Assessment of muscle properties in neuromuscular disorders: The muscle toolbox

There are over 600 different neuromuscular disorders many affecting children,
and virtually all are rare. Muscle weakness is the main characteristic of most
neuromuscular disordres, but the causes, weakness patterns, and progression
rates of the disorders are variable. Accurate assessment of disease progression
in these disorders is very important for determining disease stage, as outcome
measure in trials and to manage expectations, but is challenging in single
centres due to the rarity of the disorders. Disease progression is determined
with a wide variety of clinical measures, including imaging, muscle strength
measurements, and motor function tests. Imaging has the advantage that it is
very sensitive to small changes over time. However, clinical muscle imaging
protocols are dominated by qualitative methods instead of quantitative methods,
and each hospital makes different choices on what imaging techniques and
parameters they use. Muscle strength and function assessment is more directly
related to everyday function, but shows higher (inter-observer) variability and
may be more subjective. Up to now, a combination of assessments is rarely used.
Collaboration between centres to collect more uniform (and comparable) data
could increase insights on the natural disease progression of rare
neuromuscular disorders by increasing sample sizes and thereby accelerating
trial readiness. Therefore, we aim to implement a standardised muscle toolbox
comprising qualitative and quantitative muscle ultrasound (US) and magnetic
resonance imaging (MRI), and muscle function and strength tests in three
paediatric neuromuscular disorder expert centres in the Netherlands: Radboud
university medical center (Radboudumc), Leiden University Medical Center
(LUMC), and Utrecht University Medical Center (UMCU).

Primary objective
• To characterise natural disease progression rates of MRI- and/or US-assessed
measures of muscle properties and muscle function and strength tests in
children with neuromuscular disorders through standardized annual follow-up
examinations with our muscle toolbox over a four-year period.
Secondary objectives
• To determine the relationship between MRI- and/or US-assessed measures of
muscle properties and muscle function and strength tests;
• To predict clinical milestones such as loss or gain of ambulation, and others
- depending on the specific disease - using MRI- and US-assessed measures of
muscle properties.

This is an observational study that aims to include children with confirmed
diagnosis of spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD),
Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy (LGMD),
facioscapulohumeral muscular dystrophy (FSHD), and myotonic dystrophy type 1
(DM1). All children will be invited to undergo MRI scans and/or US scans,
muscle function, and strength tests. Functional and strength tests are part of
current clinical care. Age will determine the examination approach as follows:
* Children < 5 years will be examined with US and muscle function and strength
tests. These children will not undergo MRI examinations
* Children >= 5 years that do not have contraindications for MRI will be
examined with an MRI scan and muscle function and strength tests. US is
optional.
* Children >= 5 years that do have contraindications for MRI will be examined
with US and muscle function and strength tests.

The imaging techniques (MRI and US), muscle- and function tests can be
considered non-therapeutic interventions, as these are nog standard care for
each child.

The maximum time burden will be 90 minutes. The participants will undergo an
additional MRI scan and/or US assessment, each taking ~30 minutes each. Muscle
function and strength tests are part of standard care, though some additional
tests may be required depending on the centre and neuromuscular disease. This
potential additional testing for muscle strength will not take more than 30
minutes.
Spieren voor Spieren*s youth panel has been consulted on the acceptability of
additional imaging or strength tests, and their feedback has been incorporated
into this protocol.
There will be no direct benefit for the child. In the future, however, this
study will give more insight into disease progression at the group-level of
specific neuromuscular disorders and at the individual patient level which the
physician can use to give better, more-personalised advice. We think that the
information will also add to our understanding of the natural history of muscle
tissue quality and thereby help the design of future clinical trials. US and
MRI are safe techniques. The MRI scan can trigger claustrophobia and can cause
slight discomfort due to lying in supine position. To alleviate this potential
burden, we will*amongst other things*use pads and cushions, permit children to
listen to music or watch videos, and parents will be allowed to accompany
children during the scan.