Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04002843 |
| Other study ID # |
Local/2018/HM-01 |
| Secondary ID |
2018-A01863-52 |
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 30, 2019 |
| Est. completion date |
October 25, 2023 |
Study information
| Verified date |
February 2024 |
| Source |
Centre Hospitalier Universitaire de Nimes |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The main objective is to study the variability and evolution of single-fiber jitter and fiber
density (FD) electrophysiological parameters in a spastic muscle during botulinum toxin type
A (BTA) treatment in hemiplegic patients after stroke, according to primary or multi-injected
status.
The secondary objectives of this study are:
A. To establish a correlation between single-fibre electrophysiological parameters and the
therapeutic response to BTA, clinically estimated by the MAS scale.
B. Creation of a database on single fibre parameters to determine a Jitter numerical
threshold beyond which the effect of BTA appears to be decreasing according to the clinical
evaluation by the MAS (Modified Ashworth Scale).
Description:
Stroke is a frequent, serious and disabling condition. Spasticity interferes with the classic
motor pattern and reflects reflex motor activities normally inhibited by the central nervous
system. This term most frequently refers to a disorder that causes a speed increase dependent
on the tonic stretching reflex associated with an increase of tendon reflexes. About 30% of
patients are affected and this can occur in the short, medium and long term after stroke. It
would seem that, the more serious the initial motor and sensory impairments, the more likely
it is to develop a pattern of spasticity. The most classic upper limb (UL) pattern is that of
an internal adductum rotation of the shoulder coupled to a flessum of the elbow, wrist and
fingers. Approximately 79% of spastic patients on UL have an elbow flessum, involving at
different degrees the elbow flexor muscles (anterior brachialis, biceps brachialis).
Spasticity and its neuro-orthopedic impact, together with muscle atrophy, joint contracture,
pain resulting from the shortening of muscle fibres and ligaments, significantly impede the
progression of rehabilitation, social reintegration, the pursuit of daily living activities
and quality of life.
Recommended management of spasticity after stroke involves multidisciplinary rehabilitation
programs associated with botulinum toxin A (BTA) treatment. Despite this, the dose injected
into this muscle is ultimately more dependent on the experience, feelings and habits of the
referring physician. Some studies provide a safe framework for increasing doses, but
treatment failure by shortness of breath in initially responding patients is still possible.
BTA by blocking the neuromuscular junction (NMJ) is a source of denervation in muscle fiber
(MF), which causes the activation of a serine protease, urokinase. This degrades the
components of the basal muscle blade, causing the nerve endings to bud. The term sprouting
refers to the phenomenon of collateral reinnervation by adjacent fibres from nodal (Ranvier
nodes), terminal and ultra-terminal sites, making it possible to temporarily ensure the
function of parental synapses paralysed by BTA. Thus, initially, between 3 and 7 days, nodal
regrowth is responsible for the development of so-called "immature" NMJs. Then, secondarily,
between 4 to 8 weeks, the original synapse begins its recovery through the development of
terminal reinnervations, parallel to the regression of nodal regrowth. This explains
clinically the increase in remote spasticity of treatment and structural changes in motor
units (MU), usually observed after about 12 weeks. Compared to healthy (or naive) muscles in
this treatment, BTA-induced muscles develop amyelin-like nerve fibers with more collateral
and are characterized by the appearance of non-collateral or nodal reinnervations. Any motor
unit (MU) is normally made up of MF of the same type. The addition of adjacent denervated MFs
leads to a restructuring of the UM, which led to its functional modification.
