High-resolution sonographic visualisation of nerve morphological alterations over time in polyneuropathies: a possible new test for treatment response and prognosis

Rationale: Chronic idiopathic axonal neuropathy (CIAP), chronic inflammatory
demyelinating polyneuropathy (CIDP), multifocal inflammatory demyelinating
neuropathy (MIDN) and multifocal motor neuropathy (MMN) are chronic peripheral
nerve diseases with a high impact on physical functioning. CIDP, MIDN and MMN
occur in relatively young people and their resulting clinical deficits have an
effect on quality of life and limit work participation. There is no treatment
available for CIAP. Corticosteroids are used to treat CIDP and MIDN with
varying treatment responses. For treatment of CIDP, MIDN and MMN intravenous
immunoglobulins (IVIg) are used, which have less side-effects than chronic
corticosteroid use, but this treatment is more expensive. In the Netherlands
most patients are treated with IVIg. Standard protocols are used, which are not
based on personalised medicine. High-resolution sonography (HRUS) of the
peripheral nerves in polyneuropathies is a rapidly evolving field of research.
Standardized sonographic protocols allow assessment of multiple morphological
alterations. A few studies have demonstrated multifocal enlargement of
peripheral nerves in polyneuropathies. However, it is not known what the
morphological changes of the peripheral nerves over time are and if HRUS is
able to detect those changes in patients with CIDP, CIAP or MMN. Also it is not
known if HRUS is of added value to clinical parameters in determining prognosis
and treatment response in CIDP and MMN. Such findings might influence future
treatment decisions.

Objectives:
1. The first objective is to determine the nature and spatial distribution of
sonographic abnormalities in CIAP and in CIDP, MIDN and MMN.
2. On the basis of the findings in objective 1, we will define a standardized
HRUS research protocol. In this protocol only the most common affected nerves
will be included for follow-up to assess the highest discriminative value
between treatment responders and non-responders and in determining prognosis.
3. To determine whether this standardized HRUS protocol is of additional value
to clinical and electrodiagnostic parameters in discriminating treatment
responders from non-responders and determining prognosis, consisting of a
consecutive group of patients with CIAP and CIDP, MIDN and MMN. If HRUS is of
additional value, a prediction rule for determining treatment response and
prognosis will be defined.

Study design:
To study objective 1, nerve sonography will be performed in clearly defined,
Chronic idiopathic axonal neuropathy (CIAP), chronic inflammatory demyelinating
polyneuropathy (CIDP), multifocal inflammatory demyelinating neuropathy (MIDN)
and multifocal motor neuropathy (MMN). It will encompass extensive sonographic
measurement in multiple nerves in both arms and legs at fixed intervals.
Various sonographic parameters will be evaluated (e.g. nerve and fascicle size,
vascularisation). This study results in a description of the nature and
distribution of the sonographic abnormalities for each of the investigated
polyneuropathies prior to treatment and at follow-up.

To investigate objective 2, the demonstrated temporal distribution of the
sonographic abnormalities will be further categorized. By selecting the
parameters and nerves with the highest discriminating power between normal and
abnormal, the extensive HRUS protocol will be reduced to a standardized HRUS
protocol.

Two groups will evaluate objective 3. First, a group of consecutive patients
with newly diagnosed CIAP and CIDP, MIDN and MMN will undergo routine clinical
and electrodiagnostic evaluation, as well as the extensive HRUS protocol which
will be reduced to the standardized protocol depending on the findings of
objective 1 and 2. Patients will undergo sonography at fixed intervals. Second,
a consecutive group of patients who are already on treatment for CIDP, MIDN or
MMN will undergo the extensive HRUS protocol, which might be reduced to
standardized protocol as well, at fixed intervals. We will determine whether
this standardized HRUS protocol is of additional value to clinical and
electrodiagnostic parameters in discriminating treatment responders from
non-responders and determining prognosis. We will use the combined information
of clinical presentation (MRC-sum score, Modified INCAT Sensory Sum Score and
Vigorimetry), electrodiagnostic findings, clinical course and treatment
response to assess this question. The Inflammatory Neuropathy Cause and
Treatment (INCAT) Overall Disability Sum Score (ODSS) and Rasch-built Overall
Disability Scale (R-ODS) will be used as outcome variables (The R-ODS CIDP for
patients with CIDP and MIDN, the recently developed R-ODS MMN for patients with
MMN; for patients with CIAP the Modified Rankin Scale will be used, because no
R-ODS is available for this type of polyneuropathy). If HRUS is of additional
value, a prediction rule for determining treatment response and prognosis will
be defined.


Validation sub study:
15 participants of the HOPE study will undergo all study procedures and an
additional sonogram performed by a different investigator, to determine if the
measurements are comparable between investigators (inter-observer variability)
Five patients already participating in the HOPE study at het UMC Utrecht will
undergo a second sonogram at the Elisabeth Tweesteden Hospital Tilburg to
determine possible variation in sonographic measurements between different
sonographic devices.
Five healthy participants at the Elisabeth Tweesteden Hospital en 5 healthy
participants at the UMC Utrecht will undergo two sonograms performed by
different investigators. Furthermore five heatlhy participants will undergo a
sonogram at the UMC Utrecht and a second sonogram on a different device at the
Elisabeth Tweesteden Hospital Tilburg.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: Clinical examination, laboratory results and
electrodiagnostic studies are part of the standard clinical evaluation of
patients clinically suspected for polyneuropathy. The additional burdens that
are required for this study are two follow-up visits in which patients will
undergo nerve sonography (estimated duration 60 minutes), as well as a nerve
sonography during the primary assessment (three nerve sonographic examinations
in total). Nerve sonography has proven to be safe, reliable, effective,
non-invasive and is usually well tolerated.
In addition patients will undergo a physical examination during follow-up
visits and questionnaires will be sent to patients before follow-up visits,
which will be collected at the follow-up visit. These procedures are needed to
determine several endpoints (Vigorimetry, MRC Sum Score, Modified INCAT Sensory
Sum Score, INCAT ODSS, R-ODS and MRS).

Extra sonographic examination after 6 months for patients with newly diagnosed
CIDP, MIDN or MMN:
In the group of patients with newly diagnosed CIDP, MIDN or MMN, in addition to
the standard sonographic examinations at inclusion, 1 and 2 years follow-up, an
extra sonographic examination will be performed at 6 months follow-up. This
will be done to evaluate possible early changes in nerve morphology in this
specific group of patients with an early stage of a type of polyneuropathy for
which treatment is available. These early findings might be relevant for
determining the prognostic value of nerve sonography and early treatment
response. Those findings might be missed if the standard sonography at 1 year
follow-up is performed only.

Optional extra EMG after 2 years
In order to compare EMG and Sonographic data after follow-up participating
centres can perform an optional additional EMG at 2 year follow-up. In order to
limit burden for participating patients this will be a reduced protocol only
investigating the nerves of the most severely impaired arm.

Validation sub study:
Twenty patients already participating in the HOPE study will undergo a second
sonogram estimated duration 45 minutes. Furthermore 15 healthy participants
will undergo two sonograms estimated duration 90 minutes. In 5 of the HOPE
participants and 5 healthy participants sonographies will be performed at
different sites (ETZ and UMC Utrecht), therefore study participation for those
participants will consume more time. Those patients will receive refunds for
their travel expences in order to prevent financial costs for their
participation.