Introduction
Fifty years after its widespread recognition, a significant minority of patients with
carpal tunnel syndrome continue to experience poor outcomes from treatment. Much of
the current treatment is supported by inadequate or nonexistent evidence. Surgical
decompression, often considered the definitive solution, leads to positive results
in 75% of the cases, but leaves 8% of patients worse than before [[1]].
Open release is the preferred surgical procedure. Some patients referred failure to
relieve symptoms after decompression surgery, and reoperation is sometimes necessary.
This is consequence of incomplete release of the flexor retinaculum, scarring around
the median nerve, or incorrect diagnosis [[2],[3],[4]]. Open release is not without complications, these produce symptoms different from
those present before surgery and can be very disabling and difficult to treat. The
“major” complications are rare and consists in lesion of the recurrent motor branch,
severance of the palmar cutaneous branch of the median nerve or of palmar terminal
branches of the median or ulnar nerves with or without neuroma, bowstringing of the
flexor retinaculum, tendon or artery injuries, reflex sympathetic dystrophy. The “minor”
complication are more frequent (pillar pain, loss of grip, scar tenderness or hypertrophy,
wound infection, trigger finger) [[5],[6],[7]].
Pillar pain and loss of grip are temporary and spontaneously disappear within about
3 months, even if some authors reported the persistence of pillar pain and scar tenderness
even after 2 years of follow-up [[8]]. Endoscopic and limited-incision techniques seem to have fewer complications than
classical open surgery, but meta-analysis study was inconclusive on which is the best
surgical approach [[9]]. However endoscopic technique provides faster relief of pain, more rapid improvement
in functional abilities and earlier return to work [[10]].
The nonsurgical interventions with clear benefit are neutral-angle wrist splinting
(with a success rate of 37%), and steroids, which show better effects when administered
by local injection than orally. The initial positive response rate to injection is
70%, but there are frequent relapses as demonstrated by the 12 studies included in
the last Cochrane Review [[11]].
We have designed a randomised controlled study, realized according to apt criteria
for the appraisal of the effectiveness of every new therapeutic strategy, in order
to demonstrate the clinical effectiveness of local progesterone in the most frequent
human focal peripheral mononeuropathy and the neuroprotective effects at the level
of the peripheral nervous system in humans.
Background
Carpal tunnel syndrome (CTS) results from the compression of the median nerve at the
wrist. The typical symptoms are paraesthesiae (numbness, tingling) and pain in the
hand distribution of the median nerve, more often occurring during night or in early
morning waking up the patients. There may be also sensory loss and hand weakness and
clumsiness causing difficulties in daily activities. The prevalence of median nerve
symptoms and electrophysiological median neuropathy in the general population of Maastricht
was 3.4% for women and 0.6% for men, but another 5.8% of all adult women has undetected
CTS [[12]]. The annual average crude incidence in the Siena area is 329.4/100000 person-years
with a highest incidence in range age 50 to 59 years [[13]].
The severity of CTS ranges from mild to severe. In mild CTS, focal disturbance to
myelin is the dominant factor and indeed paranodal demyelination has been documented
[[14],[15]], whereas only with more severe nerve compression do demyelination and Wallerian
degeneration occur [[16],[17]]. Consequently, patients with mild CTS generally report intermittent symptoms can
cause permanent loss of sensation and partial paralysis in abduction and opposition
of the thumb, whereas severe CTS can cause permanent loss of sensation and paralysis
in abduction and opposition of the thumb.
The Problem
CTS can be treated with surgery or conservative options. There are many conservative
treatments commonly used in mild and moderate CTS: oral and local steroids, non steroidal
anti-inflammatory drugs (NSAIDs), diuretics, pyridoxine, wrist splints, physical therapy,
therapeutic exercises and manipulations [[18],[19]].
From the reported data it can conclude the following: (1) locally injected steroids
produce significant improvement [[20]], even if this is temporary (strong evidence, level 1) at both low and high doses,
though they may give side-effects (strong evidence, level 1); (2) vitamin B6 is ineffective
(moderate evidence, level 2) whereas NSAIDs and diuretics are effective (limited evidence,
level 3). Among physical treatments there are conflicting evidences. Only splints
are effective, especially if used full-time (moderate evidence, level 2).
The local corticosteroid injection is the principal alternative to surgery. In one
randomized comparison of management by injection or surgery, equivalent success rates
were found at 1-year follow-up [[21]] but an open follow-up study of this cohort of injected patients showed that injected
patients continue to experience relapse of symptoms up to at least 7 years after injection,
whereas, in surgically treated patients, relapse after 1 year is very rare. Although
popular in rheumatological practice, this intervention has been scorned by most surgeons.