Although it is widely accepted that the effect of BTA is temporary and reversible and that
functional muscle recovery is thus allowed through the restoration of NMJ, remodelling, and
induced myogenesis; some studies show that its effects persist at a distance from the
injection. Indeed, whether directly after injection, several months or even a year later,
there are changes in the conformation of synaptic gutters (length, width, depths and areas),
with an increase in the number of nicotine receptors for Ach (ACHR) and finally a development
of continuous nodal reinnervations over time. At present, histological studies are the only
ones that have shown this. All the changes observed are not associated with an effective
neuromuscular transmission (NMT), which is only guaranteed by the restoration of the
original, much more progressive synapse. In most cases, it's estimated that NMJ is still
under impregnation with BTA and therefore incompletely restored at a time when it is usual to
repeat this treatment. This explains why, in clinical practice, the chemo-denervation process
does not always seem entirely anatomically reversible. At present it is not clear which
mechanisms are involved: insufficient contact between reinnervations and denervated MF,
failure of the stimulation system or failure of Schwann's peri-synaptic cells.
The effects of BTA are still incompletely understood. Histological, molecular, biochemical
and genetic analyses explain the phenomena linking denervation to muscle remodelling, with a
description of muscle atrophy, a change in sarcomer structure, an increase in intramuscular
lipid cells, inflammatory cells, or collagen content, responsible for a reduction in
contractile tissue and therefore in the number of motor end plate (MEP). Unfortunately, these
histological data cannot be extrapolated to humans or used repeatedly for follow-up.
Currently, it is not known whether healthy muscles in animal models behave in the same way as
human spastic muscles, nor how to study the latter in clinical routine.
It is therefore not exceptional that after repeated injections into the same muscle, there is
an escape of the initial therapeutic effects, forcing the doses to be increased a few times
without obtaining any results either on spasticity or on the duration of the treatment. The
effect of BTA may fade over time and complex neuro-orthopaedic changes in the clinical
picture, justifying the use of new strategies such as increasing doses, which may not always
be negligible. There is no specific recommendation on how to proceed, as the situations are
diverse and complex.
The literature, our experience and the testimonies of patients followed in our department for
many years have contributed to these questions: how to explain the lack of response to BTA
treatment, after initial efficacy and after sometimes doubling / tripling the doses? Would
the investigator have a parameter capable of approaching the BTA mechanism as closely as
possible in order to study its variations and correlate them with the clinical response
established by our conventional scales? By going further, can we even consider that there may
be a tool that can predict the effectiveness of this treatment and thus establish
decision-making charts that can support physicians in their practice? In practice, the
assessment of spasticity and its evolution during this treatment is not always easy in view
of the often complex clinical pictures and readily uses clinical scales such as MAS, Tardieu.
These are based on restricted ordinal values, the mean of which is frequently used as a
reference in patient follow-up. It is lawful to question the relevance and objectivity of
these scales. MAS is easy and fast to use with satisfactory intra-evaluator reliability;
however, its reproducibility between judges remains questionable In the literature, some
tools for quantifying muscle tone alterations in spasticity and their modification following
pharmacological management by BTA are proposed and appear to be independent of the evaluator.
They are interested in the following properties: electrophysiological in EMG with the study
of neurography and H and F reflex viscoelastic in elastography and with myoton, mechanical in
mechanography structural in ultrasonography (61-63) and MRI. However, there are no
recommendations regarding these tools at this time. It seems crucial to propose within our
practice as physical medecine and rehabilitation physicians a quantitative, reproducible
evaluation, capable of abstracting itself from the evaluator's subjectivity.
The study of the single fiber EMG (SFEMG), a technique introduced in 1963 by Stålberg and
Ekstedt, has made it possible to understand the pathological process of affecting NMT and MF
rearrangement within the MU. It has been recognized as the most sensitive diagnostic test in
myasthenia gravis, more specifically in ocular myasthenia gravis or in atypical forms for
which conventional repetitive stimulation tests are rarely proven This technique has also
been used in anterior horn defects. It has made it possible to support the principle of
chronic partial denervation in amyotrophic lateral sclerosis (ALS) and to monitor its
evolution.The two main parameters of the SFEMG are jitter and fibre density (FD), for which
some reminders about NMT should be given.
The amount of acetylcholine contained in a vesicle corresponds to the base unit or quantum;
normally released at the NMJ in an amount sufficient for a motor plate potential to generate
an action potential (AP) and thus a muscle contraction: this is called the safety factor.
