What is Guillain-Barré syndrome?
Guillain-Barré syndrome (GBS) is an acute disease of the peripheral nerves, especially those that connect to muscles. It causes weakness, areflexia (loss of reflex), ataxia (difficulty in maintaining balance), and sometimes ophthalmoplegia (eye muscle paralysis). GBS demonstrates a variable, multifocal pattern of inflammation and demyelination of the spinal roots and the cranial nerves, although the brain itself is not obviously affected. By the 1990s and early 2000s, it was the most common cause of generalized paralysis in the United States, averaging one to two cases per 100,000 people per year. The disease was first described in the early twentieth century by Georges Guillain and Jean-Alexander Barré, two French neurologists. Little was known of the cause of GBS or the mechanism for its symptoms, however, until the 1970s. Since then, symposia sponsored by the National Institute of Neurological and Communicative Disorders and Stroke have shed more light on this condition.
Most individuals with GBS have a rapidly progressing muscular weakness in more than one limb and also experience paresthesia (tingling) and numbness in the hands and feet. These sensations have the effect of reducing fine muscle control, balance, and one’s awareness of limb location. The prevailing scientific opinion regarding GBS is that it is an autoimmune disorder involving white blood cells, which for some unknown reason attack nerves and/or produce antibodies against myelin, the insulating covering of nerves. The weakness is usually ascending in nature, beginning with numbness in the toes and fingers and progressing to total limb weakness. The demyelination is more prominent in the nerves of the trunk and occurs to a lesser extent in the more distal nerves. The brain and spinal cord are protected from GBS by the blood-brain barrier, although antibodies to myelin have been found in the cerebrospinal fluid of some patients.
With GBS, there is often a precipitating event such as surgery, pregnancy, upper respiratory infection, viral infection (such as cytomegalovirus), or vaccination. Preexisting debilitating illnesses such as systemic lupus erythematosus (SLE) or Hodgkin’s disease also seem to predispose a person to GBS. GBS has been diagnosed in patients having heart transplants in spite of the fact that they are receiving immunosuppressive drugs. The increased risk with such surgery may be attributable to the stress associated with the procedure. Most patients who come down with GBS have had some prior condition that placed stress on the immune system prior to the appearance of GBS.
The patient with GBS is frequently incapable of communicating as a result of paralysis of the vocal cords. Typically, motor paralysis will worsen rapidly and then plateau after four weeks, with the patient bedridden and often in need of respiratory support. Autonomic nerves can also be affected, causing gastrointestinal disturbances, adynamic ileus (loss of function in the ileum of the small intestine), and indigestion. Other, less common symptoms include pupillary disturbances, pooling of blood in limbs, heart rhythm disturbances, and a decrease in the heart muscle’s strength. These patients are usually hypermetabolic because considerable caloric energy goes into an immune response that is self-destructive and into mechanisms that are attempting to repair the damage.
In addition to the loss of myelin, cell body damage to nerves may result and may be associated with permanent deficits. If the nerve cell itself is not severely damaged, regrowth and remyelination can occur. Antibodies to myelin proteins and to acidic glycolipids are seen in a majority of patients. Blood serum taken from patients with GBS has been shown to block calcium channels in muscle, and experiments in Germany have found that cerebrospinal fluid from GBS patients blocks sodium channels.
Like most autoimmune conditions, GBS is cyclic in nature; the patient will have good days and bad days because the immune system is sensitive to the levels of steroid hormones in the body, which are known to fluctuate. In addition to paralysis, there is significant pain with GBS. Many of the nerve fibers that register the pain response (nociceptors) are nonmyelinated and therefore are not interrupted in GBS. Pain management can be difficult, requiring the use of such drugs as fentanyl, codeine, morphine, and other narcotics. The course of the disease is variable and is a function of the level of reactivity of the patient’s immune system. The autoimmune attack is augmented in those patients experiencing activation of serum complement protein induced by antibodies. Recovery usually takes months, and frequently the patient requires home health care. Complications can lead to death, but most patients recover fully, though some have residual weakness.
The physician must be careful to distinguish GBS from lead poisoning, chemical or toxin exposure, polio, botulism, and hysterical paralysis. Diagnosis can be confirmed using cerebrospinal fluid (CSF) analysis. GBS patients have protein levels greater than 0.55 gram per deciliter of CSF. Macrophages are frequently found in the CSF, as well as some B cells. Nerve conduction velocity will be decreased in these patients to a value that is 50 percent of normal in those nerves that are still functioning. These changes can take several weeks to develop.
With GBS, macrophages and T cells have been shown to be in contact with nerves, as evidenced in electron micrographs. T-cell and macrophage activation in these individuals point to an immune response gone awry, possibly precipitated by a virus or exposure to an antigen that is foreign but similar in appearance to one of the proteins in myelin. T cells, upon encountering an unrecognizable antigen, will produce interleukin II, initiate attack, and recruit macrophages to participate. The use of an anti-T-cell drug theoretically should improve nerve function, but researchers at the University of Western Ontario failed to find any benefit from the infusion of an anti-T-cell monoclonal antibody. Unexpectedly, GBS has been found in patients testing positive for the human immunodeficiency virus (HIV) who are asymptomatic, in spite of the fact that their T cells are under attack from the HIV virus and are diminished in number. Although myelin proteins are thought to be the immunogens, other candidates include gangliosides in the myelin. Antiganglioside antibodies have been seen in a majority of GBS patients. This trait may distinguish GBS from amyotrophic lateral sclerosis (Lou Gehrig’s disease) and multiple sclerosis, which seem to involve different myelin proteins as antigens.
