Session Four: Bing Special Lecture
Novel Therapeutic Approaches to the Therapy of IgM mediated neuropathies
Todd D. Levine, MD, Phoenix Neurological Associates, Phoenix, AZ

Motor and sensory nerve fibers branch out from the spinal cord to every part of the body, either controlling muscle movement or returning sensations to the brain. Neuropathy shows up as numbness and tingling, if sensory nerves are affected, or weakness if commands from the brain can no longer properly signal the muscles - though not all such symptoms result from actual nerve damage.

The nerve fibers are like little wires carrying electrical current. Each "wire" is insulated by a sheath of myelin. As the nerves approach the spinal cord they are bundled together, much in the fashion that individual telephone wires are bundled in thicker and thicker cables as they go from the individual house to the central office. The spinal cord is the last and biggest "cable" bringing the individual myelin-insulated nerve fibers to the brain.

As in any other electrical circuit, nerve impulses are prevented from reaching their destination if either of two things happens. If the nerve fiber or axon itself is damaged or destroyed, there is no conductor, just as if a wire were broken. If the myelin sheath is damaged or destroyed, it is as if the insulation were damaged in an electrical circuit; the signal short-circuits and does not get through to its destination.

If a patient shows neuropathy, which incidentally usually starts in the hands or feet, whence the term "peripheral," the neurologist can conduct a number of tests to determine its cause. First comes the clinical examination of the patient, to see by visual inspection if there is any obvious physical reason for damage to the nerves. Serology may be studied - we look at the patient's blood to see if it might be a causative factor, and in Waldenstrom's that factor is most probably the heavy IgM protein. We can do electrodynamic testing, checking the speed and strength of the nerve impulses. And finally, though it is not often done, we can do a nerve biopsy, extracting a piece of the nerve for further study.

The causes of peripheral neuropathy in WM patients may be partly physical, partly chemical. What are called immune-mediated neuropathies occur when the IgM chemically attacks the myelin sheath protecting the nerve, shorting it out. The result can be seen in numbness, tremors, gait changes, progressive weakness or other problems. Most such symptoms in a physician's practice are related to IgA or IgG, and are thus myeloma connected; about thirty percent (30%) are caused by IgM. Simply put, the anti-MAG protein is stripping away the myelin from the nerve fiber. As long as that fiber or axon is still alive, the process can be reversed. Even if the axon is dead, the body can usually re-grow it, but that takes a very long time.

The cause, however, may not be chemical attack by IgM molecules. Sometimes it is simply starvation of the neurons as the heavy IgM protein clogs the capillaries and prevents nourishment and oxygen from getting through. In other cases, the immune system mistakes the nerve for an intruder.

IgM mediated neuropathies are usually quite treatable:
- Gamma globulin can be used to decrease the effects of attack on the nerve by the immune system.
- Plasmapheresis, the physical removal of IgM from the blood, reduces the quantity of IgM and therefore its concentration.
- Chemotherapy, using Cytoxan or any of a number of other agents, attacks the cancerous cells that are producing the excess of IgM, thereby reducing its quantity over a longer period.
- More recently there is immunotherapy, using compounds like rituximab, which attacks the CD20 antigen, giving a response in three to six months. Rituxan is well tolerated, and seems to work in most cases. We are not always sure why - the numbers don't always make sense to us - but it works.

Since damaged nerves send the wrong signals, pain is often a factor. Neurontin or similar drugs reduce that pain by reducing the signal levels sent to the brain from the affected nerves. Serotonin reduces the brain's reaction to those signals. Either way, we can usually make life less difficult for the patient.

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