However, there are normal variations in the amplitude of the motor plate potential and
variability in the time it takes to reach the threshold generating the AP: these different
variations in the inter-potential interval of NMT thus constitute the jitter. This variation
is usually very short in the normal subject, about 4 microseconds. This parameter thus
reflects the membrane state and the release of acetylcholine within the motor plate. If the
NMT is very altered there may be transmission blocks.
The second diagnostic interest is the study of FD, the increase in which is observed during
reinnervation processes (after nerve section for example) but also during muscular
dystrophies. It provides information on the type of muscle fibers within the MU equivalent to
"grouping" determined by muscle biopsy. The normal FD is about 1.5 fibers per recording but
varies with age and muscle studied. In the event of nerve damage, the denervated fibres, then
reinnered as well as those in the process of being destroyed, separate from their motor
plate, resulting in a temporary elongation of the jitter, which tends to normalize (sometimes
with a duration of more than one year). Secondly, the investigator are witnessing an increase
in the FD that can be maintained at a high level over the long term.
If the Jitter, is the witness of the blockage of the NMT, then it seems to us to be a
relevant tool for the reflection of the BTA origin action. Many scientific articles have
focused on asserting or disproving subclinical manifestations of the systemic spread of BTA
using jitter elongation in muscles far from the initial injection site. Few have been
interested in the evolution of the parameters of the single fibre within the muscle itself
treated, except for work on the orbicular muscle of the eye in patients with blepharospasm or
hemifacial spasm treated with BTA. At the peak of therapeutic efficacy, jitter was
significantly the highest and the recurrence of involuntary movements and therefore the
decrease in efficacy was correlated with its normalization. Moreover, except in the fields of
aesthetics, of interest and relevance too far removed from the problem of our work, there is
no publication correlating the cumulative dose effect within the muscle itself treated with
electrophysiological parameters.
Our clinical observations of the ineffectiveness of certain injections in patients who are
usually responders and electrophysiological based on jitter and FD parameters remaining high
at a distance from the injection (suggesting the persistence of MNT blockage) led us to doubt
the scientific relevance of an on-site reoperation. The place of a paraclinical tool,
witnessing the reaching of this threshold, thus seems interesting to avoid the increase of
excessive and ineffective doses on a sufficiently denervated muscle and to be able to
distribute as well as possible this maximum authorized dose within involved muscles by
avoiding potential adverse effects and a significant additional cost.
This preliminary study aims to study the kinetics of the electrophysiological parameters
"jitter and FD" in SFEMG during BTA treatment in hemiplegic patients after stroke, spastic on
one elbow flexor muscle (such as anterior brachialis, biceps brachial muscles), depending on
the primary or multi-injected status, in order to highlight the residual effect of this
treatment on NMT. It is an objective, standardized means, capable of accurately quantifying
the blockage of NMT by decreasing the release of acetylcholine within the synapse of muscle
treated with BTA. If this tool proved to be effective, it would allow in a future work the
realization of abacuses potentially predictive of the therapeutic effect of BTA and thus
justify new actions to be taken at a given time in the life of a spastic muscle (therapeutic
window, revision of injection patterns). SFEMG analysis coupled with ultrasound tracking is
part of the dynamics of our discipline on the development and implementation of technologies
for patients and their families.
Our assumptions are as follows:
- BTA causes jitter elongation and FD increase in elbow flexor muscle after a single
injection
- Jitter is significantly longer in "multi-injected" subjects (cumulative dose > 400 IU in
one elbow flexor muscle (biceps brachialis, anterior brachialisl) compared to
primary-injected subjects
- Is Jitter elongation maximum at peak treatment efficacy (evaluation at 4-6 weeks) and
will it tend to normalize at a distance from the injection (3 months-6 months)
- There is a correlation between the Jitter-FD values and the therapeutic efficacy of BTA
estimated by the MAS scale in the elbow flexor muscle chosen.