Known risks, such as cutaneous atrophy and depigmentation, tendon rupture, and median
nerve injury from inadvertent intraneural injection, have been given great prominence,
and the therapeutic effect has generally been considered to be of lower quality than
that provided by surgery and temporary in nature. Same surgeons have argued that steroid
injection merely masks the symptoms, whereas median nerve degeneration continues to
progress to a point where subsequent surgical outcome is prejudiced [[1]]. In Cochrane study local corticosteroid injection for CTS provides greater clinical
improvement in symptoms one month after injection compared to placebo. Significant
symptom relief beyond one month has not been demonstrated [[11]]. Interestingly the improvement of nerve conduction studies found already 1 month
after treatment, remaining so until at 6 months [[22]] but spontaneous improvement of neurophysiologic measurements in CTS has been demonstrated,
but only at 10 and 15 months follow-up [[23]].
In conclusion the anti-inflammatory and anti-edema effects of the corticosteroid are
limited at 1 month and in CTS present only a symptomatic effectiveness.
The Solution
Schwann cells, the myelinating glial cells in the peripheral nervous system, synthesize
progesterone in response to a diffusible neuronal signal [[24]]. In peripheral nerves, the local synthesis of progesterone plays an important role
in the formation of myelin sheaths [[25],[26]]. This has been shown in vivo, after cryolesion of the mouse sciatic nerve, and
in vitro, in co-cultures of Schwann cells and sensory neurons. After cryolesion axons
and their accompanying myelin sheaths degenerate quickly in the frozen zone and the
distal segments (Wallerian degeneration). However, the intact basal lamina tubes provide
an appropriate environment for regeneration. Schwann cells start to proliferate and
myelinate the regenerating fibers after 1 week, and 2 weeks after surgery, myelin
sheaths have reached about one third of their final width. In the damaged portion
of the nerve, progesterone and pregnenolone (precursor) levels remain high, and even
increase 15 days after lesion. The role of progesterone in myelin repair, assessed
after 2 weeks, was indicated by the decrease of thickness (number of lamellae) of
myelin sheaths when trilostane, an inhibitor of enzyme involved in the pregnenolone
to progesterone transformation, was applied to the lesioned nerve. Such an effect
was observed in cultures of rat dorsal root ganglia. After 4 weeks in culture, in
presence of a physiological concentration of progesterone, the number of myelin segments
and total length of myelinated axons are increased enormously.
In addition Schwann cells also express an intracellular receptor for progesterone,
which thus functions as an autocrine signaling molecule [[27]].
Progesterone and its metabolites promote the viability of neurons in the brain, spinal
cord and peripheral nervous system. Their neuroprotective effects have been documented
in different lesion models, including traumatic brain injury [[28]], experimentally induced ischemia [[29]], spinal cord lesions [[30],[31]], and genetic model of motoneuron disease. In experimental diabetic neuropathy [[32],[33]] chronic treatment with progesterone had neuroprotective effects at the neurophysiological,
functional, biochemical and neuropathological levels. In this experimental diabetic
rats chronic treatment for 1 month with progesterone counteracted the impairment of
nerve conduction velocity and thermal threshold, restored skin innervation density,
improved Na+/K+ ATPase activity and mRNA levels of myelin proteins, such as glycoprotein, peripheral
myelin protein 22 (PMP22) and protein zero (P0).
Indeed aging nervous system, that is associated with a reduction in the synthesis
of P0 and PMP22, appears to remain sensitive to some of progesterone’s beneficial
effects [[34],[35]].
Progesterone may promote myelination by activating the expression of genes coding
for transcription factors and/or for myelin proteins [[36],[37]] and/or indirectly to regulate myelin formation by influencing gene expression in
neurons and may promote neuroregeneration by several different actions by reducing
inflammation, swelling and apoptosis, thereby increasing the survival of neurons,
and by promoting the formation of new myelin sheaths [[27]]. Progesterone and its derivates, dihydroprogesterone (5α-DH PROG) and tetrahydroprogesterone
(5α-TH PROG), are able to influence the synthesis of myelin proteins under the control
of classical receptors (PR, progesterone receptor) and non classical receptors (GABA-A).
