A prospective, multicenter, randomized, parallel-group controlled trial to compare conservative versus surgical treatment of foot drop in peroneal nerve entrapment.

Conservative treatment of peroneal nerve entrapment consists of physiotherapy
using stretching of the calf muscles to prevent contractures, muscle
strengthening and gait rehabilitation. Physiotherapy exercises are sometimes
combined with functional electrical stimulation and electrostimulation has been
applied for denervated muscles after peripheral nerve lesions. Ankle foot
orthoses can improve gait parameters and functional ambulation in patients with
foot drop. The available literature on the conservative treatment mainly
consists of retrospective series describing a very heterogeneous patient
population including traumatic and iatrogenic peroneal nerve lesions. The
number of patients with peroneal nerve entrapment was low varying between 14
and 33 with a follow-up ranging between three months and three years.

One multicenter prospective study of 46 patients documented follow-up data in
conservatively treated patients including 13 patients who did not receive any
treatment at all due to mild symptoms. After a mean follow-up of 6 months, 39%
of the conservatively treated patients (n = 33) needed a foot orthosis to be
able to walk and 53% had a normal gait pattern. In patients in whom no
conservative treatment was initiated 25% needed a foot orthosis and 63% had a
normal gait pattern. Overall, 79% of patients with peroneal nerve entrapment
reported improvement of ankle dorsiflexion at 6 months (n = 34). Taking all
available literature into consideration, good outcome after conservative
treatment for peroneal nerve entrapment varies between 53% and 100% in the
literature. When interpreting these range of outcome percentages, one should
realize that outcome measures differ between the studies. If data was
available, good outcome was translated to an MRC-score >= 4 for ankle
dorsiflexion. If data was not available, outcome measure of the study was
documented.

Sangwan et al. reported the results of conservative treatment of foot drop due
to prolonged squatting in a prospective case series of 30 patients (34 limbs).
Thirty-two foot drops fully recovered after 3 to 9 weeks. The other 2 patients
recovered fully after 16 and 20 weeks (100%). Cruz-Martinez prospectively
documented the clinical evolution of foot drop in 30 patients receiving no or
conservative treatment. Twenty-six patients fully recovered after a period of 3
weeks to 3 months, three other patients reported minimal weakness (97%). The
severe muscle weakness in 1 patient did not improve after 6 months (but
recovered within 2 weeks after neurolysis). Although these findings are not
confirmed in other case studies, these series describe possible recovery of
foot drop in an early stage with conservative therapy. These findings are
important regarding the timing of randomization

The surgical approach for entrapment at the fibular head aims at decompressing
the peroneal nerve as it dives under the peroneus longus muscle. Similar to the
literature on conservative treatment most studies on the surgical management
concerned retrospective patient series. Some studies had a very heterogeneous
patient population hampering extraction of required data, or did not discuss
patients with peroneal nerve entrapment. Most series suffered from a low sample
size (the smallest study included only 12 patients) with a great variability in
timing between symptom onset and surgery ranging from weeks to years. On
average patients were operated after 4.6 months (range:1 month -27 months for
the included case series) with a follow-up duration ranging from 11 months to 7
years.

We identified 2 prospective studies, one describing 14 patients with a
follow-up of one year after surgery recording improvement of ankle dorsiflexion
in 13 of 14 patients (93%), with half of the patients having normal ankle
dorsiflexion at one year. The prospective series of Nirenberg (56) described
the outcome of 17 patients with peroneal neuropathy (of unknown etiology) and a
follow-up of minimum 4 months. Seven of 17 patients (41%) reported an MRC grade
>= 4 for hallux dorsiflexion. All patients reported improvement of ankle
dorsiflexion and sensory changes within one week after surgery.

Broekx et al. described a large retrospective series of neurolysis after
excessive weight loss. In total, 200 patients were included and on average
patients were operated 4 months after symptom onset. Of all included patients,
85% had a good outcome, defined as an MRC scale for muscle strength grade >= 4
for ankle dorsiflexion. Complications after peroneal nerve are unusual. In the
largest retrospective patient series, 7 out of 200 patients suffered from wound
problems, 1 out of 200 patients suffered from postoperative abscess formation
and subsequent bacterial sepsis. Overall, good outcome after decompressive
surgery for peroneal nerve entrapment varies between 43% and 100% in the
literature. When interpreting these range of percentages, one should realize
that outcome measures differ between the studies. If data was available, good
outcome was translated to an MRC-score >= 4 for ankle dorsiflexion. If data was
not available, outcome measure of the study was documented.

