitisation
Central sensitisation involves changes in membrane excitability
and increased synaptic efficacy which, together with reduced
inhibition, may lead to reduced pain thresholds, intensified pain
perception and spread of pain to non-affected areas (Ji et al., 2003;
Latremoliere and Woolf, 2009). A state of central sensitisation may
therefore explain the occurrence of a secondary (normally
subclinical) nerve disorder.
 A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562
4.2.2. Nerve biomechanics and altered movement patterns
During movement, peripheral nerves glide relative to their
surrounding tissues (Dilley et al., 2003; Coppieters et al., 2006).
Changes in longitudinal (Hough et al., 2007) and transverse
(Greening et al., 1999; Erel et al., 2003) nerve movement have been
demonstrated in nerve disorders. Impaired nerve excursion at one
site may increase neural strain at distant sites and therefore
increase the risk for secondary nerve disorders (Osterman, 1991).
Reduced nerve movement or increased strain distant to
a compression site have however not yet been demonstrated.
The experts further suggested that altered movement patterns
may arise from pain and motor or sensory deficits following a nerve
disorder. This may put excessive strain on the nervous system
distant to the affected site. One of the few studies that investigated
this demonstrated an increased forward head posture in patients
with CTS (De-la-Llave-Rincon et al., 2009) which may affect the
spinal nerves as they exit the cervical spine.
4.2.3. Cognitive, psychological or psychosocial factors
It is well known that past pain experiences (Rollman et al., 2004),
hypervigilance or fear can lower pain thresholds (Vlaeyen and Linton,
2000). A patient’s awareness and sensitivity to a neuropathy may be
increased when having experienced similar symptoms elsewhere.
4.2.4. Immune-inflammation of the peripheral nerve and spinal
cord
As discussed above, immune-inflammation at different sites in
the nervous system may lower the firing thresholds of sensory
neurones (Moalem and Tracey, 2006). Peripheral nerve injury
models have been shown to induce immune-inflammatory reac-
tions locally as well as in the spinal cord (Eriksson et al., 1993;
Zhang and De Koninck, 2006; Hu et al., 2007).
4.2.5. Impaired microcirculation
Nerve compression affects intraneural microcirculation result-
ing in intra and extraneural oedema (Rydevik et al., 1981; Lundborg
et al., 1983). Whereas reduced microcirculation may be compen-
sated at distant sites by vascular anastomoses (Ogata and Naito,
1986; Maki et al., 1997), the absence of a lymphatic system in the
endoneurium (Powell and Myers, 1986) may challenge the evacu-
ation of intraneural oedema. If ongoing, intraneural oedema may
lead to fibrotic changes (Mackinnon, 2002). It remains unclear
whether these changes can affect the nerve at distant sites.
4.3. Combination of mechanisms
The view that dual nerve disorders are caused by a combination
of mechanisms was almost invariably rated as highly plausible.
Indeed, several of the suggested mechanisms are closely linked.
Immune-inflammation for example may increase the mechano-
sensitivity of neuromas (Grossmann et al., 2009) or lead to fibrotic
changes with subsequent impairment in nerve biomechanics.
Likewise, ongoing input from peripheral neuromas may excite the
central nervous system and maintain a state of central sensitisation.
A combination of mechanisms may also counter the criticism that
impaired axonal transport by itself is insufficient to explain dual
nerve disorders. Axonal transport obstruction has been shown to
lead to morphological changes of the cell body and to glial cell
activation in the spinal cord (Colburn and DeLeo, 1999), which may
explain the coexistence of ulnar and median neuropathies.
4.4. Considerations
Whereas the expert retention rate was high with only one
expert’s opinion lost in round three, a possible limitation of this
561
study is the low participation rate among basic scientists (19%).
Although a low response rate might influence generalisability, we
believe our expert panel (see acknowledgement) is representative
for the leaders in this field. The panel size is in accordance with
previous recommendations (Ludwig, 1997).
Categorisation of the plausibility ratings (highly plausible, plau-
sible and implausible) was based on scales used for defining expert
agreement in other Delphi studies (Gould et al., 2010). Even though
this subdivision is arbitrary, over 50% of experts needed to rate
a mechanism
7 or 4 for it to be considered highly plausible or
implausible. Considering the international standing of the experts,
we believe that these boundaries accurately reflect the plausibility of
the proposed mechanisms. It has however to be taken into consid-
eration that the plausibility ratings for most mechanisms varied
substantially. We believe that the paucity of research rather than the
heterogeneity of the expert panel was responsible for the variability.
This view is supported by the comparable plausibility ratings among
the three subgroups of experts. The variance in plausibility ratings
highlights the need for future experimental studies to evaluate the
validity of the suggested mechanisms.
