Multifocal motor neuropathy: a natural history study on prognosis, disease mechanism and new biomarkers.

Multifocal motor neuropathy (MMN) is a rare immune-mediated disorder
characterized by slowly progressive, asymmetrical weakness of limbs without
sensory deficits or upper motor neuron signs. More men than women are affected,
at a ratio of approximately 3:1. The mean age at onset is 40 years, with a
range of 20-70 years. MMN should be distinguished from other lower motor neuron
diseases, in particular variants of amyotrophic lateral sclerosis (ALS),
because prognosis is better and it is responsive to treatment with intravenous
immunoglobulins (IVIg). The diagnosis of MMN may be elusive. The hallmark of
MMN is the phenomenon of conduction block (CB) in nerves, which can be found by
means of nerve conduction studies (NCS). Facilities and skills to perform
extensive NCS using MMN specific protocols are not widely available. Tools that
facilitate diagnosis are therefore urgently needed. Treatment with high-dose
(IVIg) is the only established therapy for MMN. There are no alternatives.
Prednisone and plasmapheresis may even increase weakness and mycophenolate
mofetil was shown not effective. IVIg improves muscle strength within two weeks
in the large majority of patients, but treatment effects last only several
weeks and maintenance treatment is therefore required. Moreover, disease course
is slowly progressive resulting in permanent axonal loss despite IVIg treatment
in many patients. At least 20% of patients develop significant disability of
the arms in the course of the disease.
Long-term follow up studies with a relatively large number of MMN patients to
document the rate of progression have not been performed. Such studies are
needed to identify risk factors that are associated with an increased risk of
poor outcome. The optimal IVIg dose and treatment frequency for patients with
MMN has not been established. Finally, we need more insight in the immune
pathogenesis of MMN in order to develop new treatment strategies.

1.To document natural history in this patient group and to establish which
factors put patients at risk for an unfavourable outcome.
2.To determine which factors contribute to (reduced) quality of life (QoL) in
patients with MMN.
3.To investigate the potential of modern high resolution ultrasound (HRUS) and
MRI techniques of the brachial plexus and peripheral nerves to
facilitate the diagnosis of MMN and test its values as a biomarker for
disease progression.
4.To study the pharmacokinetics of IVIg treatment and its relation to treatment
efficacy and natural history.
5.To test validation of- and contribution of potassium channels by-
excitability tests on EMG in MMN patients.
6.To further investigate the immune pathogenesis of this disorder.
7.To further test the hypothesis that MMN is caused by a chronic infection.

All the patients with MMN are asked to consent and to fill in quastionnaires.
All the research (interventions) will take place in one extra outpatient clinic
vist.
Patients will be asked to draw blood and a throat swab.

After that, there are 4 substudy parts:
1. MRI/US and/or EMG
2. Excitability
3. Long term follow up US
4. IVIg concentration and US followed over time.

Patients will visit the outpatient clinic of the department of
Neurology/Neuromuscular diseases once. The burden consists of undergoing an
interview, physical examination, throat swab and venapuncture. A subgroup of
patients will be asked to participate in an MRI, EMG or HRUS study. These
studies will take an additional 30 minutes each for MRI, excitability testing
and HRUS, and 45 minutes for EMG. The cumulative burden for patients is
limited. For venapuncture, transient local pain and blue spots from the
injection is mentioned. Throat swabs can sometimes give an unpleasant feeling
during the procedure but takes only a short time.
For excitability testing and HRUS, no specific burdens are mentioned and for
MRI, scalds are seen sometimes when patients have tattoos containing
ferromagnetic components. Prior to MRI all patients are checked for iron
containing materials since this can be of harm when magnetized and launched by
the MRI.
Patients will feel nerve stimulation during NCS but this is generally well
tolerated. NCS are harmless and do not lead to complications.