There is indeed insufficient data in the available literature to make any
recommendations. No studies have compared surgical versus conservative
treatment in a prospective manner and currently no guidelines are available.
Even data on the prevalence and the spontaneous evolution of peroneal
neuropathy are virtually non-existent.
The lack of prospective studies on this topic is remarkable since most patient
series on both the conservative and surgical treatment are retrospective in
nature. Most patient series are very heterogeneous given the fact that patients
with peroneal nerve damage due to different causes were included, which makes
it difficult to draw conclusions on the clinical management. Data concerning
the spontaneous evolution of peroneal nerve entrapment (without any
intervention) is almost absent, except for 15 patients. Furthermore, studies
discussing prevalence, report contrasting percentages.

After reviewing the current literature, we identified several methodological
issues when comparing the various studies. Good outcome was not uniformly
defined and duration of follow-up differed not only between, but even within
studies (where follow-up could range from 5 months to 3 years). Additionally,
the number of patients was low to very low in most studies.
Most studies on decompressive surgery for the treatment of peroneal entrapment
were retrospective in nature and for most studies the sample size was small.
Similar to the studies on the conservative treatment, they involved a
heterogeneous patient population and variable follow-up durations.

Since peroneal nerve entrapment represents one of the most common entrapments,
and no practice guidelines exist on its preferred treatment, this prospective
study will provide important outcome data after conservative treatment (current
data very limited), as well as surgical treatment (current data very biased,
retrospective in nature and uncontrolled). The impact on quality of life will
be assessed and the complications (surgical, chronic pain, sensory changes, *)
of both treatments will be recorded. These data will define future treatment
guidelines for this mononeuropathy and is thus relevant for all physicians
treating entrapment neuropathies (neurology, neurosurgery, physical medicine,
orthopaedic surgery, *).



1. Aprile I, Tonali P, Caliandro P, Pazzaglia C, Foschini M, Di Stasio E, et
al. Italian multicentre study of peroneal mononeuropathy: multiperspective
follow-up. Neurol Sci. 2009;30(1):37-44.
2. Eberstein A, Eberstein S. Electrical stimulation of denervated muscle: is it
worthwhile? Med Sci Sports Exerc. 1996;28(12):1463-9.
3. Salmons S, Ashley Z, Sutherland H, Russold MF, Li F, Jarvis JC. Functional
electrical stim

The primary research question of the trial is to assess whether foot drop,
caused by peroneal nerve entrapment in adult patients* recovers better within 9
months after decompressive surgery compared to prolonged standard conservative
treatment.

* Exclusion of iatrogenic or traumatic peroneal nerve palsies. Exclusion of
peroneal nerve compression caused by cysts or tumours. Exclusion of patients
with polyneuropathy. Exclusion of other surgical techniques than neurolysis.

Intervention A: Decompressive release of the peroneal nerve at the level of the
fibular head in patients with foot drop due to peroneal nerve entrapment.
Intervention B: Prolonged conservative treatment of foot drop due to peroneal
nerve entrapment.
Null hypothesis: There is no difference in recovery of foot drop due to
peroneal nerve entrapment after intervention A or intervention B.
Alternative hypothesis: Recovery of foot drop due to peroneal nerve entrapment
is superior after intervention A compared to intervention B.

The overall objective of the foot drop trial is to test the superiority of
surgical release of the peroneal nerve at 10 +/- 4 weeks after symptom onset to
maximal conservative treatment. The foot drop trial is designed as a
prospective, multicenter, randomized, parallel-design study. A double-blind
design is not possible, given the fact that both the treating physician and the
patient will always know the allocated treatment strategy. The clinical
researcher (= outcome assessor) will be blinded for treatment.
Subjects will be randomized 1:1 to surgery or conservative treatment (simple
randomization based solely on a single, constant 1:1 allocation ratio). If a
patient, that signed the informed consent form (ICF), cannot be randomised
because the foot drop has recovered, this will be documented in the eCRF. After
randomization, the patients allocated to conservative treatment will enter a
treatment period of approximately 9 months (individualised physiotherapy
program). Patients allocated to the surgical arm will undergo surgery as soon
as feasible after randomization (maximum within 1 week, preferably within 2
days). For all participating patients that signed the informed consent at the
screening visit, an operation day will be scheduled, maximum one week after the
randomization visit (due to practical scheduling reasons). At the moment of
scheduling, the patient will be unaware of this date to prevent bias (and
orientation of the mindset of patients toward surgery). If a patient is
allocated to the conservative arm of the trial, the scheduled operation date
will be cancelled, without knowledge of the patient. Patients in the surgical
arm of the trial, are allowed to follow physiotherapy after surgery. The
frequency and intensity are to be determined by the treating physician. All
participants are allowed to use an ankle-foot orthosis. The use of
electrostimulation is not advised, although not forbidden.
The endpoints will be evaluated at fixed time-points: 6 weeks, 3 months, 6
months and 9 months after randomization. Extended follow-up is scheduled 9
months after the primary endpoint is reached i.e. 18 months after
randomization. Most trial assessments will be performed by the site-specific
blinded researcher, ideally an independent physiotherapist. Patients allocated
to the surgical arm of the trial will be evaluated 10 days after neurolysis. A
postoperative control is considered standard of care. Sensorimotor function,
quality of life and complications will be assessed during this postoperative
control. Assessment of MRC-scores for ankle dorsiflexion and ankle eversion, as
well as ankle range of motion is considered standard of care and shall be
performed by the treating physician. The treating physician can also assess
ankle dorsiflexion strength measured by isometric dynamometry. This cannot be
done by the outcome assessor because this would lead to unblinding.
A list of standard assessments (clinical records, considered daily practice =
SOC; including motor and sensory function,, ability to walk (barefoot), need
for orthosis, treatment) will be composed for uniformity across centers.
Standard assessments will be conducted at each study visit.