This study resulted in a comprehensive list of potential mech-
anisms to explain the occurrence of a secondary nerve disorder
following a primary nerve disorder. The identification of many new
mechanisms shines fresh light on the double crush hypothesis and
assists in the development of a research agenda to further under-
stand dual nerve disorders. The large variability in plausibility
ratings supports our initial choice for a policy Delphi study to reveal
current opinion on mechanisms and rate their acceptance, rather
than conducting a classical Delphi to reach consensus. More
research in this domain is needed before reaching consensus on
underlying mechanisms can be attempted.
Acknowledgements
The authors would like to thank the expert panel for their time
and effort in making this study possible (Prof Marshall Devor, Prof
Ze’ev Seltzer, Prof Troels Jensen, Prof Adrian Upton, Prof Elspeth
McLachlan, Dr Michael Thacker, Prof Robert Myers, Prof Lars Dahlin,
Dr Toby Hall, A/Prof Geoffrey Bove, Prof A Lee Osterman, Dr David
Butler, Prof A Lee Dellon, Mr Max Zusman, Prof Lawrence Hurst, Dr
Wayne Massey and Dr James Richardson). Furthermore, we are
grateful to Prof Lucas Bachmann and A/Prof Warren Laffan for their
valuable contribution to the methodology of this study.
Appendix. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.math.2011.05.005.
References
Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of
pain sensation like those seen in man. Pain 1988;33(1):87e107.
Briemberg HR. Peripheral nerve complications of medical disease. Semin Neurol
2009;29(2):124e35.
Brunner F, Lienhardt SB, Kissling RO, Bachmann LM, Weber U. Diagnostic criteria
and follow-up parameters in complex regional pain syndrome type I-a Delphi
survey. Eur J Pain 2008;12(1):48e52.
Cassvan A, Rosenberg A, Rivera LF. Ulnar nerve involvement in carpal tunnel
syndrome. Arch Phys Med Rehabil 1986;67(5):290e2.
Colburn RW, DeLeo JA. The effect of perineural colchicine on nerve injury-induced spinal
glial activation and neuropathic pain behavior. Brain Res Bull 1999;49(6):419e27.
Coppieters MW, Alshami AM, Babri AS, Souvlis T, Kippers V, Hodges PW. Strain and
excursion of the sciatic, tibial, and plantar nerves during a modified straight leg
raising test. J Orthop Res 2006;24(9):1883e9.
Dahlin LB. Aspects on pathophysiology of nerve entrapments and nerve compres-
sion injuries. Neurosurg Clin N Am 1991;2(1):21e9.
Dahlin LB, Lundborg G. The neurone and its response to peripheral nerve
compression. J Hand Surg [Br] 1990;15(1):5e10.
562 A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562
Dahlin LB, Rydevik B, McLean WG, Sjostrand J. Changes in fast axonal transport
during experimental nerve compression at low pressures. Exp Neurol 1984;
84(1):29e36.
Dalkey NC. The Delphi method: an experimental study of group opinion Santa
Monica. The Rand Coorporation; 1967.
De-la-Llave-Rincon AI, Fernandez-de-las-Penas C, Palacios-Cena D, Cleland JA.
Increased forward head posture and restricted cervical range of motion in
patients with carpal tunnel syndrome. J Orthop Sports Phys Ther 2009;39(9):
658e64.
Dib-Hajj SD, Fjell J, Cummins TR, Zheng Z, Fried K, LaMotte R, et al. Plasticity of
sodium channel expression in DRG neurons in the chronic constriction injury
model of neuropathic pain. Pain 1999;83(3):591e600.
Dilley A, Bove GM. Disruption of axoplasmic transport induces mechanical sensi-
tivity in intact rat C-fibre nociceptor axons. J Physiol 2008;586(2):593e604.
Dilley A, Lynn B, Greening J, DeLeon N. Quantitative in vivo studies of median nerve
sliding in response to wrist, elbow, shoulder and neck movements. Clin Bio-
mech (Bristol Avon) 2003;18(10):899e907.
Erel E, Dilley A, Greening J, Morris V, Cohen B, Lynn B. Longitudinal sliding of the
median nerve in patients with carpal tunnel syndrome. J Hand Surg Br 2003;
28(5):439e43.
Eriksson NP, Persson JK, Svensson M, Arvidsson J, Molander C, Aldskogius H.
A quantitative analysis of the microglial cell reaction in central primary sensory
projection territories following peripheral nerve injury in the adult rat. Exp
Brain Res 1993;96(1):19e27.
Fitzpatrick KF. Cyclists - ulnar nerve and double crush. Clin J Sport Med 2010;20(1):
69e70.