PR involvement in the expression of P0 is confirmed by the finding that in cultured
rat Schwann cells an antagonist such as mifestone is able to block the stimulatory
effect exerted by progesterone and 5α-DH PROG (i.e. classical ligands of PR). This
antagonist is also effective in blocking the effect of 5α-TH PROG (i.e. a neuroactive
steroid which is able to interact with GABA-A receptor) on P0. Indeed, the activity
of the 3α hydroxysteroid dehydrogenase is bi-directional and consequently 5α-TH PROG
might be retroconverted into 5α-DH PROG, exerting its effect on P0 via activation
of PR [[25],[38],[39]].
GABA-A involvement in the expression of PMP22 is confirmed by the finding that in
cultured rat Schwann cells a specific GABA antagonist such as bicuculline completely
abolishes the stimulatory effect exerted by 5α-TH PROG, while an agonist such as muscimol
increase this effect [[40]].
Finally, progesterone is also well known to have anti-inflammatory property, in view
of his effects on pro-inflammatory cytokines [[41]] and prostaglandins [[42]]; in addition this hormone has demonstrate capability to decrease edema formation
after brain injury [[43]]. By means of these two properties, progesterone could reduce pain in CTS patients,
like the cortisone do [[44]].
The safety of the progesterone in humans has been demonstrated [[28],[45]].
In summary progesterone can to be a therapeutic opportunity in the myelin neuropathy
[[46]] and the mild CTS is a perfect model of the localized myelin damage.
This is a first randomized clinical trial protocol study in humans for the local therapy
in CTS: cortisone versus progesterone.
Recommendations And Methods
Recommendations And Methods
The study is designed as a monocentric randomized clinical trial. The Medical Ethics
Committees of the University of Siena approved the study protocol.
Study population
Patients were enrolled in the study if the symptoms compatible with clinical diagnosis
of CTS were confirmed by electrodiagnostic evidence of delay of the distal conduction
velocity of the median nerve (for details see respective paragraphs).
Patients who are eligible for participation will be informed about the trial by the
neurologist. If they show interest, they will receive written information about the
trial with a detailed description of the aim of the study and of the implications
of participation. Only subjects able to read, understand and sign the informed consent
are included in the study. The information about the trial is also missed to the general
practitioner of the patient.
Clinical criteria
Patients with suspected CTS referred to our electrodiagnostic laboratory to confirm
clinical suspicion of CTS will be eligible for including in the trial from 01.06.2008.
Patients will be recruited if they will complain at least three months of the following
symptoms: nocturnal awaking or activity-related numbness, tingling, burning, pain
in the hand distribution of the median nerve according to hand diagram by Katz et
al. modified by consensus criteria of classification of the CTS. Only “classic/probable”
and “possible” cases will be enrolled [[47],[48]]. Then only patients with “mild” CTS will be successively included in the trial.
Mild cases are defined as those patients who complain only symptoms without objective
sensory loss, weakness of abduction/opposition of the thumb and hypotrophy/atrophy
of thenar eminence, i.e. these patients belonging to stage 1 and 2 of a validated
clinical CTS severity scale [[49]]. Other mandatory inclusion criteria are female gender (because the progesterone
is a natural female hormone) and age between 18 and 60 years.
Exclusion criteria are: previous conservative or surgical treatments for CTS, diabetes,
connective tissue and thyroid diseases, renal failure, gout, pregnancy, lactation,
estrogen drugs, arthritis and deforming arthrosis, onset of CTS symptoms after hand
trauma, polyneuropathy, brachial plexopathy, neuropathy of the ulnar nerve at elbow,
thoracic outlet syndrome and history of cervical radiculopathy.
Physical examination consisted of evaluating of muscular strength and trophism, sensory
function, evocation of deep reflexes and provocative clinical test (Phalen and Tinel
signs) will be performed by neurophysiologist before the electrodiagnostic tests.
For subjective evaluation of severity of symptoms, the Boston Questionnaire will be
completed by patients just before the injection [[50],[51]]. The questionnaire is divided into two parts. The first part (11 items) evaluates
symptoms, and the second part (8 items) evaluates the functional status of the hand.
Five answers are possible to each question; they are scored 1 to 5 according to the
severity of symptoms or the difficulty of performing a certain activity. Each score
is calculated as the mean of the score of individual item. Severe impairment is indicated
by a high score.
In addiction visual analogue pain scale (VAS) will be administrated. The patient will
be instructed to point to the position on the line between the faces to indicate how
much hand pain they are currently feeling. The far left end indicates ’No pain’ and
the far right end indicates ’Worst pain ever’.