Cross-over is not allowed until the primary endpoint at 9 months is assessed.
After the primary endpoint is assessed, cross-over from the conservative arm to
surgery is allowed and patients will be treated according to standard of care
(decision between treating physician and patient). Extended follow-up for all
patients will be organised, 18 months after randomization. All primary and
secondary endpoints, with the exception of electrodiagnostics, WPAI and return
to work, will be assessed at 18 months. The End-of-Study (EOS) visit will take
place at 18 months post-randomization.

A pilot study will be conducted in 6 centers to assess feasibility of the foot
drop trial, since studies of surgery compared to no or delayed surgery are
challenging. These 6 centers include:
1. University hospitals of Leuven (UZL, prof. dr. Tom Theys)
2. CHU de Liège (ULG, prof. dr. Annie Dubuisson)
3. Ziekenhuis Oost-Limburg (ZOL, prof. dr. Frank Weyns)
4. Leids Universitair Medisch centrum (LUMC, dr. Justus Groen)
5. AZ Groeninge Kortrijk (dr. Jeroen Ceuppens)
6. ULB Erasme Brussel (dr. Sophie Schuind)
The pilot centers will include patients over a period of six months. Inclusion
criteria and exclusion criteria are the same as in the full-scale trial.

The assessments conducted in the pilot study will be the same as in the
full-scale study. The go/no go criterion to embark on a full-scale trial is a
recruitment rate of at least 14 patients in the 6 including centers at 6
months.

Surgical decompression of the peroneal nerve can be performed under local,
locoregional or general anaesthesia. Pneumatic compression to restrict blood
flow in the operation area during surgery can be used (and will be recorded in
the surgery report).
The surgical approach for entrapment at the fibular head is usually through a
curvilinear incision just distal to the fibular head. The length of the
incision can vary between 3 and 10 centimeters. The subcutaneous tissue is
bluntly dissected, and the common peroneal nerve is identified proximal to the
peroneus longus muscle. The peroneal nerve is then released from the
surrounding fibrous tissue and fascia. The anterior intermuscular septum is
usually not cut, but this can be done if deemed necessary. The nerve is
decompressed distally as it dives under the peroneus longus muscle. The
decompression at this site is essential. Certain authors state that an adequate
decompression should extend beyond the bifurcation in the deep and superficial
peroneal nerve and should involve cutting the intermuscular septa. It is up to
the surgeon to decide if decompression beyond the bifurcation is necessary,
based on intraoperative findings (recorded in the surgery report).

As mentioned, both treatment arms of the trial are considered standard of care.
Risks and complications of treatment are limited.
Broekx et al. published a large retrospective case series on operative
treatment of peroneal nerve entrapment and found complications of surgery in
4.5% of included patients (n = 200). These risks were mostly limited to wound
problems (infections, hematoma) or residual pain at the level of the scar. One
patient with severe pre-existing comorbidities (aged 87) developed a
postoperative abscess and S. aureus sepsis. She died of sepsis 28 days after
surgery. Globally, surgery is considered very safe.

We inform patients about the risks at screening and randomization visits and
these risks are discussed in the informed consent form. Since risks are minimal
and the other study group receive physiotherapy no additional measures are
taken.

Contact numbers of the study team are provided. In the highly unlikely event of
an emergency after surgery (which again, is standard of care), patients are
advised to consult the emergency department.

The trial assessments are not invasive. During EMG patients can experience some
discomfort (pain, or a limited electric shock). The EMG in follow-up will be
limited since there is no need to make a diagnosis anymore.


There are no direct advantages for trial participants expect for the fact that
follow-up of the foot drop will be optimal.
Patients are financial compensated for their participation (voucher of ¤175)
and this can be considered an advantage.


Results of the trial can be used to council and treat future patients in the
best way possible. This is important since peroneal neuropathy is the most
frequent neuropathy in the lower limb and a frequent cause of foot drop.