Influence of IVIG on nerve excitability in multifocal motor neuropathy (MMN)

MMN is a progressive disorder of peripheral nerves in adults which leads to
muscle weakness in arms and legs without sensory deficits. Nerve conduction
studies in MMN show localized sites in peripheral nerves where impulse
conduction is blocked in motor axons but normal in sensory axons. Half of MMN
patients exhibit high-titer serum antibodies against a peripheral nerve
ganglioside. MMN is treated by immunoglobulin courses which result in temporary
improvement in about 80% of the patients. Several immunological mechanisms of
action were hypothesized to be beneficial, including those which stimulate
remyelination and axonal regeneration. Still none of those is consistent with a
rapid clinical improvement seen after IVIG infusion. Thus it was proposed that
IVIG could normalize axonal membrane properties and nerve excitability, still
without preventing permanent muscle weakness and muscle atrophy due to loss of
affected motor axons. Prevention of this unfortunate course of events first
requires more knowledge of pathogenesis in MMN. This is largely unknown because
there is no animal model and because state-of-the-art nerve pathology studies
are lacking in MMN.

To assess the change in excitability parameters induced by IVIG infusion. This
will be achieved by comparing excitability-parameters between the time of
maximal weakness (just before the next IVIG infusion) and the time of maximal
clinical improvement.

We will investigate 45 MMN patients on the IVIG treatment, included from the
UMC Utrecht database together with newly diagnosed MMN patients. IVIG is not a
study procedure, but a standard treatment for MMN patients, so the schedule of
infusions will not be influenced by that research. Three groups, each
consisting of 15 MMN patients, will be investigated: one with motor nerve
conduction abnormalities without loss of motor axons, one with loss of motor
axons without conduction abnormalities, and one group without abnormalities. In
each group the forearm segment of the median nerve will be investigated. Pre-
and post- IVIG infusion excitability variables will be compared within MMN
patients, as well as with healthy controls excitability data. 15 healthy
controls will be selected from a larger cohort of healthy subjects with similar
age and sex distribution who already have been investigated, using completely
identical measurement procedures as those of the MMN patients.

Per patient, two sets of excitability-tests will be performed on the median
nerve at the wrist: one just before next IVIG infusion (as close as possible to
the next infusion when the patients are at the maximal of their muscle
weakness) and one on the peak of the clinical improvement, which is individual
and will differ between subjects. For newly diagnosed patients the first
excitability measurement will be done prior to their very first IVIG infusion,
on the same day; for the second visit they will be asked to contact the
coordinating investigator when they start to feel motor improvement after their
first IVIG infusion to agree on the appointment. After each set of recordings
clinical testing will be performed. The whole investigation during the first
visit takes 1 hour and 30 minutes and consists of the following procedures: 1.
Motor nerve conduction study of the median nerve in the forearm in order to
verify the EMG-abnormalities still occur; this entails delivering electrical
stimuli at the wrist and elbow. Duratiion 5-10 min. 2. Sensory conduction of
the median nerve of the third and fourth finger to exclude carpal tunnel
syndrome; this is important since carpal tunnel syndrome affects
excitability-variables. Duration: 10-15 minutes. 3. Warming the forearm and
hand to 37°C by wrapping them into a plastic blanket through which water at
37°C flows. Duration: 30 minutes. 4. Excitability-test of median nerve motor
axons at the wrist. Duration: 30 minutes. 5. Clinical assessment of the median
nerve by MRC grading of the abductor pollicis brevis muscle. Duration: 15 min.
The examination on the second visit includes points 3-5 and will last around 1
hour.

Slight physical discomfort due to electrical stimulation and brief local skin
reddening due to skin electrode adhesive gel may occur. There are no known
risks for the study procedure based on the literature and on our experience in
previous excitability and nerve conduction studies (excitability protocol
*Sensory axons in MMN* NL53422.041.15). Patients will benefit indirectly from
the study because more will be known about pathogenetic mechanisms in MMN
which, in turn, may lead to development of treatment strategies aimed at axonal
protection.