Electrophysiological criteria
The median and ulnar nerve conduction velocity (NCV) study is performed according
to the guidelines of the American Association of Neuromuscular & Electrodiagnostic
Medicine for CTS [[52]]. Surface recording electrodes are placed over the motor point of the abductor pollicis
brevis muscle for the median nerve and over that of the abductor digiti minimi for
the ulnar nerve. The reference electrode is placed over the tendon. Maximum motor
conduction velocity was calculated from elbow to wrist for the median nerve and below-elbow
to wrist for the ulnar nerve. Distal motor latency (DML) is measured with a distance
of 7 cm between the stimulation point of the nerves at the wrist and the above mentioned
muscles. DMLs are measured from the stimulus onset to the initial negative response,
and amplitudes are measured from baseline to negative peak. Electrical stimuli are
delivered by a constant current stimulator through bipolar surface electrodes. The
sensory nerve action potentials are recorded orthodromically with stimulating ring
electrodes placed around the proximal and distal interphalangeal joints. Maximum sensory
conduction velocity and maximum sensory action potential amplitude (SAPa) of the median
(M3, middle finger-wrist; M4 ring fringer-wrist) and ulnar (U4 ring finger-wrist)
nerves are determined. The difference between U4-M4 SCV is also calculated. Skin temperature
was maintained > 32°C with an infrared lamp and recorded with a digital thermometer.
Neurographic values at least 2 SD above or below the mean of the normative data of
our laboratory (see below) are considered abnormal. Patients are eligible for the
study if electrodiagnostic studies demonstrates any one of the following: I) abnormal
comparative test i.e. a difference of >10 m/s between sensory conduction velocity
of the median (M4) and ulnar (U4) nerves; II) abnormal digit/wrist sensory conduction
velocity (M3 < 45 m/s and/or M4 < 43 m/s) and normal distal motor latency (DML <4.3
ms) of the median nerve. In other words, we will select only patients belonging to
class I and II of the electrophysiological classification of CTS severity reported
by Padua et al. [[53]], excluding subjects with absence of the sensory action potential or delayed DML
or absence of the compound muscle action potential (CMAP) of the median nerve.
Finally, recruitment properties of the median nerve were studied by analyzing the
relationship between the intensity of electrical stimulation and the size of motor
and sensory responses, i.e. the input-output curve (I-O curve). This technique is
capable to reveal focal conduction slowing in the median nerve, not detectable by
conventional electrodiagnostic tests, in mild CTS patients [[54],[55]]. In fact, the relationship between the stimulus intensity (input) and the size
of the response (output) defines the characteristic of motor/sensory axon recruitment
and, in addition to conventional parameters such as maximum amplitude, latency and
maximum conduction velocity of a peripheral nerve, allows us to analyse the following
variables: a) threshold value (the initial component), reflecting the most excitable
axons; b) slope (the second component), indicating the recruitment efficiency (gain);
c) plateau phase (the third component), reflecting the maximal size of CMAP, as well
as the activation of axons that are ultimately recruited.
In order to determine the relationship between the intensity of electrical stimulation
and the size of the median nerve motor response, the stimulating electrode is initially
placed over the wrist, and its position adjusted until the site with the lowest threshold
for eliciting a CMAP of 0.1 mV (baseline-negative peak) will be established. In order
to determine median nerve (M3) SAPa we use the threshold that produced a SAPa of 1
uV; all sensory responses will be averaged. Stimulus intensities are increased in
steps of 0.2 mA until the maximum (motor and sensory)-wave will be obtained. I-O relationship
data will be fitted to a Boltzmann sigmoidal function by the Lavenberg-Marquard non
linear least-mean-square algorithm [[56]]. Recruitment curves are constructed by normalizing stimulus currents and response
amplitudes. This enabled comparison of individual I-O relationships. Parameters of
the curves obtained before treatment will be compared with those obtained one, six
and 1 year months later.
The same neurophysiologist will perform all electrodiagnostic tests at baseline and
follow-ups.
Ultrasonographic criteria
High-resolution ultrasonographic examination at wrist is a powerful tool in the diagnosis
of compression mononeuropathies, particularly CTS [[57],[58]] and allows to eliminate rheumatological pathology: arthritis, deforming arthrosis,
flexor tenosynovitis, trigger finger.
In the uncertain situations standard rx is performed.
