Simply Stated . . . Inflammation

Usually, inflammation of tissue occurs with an injury or an infection, but it's also an important part of certain neuromuscular diseases.

Ask anyone for a snap definition of inflammation, even a doctor, and he or she will probably say it's redness, swelling, sensations of heat and pain, or all of the above. It's true that those are the hallmark symptoms of inflammation, but they describe a mosquito bite or a sore throat better than they describe an inflammatory neuromuscular disease. To understand the role of inflammation in neuromuscular disease, it's important to look beyond symptoms, and consider the underlying process.

Inflammation in Health . . .

Inflammation is really the immune system's first line of defense in tissue that's been damaged by injury or infection. Essentially, it's an increase in blood flow and a mass invasion of blood-borne immune cells into the damaged tissue.

In inflammatory neuromuscular diseases, macrophages home in on signals from abnormal or dying muscle fibers, and release chemicals that recruit lymphocytes. Both cell types might inadvertently attack the muscle in the same way they would attack an infection.

At the beginning of the inflammatory process, chemicals released by the body's own dying cells or by foreign microbes attract immune cells to the injured or infected area. Among the first cells to respond are macrophages, which eliminate the dying cells and microbes by engulfing them and/or breaking them apart with destructive chemicals. (Derived from Greek, macro means big and phage means eater.)

The macrophages also release proteins called cytokines, and fatlike chemicals called leukotrienes and prostaglandins.

Cytokines and certain leukotrienes are strong attractants for other immune cells, including the lymphocytes, which mount a focused attack against infectious microbes. As the inflammatory response intensifies, lymphocytes continue to invade the area and proliferate.

Other leukotrienes and prostaglandins cause widening of nearby blood vessels (vasodilation) and increased permeability of capillaries. Histamine, the target of antihistamine cold and allergy remedies, is produced from yet other immune cells and has similar effects. The resulting increase in blood flow allows a steady influx of immune cells into the damaged area.

The increased blood flow is also largely responsible for the telltale symptoms of inflammation. The rush of warm blood causes redness, heat and swelling. At the same time, pressure from the swelling and the accumulation of immune cells, along with the destructive chemicals released by the cells, irritate local nerve endings and cause pain.

. . . And In Disease

In many disease states, the inflammatory process spins out of control and becomes harmful. In some neuromuscular diseases (like certain muscular dystrophies), inflammation is probably a secondary response to muscle degeneration, while in others (like the inflammatory myopathies), it might be a primary cause of degeneration. In either case, the inflammation can contribute to disease progression.

In Duchenne muscular dystrophy, degenerating muscle fibers are often surrounded by inflammatory cells (mostly macrophages). Although the macrophages are probably there to clear away dead tissue, they might hasten muscle decay in the process.

Severe cases of myotonic dystrophy and facioscapulohumeral MD sometimes show similar patterns of inflammation. In the inflammatory myopathies — polymyositis (PM), dermatomyositis (DM) and sporadic inclusion-body myositis (IBM) — macrophages and lymphocytes intensely invade muscle tissue.

In DM, macrophages and lymphocytes appear to attack the capillaries in muscle tissue, ultimately causing muscle fibers to degenerate by cutting off their blood supply. In PM and IBM, the immune cells actually swarm around the muscle fibers themselves, even fibers that otherwise appear healthy. The invading cells appear to directly damage muscle in PM, but it's not clear how they contribute to muscle degeneration in IBM.

Finally, there's some evidence of inflammation in amyotrophic lateral sclerosis, a disease caused by the death of muscle-controlling nerve cells. In some cases of ALS, the brain and spinal cord contain enhanced numbers of macrophagelike cells called microglia and elevated levels of cytokines and prostaglandin. The significance of these observations hasn't been established.

Surprisingly, inflammation isn't typical of myasthenia gravis or Lambert-Eaton syndrome, autoimmune diseases in which the immune system attacks the body's own tissues.

Treatments

Several immunosuppressants (drugs that suppress immune system activity) have been used in attempts to reduce the inflammation associated with DMD, the inflammatory myopathies and ALS.

Steroid-based drugs like prednisone have broad anti-immune and anti-inflammatory effects, including blocking the proliferation of lymphocytes and the production of cytokines, prostaglandins and histamine. Other immunosuppressants have more focused inhibitory effects on lymphocyte proliferation (methotrexate and azathioprine) or macrophage activity (IVIG).

For DM and PM, the most effective treatment is often a combination of prednisone and other immunosuppressants. Prednisone can help slow the course of DMD, but other immunosuppressants that have been tested aren't effective. (Actually, it's unclear whether prednisone works via its anti-inflammatory effects or by some other means.) Immunosuppressant therapies for IBM and ALS have generally been unsuccessful, but are still under investigation.