Frieboes LR, Palispis WA, Gupta R. Nerve compression activates selective nocicep-
tive pathways and upregulates peripheral sodium channel expression in
Schwann cells. J Orthop Res 2010;28(6):753e61.
Golovchinsky V. Relationship between damage of cervical nerve roots or brachial
plexus and development of peripheral entrapment syndromes in upper
extremities (double crush syndrome). J Neurol Orthop Med Surg 1995;16:61e9.
Gorodetskaya N, Constantin C, Janig W. Ectopic activity in cutaneous regenerating
afferent nerve fibers following nerve lesion in the rat. Eur J Neurosci 2003;
18(9):2487e97.
Gould SJ, Weber MA, Sebire NJ. Variation and uncertainties in the classification of
sudden unexpected infant deaths among paediatric pathologists in the UK:
findings of a National Delphi Study. J Clin Pathol 2010;63(9):796e9.
Greening J, Smart S, Leary R, Hall-Craggs M, O’Higgins P, Lynn B. Reduced move-
ment of median nerve in carpal tunnel during wrist flexion in patients with
non-specific arm pain. Lancet 1999;354(9174):217e8.
Grossmann L, Gorodetskaya N, Baron R, Janig W. Enhancement of ectopic discharge
in regenerating A- and C-fibers by inflammatory mediators. J Neurophysiol
2009;101(6):2762e74.
Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel
expression in second-order spinal sensory neurons contributes to pain after
peripheral nerve injury. J Neurosci 2004;24(20):4832e9.
Herczeg E, Otto A, Vass A, Piza-Katzer H. Significance of double crush in carpal
tunnel syndrome. Handchir Mikrochir Plast Chir 1997;29(3):144e6.
Hough AD, Moore AP, Jones MP. Reduced longitudinal excursion of the median
nerve in carpal tunnel syndrome. Arch Phys Med Rehabil 2007;88(5):569e76.
Hu P, Bembrick AL, Keay KA, McLachlan EM. Immune cell involvement in dorsal root
ganglia and spinal cord after chronic constriction or transection of the rat sciatic
nerve. Brain Behav Immun 2007;21(5):599e616.
Jänig W, Grossmann L, Gorodetskaya N. Mechano- and thermosensitivity of regen-
erating cutaneous afferent nerve fibers. Exp Brain Res 2009;196(1):101e14.
Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and
memory share similar mechanisms? Trends Neurosci 2003;26(12):696e705.
Kuntzer T. Carpal tunnel syndrome in 100 patients: sensitivity, specificity of multi-
neurophysiological procedures and estimation of axonal loss of motor, sensory
and sympathetic median nerve fibers. J Neurol Sci 1994;127(2):221e9.
Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity
by central neural plasticity. J Pain 2009;10(9):895e926.
Liveson JA. Peripheral neurology: case studies in electrodiagnosis. 2nd ed. Phila-
delphia: F. A. Davis Company; 1991.
Loo R. The Delphi method: a powerful tool for strategic management policing. Int J
Police Strateg Manage 2002;25(4):762e9.
Ludwig B. Predicting the future: have you considered using the Delphi method-
ology? J Extension 1997;53(5):1e4.
Lundborg G. Ischemic nerve injury. Experimental studies on intraneural micro-
vascular pathophysiology and nerve function in a limb subjected to temporary
circulatory arrest. Scand J Plast Reconstr Surg Suppl 1970;6:3e113.
Lundborg G, Dahlin LB. The pathophysiology of nerve compression. Hand Clin 1992;
8(2):215e27.
Lundborg G, Myers R, Powell H. Nerve compression injury and increased endo-
neurial fluid pressure: a "miniature compartment syndrome". J Neurol Neuro-
surg Psychiatry 1983;46(12):1119e24.
Mackinnon SE. Double and multiple "crush" syndromes. Double and multiple
entrapment neuropathies. Hand Clin 1992;8(2):369e90.
Mackinnon SE. Pathophysiology of nerve compression. Hand Clin 2002;18(2):231e41.
Mackinnon SE, Dellon AL. Experimental study of chronic nerve compression. Clin-
ical implications. Hand Clin 1986;2(4):639e50.
Maki Y, Firrell JC, Breidenbach WC. Blood flow in mobilized nerves: results in
a rabbit sciatic nerve model. Plast Reconstr Surg 1997;100(3):627e33.
Mavrogenis AF, Pavlakis K, Stamatoukou A, Papagelopoulos PJ, Theoharis S,
Zoubos AB, et al. Current treatment concepts for neuromas-in-continuity. Injury
2008;39(Suppl. 3):S43e8.
Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain.
Brain Res Rev 2006;51(2):240e64.
Moghtaderi A, Izadi S. Double crush syndrome: an analysis of age, gender and body
mass index. Clin Neurol Neurosurg 2008;110(1):25e9.
Morgan G, Wilbourn AJ. Cervical radiculopathy and coexisting distal entrapment
neuropathies: double-crush syndromes? Neurology 1998;50(1):78e83.
Ogata K, Naito M. Blood flow of peripheral nerve effects of dissection, stretching
and compression. J Hand Surg [Br] 1986;11(1):10e4.
Osterman AL. The double crush syndrome. Orthop Clin North Am 1988;19(1):
147e55.
Osterman AL. Double crush and multiple compression neuropathy. In:
Gelberman RH, editor. Operative nerve repair and reconstruction. Philadelphia:
Lippincott; 1991. p. 1211e29.
Peltier AC, Russell JW. Advances in understanding drug-induced neuropathies. Drug
Saf 2006;29(1):23e30.
Pierre-Jerome C, Bekkelund SI. Magnetic resonance assessment of the double-crush
phenomenon in patients with carpal tunnel syndrome: a bilateral quantitative
study. Scand J Plast Reconstr Surg Hand Surg 2003;37(1):46e53.
Powell HC, Myers RR. Pathology of experimental nerve compression. Lab Invest
1986;55(1):91e100.
Radhakrishnan K, Litchy WJ, O’Fallon WM, Kurland LT. Epidemiology of cervical
radiculopathy. A population-based study from Rochester, Minnesota, 1976
through 1990. Brain 1994;117(Pt 2):325e35.
Rempel D, Keir PJ, Smutz WP, Hargens A. Effects of static fingertip loading on carpal
tunnel pressure. J Orthop Res 1997;15(3):422e6.
Rollman GB, Abdel-Shaheed J, Gillespie JM, Jones KS. Does past pain influence
current pain: biological and psychosocial models of sex differences. Eur J Pain
2004;8(5):427e33.
Rydevik B, McLean WG, Sjostrand J, Lundborg G. Blockage of axonal transport
induced by acute, graded compression of the rabbit vagus nerve. J Neurol
Neurosurg Psychiatry 1980;43(8):690e8.
Rydevik B, Lundborg G, Bagge U. Effects of graded compression on intraneural blood
blow. An in vivo study on rabbit tibial nerve. J Hand Surg [Am] 1981;6(1):3e12.
Salemi G, Savettieri G, Meneghini F, Di Benedetto ME, Ragonese P, Morgante L, et al.
Prevalence of cervical spondylotic radiculopathy: a door-to-door survey in
a Sicilian municipality. Acta Neurol Scand 1996;93(2e3):184e8.
Schmid AB, Coppieters MW. Clinician’s opinion on the existence of the double crush
syndrome-an online survey. Newsletter of the American Association of
Neuromuscular and Electrodiagnostic Medicine 2010;3(4):1e2.
Simpson RL, Fern SA. Multiple compression neuropathies and the double-crush
syndrome. Orthop Clin North Am 1996;27(2):381e8.
Smith TM, Sawyer SF, Sizer PS, Brismee JM. The double crush syndrome: a common
occurrence in cyclists with ulnar nerve neuropathy-a case-control study. Clin J
Sport Med 2008;18(1):55e61.
Turoff M. The design of a policy Delphi. Technol Forecast Soc Change 1970;2:149e71.
Upton AR, McComas AJ. The double crush in nerve entrapment syndromes. Lancet
1973;2(7825):359e62.
Vlaeyen JW, Linton SJ. Fear-avoidance and its consequences in chronic musculo-
skeletal pain: a state of the art. Pain 2000;85(3):317e32.
Waxman SG, Cummins TR, Dib-Hajj SD, Black JA. Voltage-gated sodium channels and
the molecular pathogenesis of pain: a review. J Rehabil Res Dev 2000;37(5):517e28.
Wilbourn AJ, Gilliatt RW. Double-crush syndrome: a critical analysis. Neurology
1997;49(1):21e9.
Yu J, Bendler EM, Mentari A. Neurological disorders associated with carpal tunnel
syndrome. Electromyogr Clin Neurophysiol 1979;19(1e2):27e32.
Zhang J, De Koninck Y. Spatial and temporal relationship between monocyte che-
moattractant protein-1 expression and spinal glial activation following
peripheral nerve injury. J Neurochem 2006;97(3):772e83.
Zhao P, Waxman SG, Hains BC. Sodium channel expression in the ventral
posterolateral nucleus of the thalamus after peripheral nerve injury. Mol Pain
2006;2:27.