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
Article history:
Received 7 January 2011
Received in revised form
7 April 2011
Accepted 9 May 2011
Keywords:
Double crush syndrome
Nerve compression syndromes
Neuropathic pain
Delphi study
a b s t r a c t
A high prevalence of dual nerve disorders is frequently reported. How a secondary nerve disorder may
develop following a primary nerve disorder remains largely unknown. Although still frequently cited,
most explanatory theories were formulated many years ago. Considering recent advances in neurosci-
ence, it is uncertain whether these theories still reect current expert opinion. A Delphi study was
conducted to update views on potential mechanisms underlying dual nerve disorders. In three rounds,
seventeen international experts in the eld of peripheral nerve disorders were asked to list possible
mechanisms and rate their plausibility. Mechanisms with a median plausibility rating of 7 out of 10
were considered highly plausible. The experts identied fourteen mechanisms associated with a rst
nerve disorder that may predispose to the development of another nerve disorder. Of these fourteen
mechanisms, nine have not previously been linked to double crush. Four mechanisms were considered
highly plausible (impaired axonal transport, ion channel up or downregulation, inammation 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 classied 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 insufcient to explain the high prevalence of
dual nerve disorders.
2011 Elsevier Ltd. All rights reserved.
1. Introduction
The double crush hypothesis was rst 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
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
mainpoint of debateis whether a primary nerve disorder canindeed
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 beenshown
* Corresponding author. Tel.: 61 7 3365 1644; fax: 61 7 3365 1622.
E-mail address: m.coppieters@uq.edu.au (M.W. Coppieters).
Contents lists available at ScienceDirect
Manual Therapy
j ournal homepage: www. el sevi er. com/ mat h
1356-689X/$ e see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.math.2011.05.005
Manual Therapy 16 (2011) 557e562
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 inuence 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 eld 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
specically intends to develop alternatives to already existing
theories and to examine their acceptability rather than aiming to
reach consensus (Turoff, 1970; Loo, 2002). This modication 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 specically on the double crush hypothesis
(n 12), basic scientists with at least 15 articles in the eld of
peripheral nerve injuries published in international peer-reviewed
journals identied via ISI Web of Knowledge (n 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 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 rst 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 rst-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
modication 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 sufcient knowledge in that
particular eld. 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 classied 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 4),
Canada (n 1), Denmark (n 1), Israel (n 1), Sweden (n 1),
United Kingdom (n 1) and United States of America (n 8))
completed the rst round of the study. Sixteen experts completed
the entire study. The panel consisted of six clinical researchers, six
basic scientists and ve university lecturers.
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.
A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562 558
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 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, inammation 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 rst 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 9.5; IQR 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 fromrating 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
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 fromcontinuing 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 reect 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 rst nerve disorder which
may trigger a secondary nerve disorder.
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.
A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562 559
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 insufcient to
explain howa nerve disorder may render the nervous systemmore
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 briey 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 insufcient 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 sufcient 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 ring threshold of neurons.
There is growing evidence for upregulation of specic 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-inammation 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 ring 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-inammation 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-inammation, 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
reect human neuropathies, often characterised by minimal
bre 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 (Jnig
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 sufcient 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 efcacy which, together with reduced
inhibition, may lead to reduced pain thresholds, intensied 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.
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.
A.B. Schmid, M.W. Coppieters / Manual Therapy 16 (2011) 557e562 560
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 frompain and motor or sensory decits 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),
hypervigilanceor fear canlower painthresholds (VlaeyenandLinton,
2000). A patients awareness and sensitivity to a neuropathy may be
increased when having experienced similar symptoms elsewhere.
4.2.4. Immune-inammation of the peripheral nerve and spinal
cord
As discussed above, immune-inammation at different sites in
the nervous system may lower the ring thresholds of sensory
neurones (Moalem and Tracey, 2006). Peripheral nerve injury
models have been shown to induce immune-inammatory 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 brotic 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-inammation for example may increase the mechano-
sensitivity of neuromas (Grossmann et al., 2009) or lead to brotic
changes with subsequent impairment in nerve biomechanics.
Likewise, ongoing input from peripheral neuromas may excite the
central nervous systemand maintain a state of central sensitisation.
A combination of mechanisms may also counter the criticism that
impaired axonal transport by itself is insufcient 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
experts opinion lost in round three, a possible limitation of this
study is the low participation rate among basic scientists (19%).
Although a low response rate might inuence generalisability, we
believe our expert panel (see acknowledgement) is representative
for the leaders in this eld. 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 dening 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,
webelieve that theseboundaries accuratelyreect theplausibilityof
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 researchrather thanthe
heterogeneity of the expert panel was responsible for the variability.
This viewis supportedby 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 identication 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
Zeev 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.
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