In GBS, the white blood cells attack peripheral motor nerves more often than other types of nerves, implying a biochemical difference between motor and sensory nerves that has yet to be discovered. One possible cause of this disease is a similarity between a protein or glycolipid that is present normally in myelin and coincidentally on an infectious agent, such as a virus. The immune system responds to the agent, resulting in a sensitization of the macrophages and T cells to that component of myelin. B cells are then stimulated to produce antibodies against this antigen, and they unfortunately cross-react with components of the myelin protein. The severity of the disease will depend on the number of macrophages and lymphocytes activated and whether serum complement-binding antibodies are being produced. Serum complement proteins are activated by a particular class of antibodies, resulting in the activation of enzymes in the blood that potentiate tissue destruction and neurogenic atrophy. Serum complement levels can be determined by a serum complement fixation test.
In severe cases of GBS, intercostal muscles are more severely compromised and respiratory function needs to be monitored closely. The immune response will subside when T-suppressor cells have reached their peak levels. Halting the autoimmune response will not reverse the symptoms immediately, since it takes time for antibody levels to decrease and for the nerves to regrow and remyelinate, which occurs at the rate of 1 to 2 millimeters per day. Some nerves will undergo retrograde degeneration and be lost from the neuronal pool. Other nerves will have more closely spaced nodes and conduct impulses at a lower velocity. Nerve sprouting will also occur, which will result in one nerve’s being responsible for more muscle fibers or serving a larger sensory area and in decreased fine motor control.
In Guillain-Barré syndrome, the amount of muscle and nerve involvement can be assessed by performing an electromyogram, which can reveal the amount of motor nerve interruption and the conduction velocity of the nerves that continue to function. Based upon the assumption that an autoimmune response was in progress, corticosteroids such as prednisolone and methylprednisolone were once administered in high doses, but such drugs have been shown to have a deleterious effect on the disease and are no longer used.
More recently, a procedure known as plasmapheresis has been tried with better results, especially when performed in the first two weeks. This procedure involves removing 250 milliliters (a little more than a pint) of plasma from the blood every other day and replacing this volume with a solution containing albumin, glucose, and appropriate salts. Six treatments are typical and usually result in a faster recovery of muscle control than for those not receiving plasmapheresis. Because relapses may occur if the patient produces new antibodies to myelin, immunosuppressants are given to the patient after plasmapheresis. Another procedure, intravenous immunoglobulin therapy, is based on the strategy of blocking the binding of antibodies to nerves, which lessens the severity of the immune attack.
Cyclosporine, a T-cell inhibitor, is also being tried, with some promising results. Some researchers note, however, that transplant patients, who routinely take cyclosporine, have a higher-than-normal risk of developing GBS. Others emphasize that no one knows what their risk for GBS would be without the administration of cyclosporine. Because of the variability of the body’s immune response, the benefits of this drug will depend on whether, in a given individual, it is an antibody response or T-cell response. Cyclosporine will benefit those who have a strong T-cell response. T-cell reactivity can be tested with the mixed lymphocyte assay, and T-cell counts can be done.
Cerebrospinal fluid filtration is also being tried in order to remove antibodies. Serum so filtered loses its nerve-inhibiting effect, as evidenced by its application to in vitro nerve and muscle cells. GBS has been mimicked in animal models, which show antibody and T-cell reactivity to myelin protein. Guillain-Barré syndrome has many of the characteristics of an autoimmune disease and could serve as a model for an acquired autoimmune condition.
Not related to the neurology of this sudden-onset disease, but equally devastating, is the protracted psychological impact of simultaneously being able to think and have emotions while not being able to move limbs, fingers, toes, and facial and eye muscles. Even though most patients recover, progress is always torturously slow, as the myelin sheath gradually regenerates. Ongoing psychological support is an important element in treating these patients.
Guillain-Barré syndrome is an example of a delicate physiological balance gone awry. The immune system has the difficult task of distinguishing between self and enemy, and if it detects the latter it must either inactivate or eliminate the intruder. Mistakes in recognition or communication between immune cells can cause either an unintended attack or the failure to attack when appropriate. GBS probably represents an unnecessary self-attack on tissue, in this case myelin, and may be considered a form of hyperimmunity. Many diseases fall into this category. They include rheumatoid arthritis, juvenile diabetes, Crohn’s disease, ulcerative colitis, Graves’ disease, multiple sclerosis, amyotrophic lateral sclerosis, ankylosing spondylitis (inflammation of the joints between the vertebrae), and systemic lupus erythematosus. The other type of response, hypoimmune, is seen in cancer and immunodeficiency diseases such as Acquired immunodeficiency syndrome (AIDS).
Questions that arise with GBS are the same ones that arise in many other diseases. It must be determined why the immune system chose this time to initiate an attack against a self-antigen. The answer could be a mistake in recognition, an error in translating the deoxyribonucleic acid (DNA) code in the bone marrow cells, an alteration of the antigen by some environmental factor, or an alteration of an antigen-detector protein on a white blood cell. Researchers also try to discover if there is a genetic predisposition for GBS. Seeking answers about GBS may shed light on other conditions as well, and treatments beneficial to GBS patients have a high probability of benefiting patients with other immune disorders. GBS is a reminder that physiological stress can translate to immunological stress, and under stress the immune system can make mistakes.
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