Assessing ion-channel dysfunction in ALS using surface-EMG and high-resolution ultrasound

Amyotrophic lateral sclerosis (ALS) is a devastating disorder characterized by
the progressive degeneration of upper and lower motor neurons. Survival varies
considerably between patients due to different genetic and pathophysiological
mechanisms contributing to the disease. A major challenge is to identify these
mechanisms, and find sensitive biomarkers to measure treatment efficacy in
humans directly. A promising target for disease-modifying treatment involves
ion channels of which their dysfunction has been associated with motor neuron
degeneration in ALS.

Human peripheral nerve excitability studies indicate that changes in axonal
excitability of lower motor neurons induced by the altered functioning of ion
channels are an important early mechanism in ALS, that precedes the clinical
dysfunction and deterioration. Up till now, most nerve excitability studies
have been conducted after the diagnosis has been made. These studies,
therefore, do not involve treatment-naive patients, which may mask highly
relevant, but subtle differences in ion channel dysfunction. Furthermore, the
diagnostic phase provides the opportunity to capture their dysfunction as early
as possible in muscles without clinical symptoms. Ion channel dysfunction has
further been suggested to facilitate fasciculations, a clinical hallmark in
ALS. High resolution ultrasound has become an emerging tool into the diagnostic
phase of ALS to assess presence of fasciculations. Compared to standard
invasive needle-EMG to assess presence of fasciculations, high-resolution
ultrasound has the benefit to be non-invasive and to cover a large portion of
the investigated muscle avoiding patient discomfort and mitigating sampling
bias. Next to assessing lower motor neurons fasciculations, it also forms a
practical, bedside tool that enables capturing morphological consequences of
motor neuron degeneration along the neural axis. It may therefore be an
additional relevant diagnostic tool, complementary to current clinical
electrodiagnostic studies.

This project aims to identify ion channel dysfunction in axons of lower motor
neurons of individual ALS patients, that contributes to loss of these axons,
together with techniques that enables quantification of their loss, function
and morphology. This is important since currently available drugs can modify
ion channel dysfunction in such a way that the death of these nerves may be
delayed or avoided. Assessment in a large group of individual patients is
necessary because molecular biological mechanisms may differ between patients,
and which may therefore also have different practical implications in the
diagnosis of these patients.

Main objective is to identify ion-channel dysfunction in motor nerve cells of
individual ALS patients, that contributes to their death, by assessing the
association between ion-channel function tests in lower motor neurons and
survival of patients with ALS using nerve excitability testing.

Secondary objectives:
1. To determine unique features of ion channel dysfunction that can help to
further dissect pathophysiologic processes of ALS.
2. To explore the potential diagnostic value of excitability testing and
high-resolution ultrasound in patients with suspected ALS, based on assessing
distinctive profiles of ion channel dysfunction that can help to accurately
identify ALS patients early in their disease course.
3. Based on the most discriminative markers, we will define an optimized
protocol that can be easily implemented in future clinical trials and also
performed in routine clinical practice.

It concerns an observational single-center study. The study will be performed
in the Department of Neuromuscular Disorders of the University Medical Center
Utrecht, The Netherlands. The duration depends on the inclusion rate with
current estimates it is set at 3 years.

All applied recordings are non-invasive and form an extension of routine
clinical diagnostic examination. There are no known risks for the recordings
based on the literature and on our experience in previous high-resolution
ultrasound, excitability and nerve conduction studies. The main burden concerns
the time investment on part of the participants. Slight physical discomfort due
to electrical stimulation and brief local skin reddening due to skin electrode
adhesive gel may occur. Patients will benefit indirectly from the study because
more will be known about pathogenic mechanisms in ALS which, in turn, may
potentially lead to development of treatment strategies aimed at motor neuronal
protection. Especially for family members of ALS patients, we anticipate that
being asked to participate in a study investigating neural alterations in
asymptomatic family members may raise questions. In such instances,
participants will be informed that - may they have such questions - they can be
referred to the Department of Medical Genetics for adequate counselling and
information.