High-resolution ultrasonographic examination is performed by the same rheumatologist,
experienced in musculoskeletal disorders, after electrodiagnostic test. A real-time
scanner (Esaote Technos Mp) with a 5-10 MHz linear array transducer will used. Patients
are seated in a chair with arms extended, hands resting in a horizontal supine position
on the examination couch, and fingers semi-extended. It will perform longitudinal
and transverse scans of the median nerve from the distal segment of the forearm to
the tunnel outlet. The median nerve cross-section area (CSA) is measured at the tunnel
inlet (just before the proximal margin of the flexor retinaculum) because the highest
concordance with nerve conduction study is detected. CSA measurements are performed
at the inner border of the thin surements hyperechoic rim of the nerve (perineurium)
using the manual tracing technique. The weight of the probe is applied without additional
pressure. The intra-observer reliability for nerve measurement has been tested previously
and published elsewhere [[59]]. The same expert will perform all ultrasonographic examinations at baseline and
during the follow-ups.
Treatment
Patients are randomly allocated to one of two groups: (i) single cortisone (Triamcinolone
acetonide 20 mg/1 ml, Triamvirgi, Fisiopharma), or (ii) single progesterone (Hydroxyprogesterone
caproate 170 mg/1 ml, Lentogest, A.M.S.A.) echo-guided injection. If bilateral symptoms
are present, only the hand the patient retains as having the most severe symptoms
will be treated. The randomization is done with a dedicated script in MS Office Excel®. Since the injected substance can be easily identified by the treating rheumatologist,
the only persons blinded to the treatment, beside the patient, will be the professionals
performing the echography and the electrophysiology tests.
Sample size
The main output parameter is the Symptom Severity Scale (SSS) score of the self-administered
Boston Carpal Tunnel Questionnaire. The values reported in the literature assessing
the cortisone treatment effect after 2 and 3 months are ranging between 1.37 - 2.3
(mean ± standard deviation: 1.6 ± 0.7). It has been estimated that a minimum number
of n = 26.2 subjects for each group would be necessary to reveal a significant (α
= 0.05) decrease in the SSS score from 1.6 to 2.0 with enough power (90%). If a drop-out
of 4 subjects is considered, the minimum number of subjects required should be adjusted
to no. = 30.
Data analysis
The values for each recorded parameter (NCV, CSA, BQ, VAS) will be submitted to a
two-way ANOVA, with the main factors TREATMENT (cortisol vs progesterone) and TIME
(baseline, 1 month, 6 months, and 12 months after the injection). The significance
level will be set at p < 0.05. Tukey’s test post-hoc analysis will be performed when necessary, in order
compensate for possible type I errors.
Design of the trial
Sixty women with idiopathic mild CTS will be evaluated at before (baseline), 1, 6
and 12 months after injection.
The major outcome of this study is to determine that locally-injected progesterone
may be more beneficial than cortisone in carpal tunnel syndrome at clinical level
(SSS-BQ, VAS). Secondary outcome measures are:
- duration of experimental therapy, with a short (after 1 month) and long follow-up
(after 6 to 12 months);
- improvement of electrodiagnostic and ultasonographic anomalies at various follow-up;
- correlation of the neurophysiologic and ultrasonographic data with clinical evaluation;
- comparison of the beneficial and harmful effects of the cortisone versus progesterone.
The Limit
The hydroxyprogesterone caproate is a synthetic steroid hormone which possesses progestational
activity in pregnancy to prevent preterm birth. It is a non selective agonist for
the classical progesterone receptors because it is able to bind both to androgen and
glucocorticoid receptors.
The absence of natural injectable progesterone commercially available could bias our
results to some extent.
Conclusion
Peripheral nerves are able to synthesize and metabolize neuroactive steroids, as progesterone,
and are a target for these molecules, since they express classical and non-classical
steroid receptors [[46]]. Progesterone modulate the expression of key transcription factors for Schwann
cell function, regulate Schwann cell proliferation and promote the expression of myelin
proteins involved in the maintenance of myelin multilamellar structure, such as myelin
protein zero and peripheral myelin protein 22. These actions may result in the protection
and regeneration of peripheral nerves affected by different form of pathological alterations.
Indeed, progesterone is able to counteract biochemical, morphological and functional
alterations of peripheral nerves in different experimental models of neuropathy, including
the alterations caused by aging, diabetic neuropathy and physical injury.
In our case local corticosteroid injection for CTS is no effective treatment that
can stop or reverse median nerve damage and progesterone could to represent really
a new therapeutic approach. Therefore the main goal of our study is to show the neuroprotective
effects of the progesterone at the level of the peripheral nervous system in humans
and “mild” CTS represents a good model.
The results of this trial will be presented as soon as they are available.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All co-authors participated in study design and read/approved the final manuscript.
Cite this article as: Milani et al., Progesterone - new therapy in mild carpal tunnel syndrome? Study design of a randomized
clinical trial for local therapy Journal of Brachial Plexus and Peripheral Nerve Injury 2010, 5:11
