Challenges and Progress
Multifocal Motor Neuropathy (MMN) is a rare condition that causes weakness without significant loss of sensation. The disorder affects less than 1 person per 100,000 people. Men are almost twice as likely as women to develop the illness and most people contract the disease between the ages of 35 and 70. With very rare exceptions, MMN does not shorten life, or cause major problems with breathing or swallowing. However, it can cause a great deal of dysfunction and disability and the disorder appears to persist indefinitely and rarely goes into a long-term remission.
The initial symptoms are typically in one hand or arm in the distribution of one or two nerves. Other nerves become involved in either arm or in the legs and muscles become atrophied and may have muscle twitching, called fasciculations. Fasciculations are a prominent finding in amyotrophic lateral sclerosis (ALS), an untreatable progressive disorder that dramatically shortens life. It is crucial for doctors to determine if someone with fasciculations and weakness has MMN instead of ALS since MMN is potentially treatable and has a much better prognosis. In contrast to ALS, MMN does not affect the brain or the central nervous system tracts (upper motor neuron tracts) that send the signals to the motor neurons. MMN is a disorder only of the lower motor nerve fibers, the axons that originate in the motor neurons- but the cell bodies themselves (motor neurons) are not affected by the disease.
The diagnosis of MMN is based on the pure motor symptoms and signs, and the lack of upper motor neuron signs. The hallmark of the disorder is the finding of “conduction block” on the nerve conduction studies. Conduction block (CB) is the phenomenon of the failure of the electrophysiologic impulse to travel all the way down the nerve because the transmission is impeded by changes that do not destroy the nerve fiber (axon). In practice, this is demonstrated on nerve conduction testing by finding a strong response when stimulating the nerve close to the muscle but a weak response when the stimulus is given to a portion of the nerve that is above (proximal to) the nerve lesion causing the block of transmission.
There are a number of studies that support the idea that MMN is due to abnormalities of the patient’s immune system. Specific proteins, called antibodies have been found in a significant number of MMN patients. These antibodies attack a constituent of the nerve fiber, called GM 1. Detecting very high amounts of this antibody in the blood of someone suspected of having MMN strongly supports this diagnosis.
It is now well established that treating patients with intravenous immunoglobulin (IVIg) benefits patients with MMN. It can reverse the conduction block, reduce the chances of developing new nerve lesions and most likely slows progression of deficits. However, it does not cure the disease, requires repeated treatments and may lose its efficacy over time. No other treatment has been convincingly shown to be effective although there are case reports and small series of patients that suggest some benefit with a number of immunosuppressive agents.
Despite responses to IVIg, many patients will get progressive destruction of the axons causing permanent weakness. The search for treatments that can prevent this axonal loss is ongoing and is a major goal of investigators.
There is much to learn and understand about this disease and there is clearly a need to improve our therapies. The following are a few of the questions that need to be answered and some of the progress that has been made in the past few years.
Topics
Progress: Although challenges remain, it is clear that there are aspects of the anatomy and electrophysiologic properties of the nerve fibers that are different between motor and sensory nerves. This makes the motor fibers more vulnerable to the immunologic attack as well as to development of CB.
Progress: It is still not entirely clear whether the GM1 antibodies are the specific cause of MMN. However, it is known that GM1 is prominent at the nodes of Ranvier and is different in structure in sensory nerve fibers compared to the motor nerves which would potentially make the motor fibers more vulnerable to antibody attacks and that similar antibodies cause AMAN, a purely motor disorder. However, reproducing MMN in animals has not been accomplished by either giving them GM1 antibodies or stimulating the animal to make the antibodies.
The fact that only 35-50% of patients with MMN had the antibodies (in most reports) was particularly troubling. This issue may have been resolved with a recent study from Dr. Hugh Willison’s laboratory (MAB member) that the antibodies are detected in over 85% of patients with MMN if the test combines MMN with other similar glycoproteins (gangliosides). This detection of antibodies to complexes of gangliosides, if confirmed, will not only give us a better understanding of the disease but also provide an important diagnostic test that will more definitively determine if someone has MMN.
Progress: There remains a great deal of work that is needed to answer these questions but progress is being made. Recognizing that the primary site of attack in MMN is at the Node of Ranvier now points to the axon as being primarily involved. Attack on the nodes does not only cause CB, but also affects the energy transport down the nerve fiber which over time can cause degeneration of the must vulnerable aspects of the nerve, the distal twigs that are farthest from the cell body. This concept is being considered in other disorders that affect the nodes but needs further study in MMN. Some of the axonal elements at the nodes of ranvier may be amenable to therapy.
Challenges: The fact that there are no treatments other than IVIg that have been proven to be effective has been very disappointing. There are a number of challenges to identifying new treatments.
- MMN is a hard disorder to study treatments. It is very rare and requires many centers to recruit patients. This is very expensive and it is difficult to obtain funding to support such an effort.
- Developing outcome measures that can accurately and sensitively determine if a treatment is effective is an important requirement for good clinical trials. The GBS-CIDP FI supported Peripheral Neuropathy Outcome Measure Study (PERINOMS) has developed and validated a number of outcome measures that can be used in clinical trials in MMN and other immune neuropathies.
- We know that MMN is both under-diagnosed and mis-diagnosed. The potential for the antibody testing against GM1 complexes providing specific and sensitive diagnostic information will help improve our diagnostic accuracy which will improve our ability to determine if a treatment is effective.
- We need a better understanding of the natural history of the disease, the different symptoms and signs that encompass MMN. Having a more specific way of determining who has MMN will be a big step in this regard. Some larger series have provided important information but an international registry and database is needed.
The ARDA study is designed to assess the safety and effectiveness of the investigational study drug compared to a placebo for the treatment of adults living with MMN. Participants enrolled in the study will be randomly assigned by a computer to either receive the investigational drug or a placebo. Participants will have 2 out of 3 chances to receive the study drug.
The study will consist of a screening period to ensure eligibility, followed by IVIG study treatment period to confirm that the disease responds to study treatment. There is then a 4 month treatment period, followed by an optional long-term extension and a 9-month safety follow-up period. All participants will be monitored and supported by the study team.
To learn more, visit https://clinicaltrials.gov/ct2/show/NCT05225675 or email clinicaltrials@argenx.com
Conclusions
We have learned a great deal about MMN and the recent progress is very encouraging but the search for new and better treatment is ongoing. A concerted effort by investigators, partnering with patient organizations such as the GBS-CIDP FI is crucial to make further progress.
