Several important neurologic disorders are related to the immune system. The immune system may play an important role in the pathogenesis and cause of myasthenia gravis and multiple sclerosis. In addition, amyotrophic lateral sclerosis (ALS) has become one of the prime subjects of modern neuro logic research.

Amyotrophic Lateral Sclerosis

 Along with Alzheimer’s disease and Parkinson’s disease, ALS is one of the so-called degenerative diseases of the aging nervous system. The immune system has been implicated in ALS. Monoclonal paraproteinemia seems to be disproportionately frequent in patients with ALS. It has also been suggested that ALS patients have a higher incidence of lymphoproliferative disease—lymphoma, Waldenström’s macroglobulinemia, and myeloma. There also seems to be an increased frequency of antibodies to a neuronal ganglioside, GM-1.

Inflammatory Polyneuropathies

 This group of idiopathic disorders, which includes the acute disorder Guillain-Barré syndrome (GBS), is characterized clinically by the subacute onset of generally symmetric weakness, ranging from modest lower extremity weakness to total, life-threatening involvement of motor and even cranial nerves. Sensory symptoms are less prominent. Unstable blood pressure and potentially fatal arrhythmias have also been observed. Progression of GBS can be rapid; however, most patients do recover.

The cause of GBS is unknown, but it is likely that an abnormal immune response against the peripheral nervous system (PNS) is involved. This may be triggered by an antecedent viral infection. There is infiltration of the PNS with lymphocytes and macrophages and patchy myelin destruction. Some patients display deposition of IgG, IgM, and IgA in PNS tis sues. Greatly elevated immunoglobulin levels in the cerebrospinal fluid (CSF), sometimes with oligoclonal bands, suggests locally altered immunoregulation. The antigenic targets of these immunoglobulins remain unknown.

Myasthenia Gravis

Myasthenia gravis is a disorder of the neuromuscular junction characterized by neurophysiologic and immunologic abnormalities (Box 1). A postsynaptic defect is caused by a decrease in receptors for acetylcholine and frequently an anatomic defect in the neuromuscular junction plate. Acetylcholine receptor (AChR)–binding antibody is directed against acetylcholine receptors at neuromuscular junctions of skeletal muscle and AChR-blocking antibodies. The ligand bungaro toxin or acetylcholine is important in producing a neuromuscular block. About one third of patients with myasthenia gravis demonstrate AChR-blocking antibodies.

Box1. Abnormalities Associated With Myasthenia Gravis

The role of these antibodies in producing disease is unclear. Complement-mediated, antibody-determined damage may be an important mechanism in myasthenia gravis because IgG, C3, and C9 can be demonstrated at the neuromuscular junction and the motor endplate is often abnormal. This suggests that antibody to AChR is capable of increasing the normal rate of degradation, resulting in fewer available receptors.

Multiple Sclerosis

 Multiple sclerosis (MS) is the most common demyelinating disorder of the CNS related to abnormalities of the immune system. It is characterized by regions of demyelinization of varying size and age scattered throughout the white matter of the CNS. Demyelinization plaques have a propensity to form in the cerebrum, optic nerves, brainstem, spinal cord, and cerebellum.

Etiology. After more than a century of study, the cause of MS remains unknown. Although research studies support genetic and environmental components of susceptibility, epidemiologic findings are most consistent with an environmental influence against a background of genetic susceptibility as the cause of MS. There is little evidence for a single or unique environmental cause. Viral infection (e.g., human herpesvirus type 6 [HHV-6]) is highly suspected but unconfirmed. In addition, Epstein–Barr virus (EBV), which causes infectious mononucleosis and is associated with other diseases, may increase the risk of MS.

Epidemiology. The incidence, prevalence, and mortality rates of MS vary with latitude. MS is rare in tropical and subtropical areas. The higher risk for MS in Europeans and in relatives of patients with MS and the existence of MS-resistant ethnic groups (e.g., Eskimos, Norwegian Lapps, Australian aborigines) support a genetic predisposition to MS. A low prevalence of MS occurs in Africa, India, China, Japan, and Southeast Asia. In the United States, the incidence is 1/1000 individuals.

MS is the major acquired neurologic disease in young adults. Most patients develop symptoms between the ages of 18 and 50 years. Women are more often affected than men (2:1 ratio). Approximately 1/1000 persons of northern Euro pean origin residing in temperate climates will develop proto typical MS in their lifetime. Up to 400,000 people in the United States have MS.

Pathophysiology. MS results from T cell–dependent inflammatory demyelination of the CNS. Inflammatory demyelination caused by T lymphocytes induces B lymphocytes to produce antimyelin antibodies.

The ongoing pathologic process involves the formation of CNS lesions, called plaques, characterized by inflammation and demyelination. Plaques result from a localized inflammatory immune response, initiated by the entry of activated blood T cells into the CNS. These T cells cross the blood-brain barrier by binding to endothelial cells in blood vessels via reciprocal adhesion molecules. The release of enzymes, called matrix metalloproteinases (MMPs), allows them to penetrate the basement membrane and extracellular matrix. At the same time, other blood immune system cells penetrate the CNS, causing additional local synthesis and release of damaging inflammatory mediators. The net result is the destruction of myelin sheaths, injury to axons and glial cells, and formation of permanent scar tissue.

Research studies have demonstrated that osteopontin, which is known to play a role in enhancing inflammation, may play a critical role in the immune attack in MS and its progression. Osteopontin has been found to be very active in areas of myelin damage during relapse and remission and in myelin synthesizing cells and nerve cells. More research is required to determine the exact role of this protein, as well as the therapeutic possibilities it presents.

Signs and Symptoms. MS begins as a relapsing illness with episodes of neurologic dysfunction lasting several weeks, followed by substantial or complete improvement (relapsing remitting MS). Initial signs of MS are difficulty walking, abnormal sensations (e.g., numbness, possible pain, ineffective vision). Primary symptoms caused by demyelination include fatigue, bladder and bowel dysfunction, loss of balance, loss of memory, slurred speech, difficulty swallowing, and seizures. Depression is a common symptom.

Relapsing MS is the most common form; 85% of patients are symptomatic at onset. The other forms of MS are as follows:

• Primary progressive

• Secondary progressive

• Progressive relapsing

Primary progressive MS advances insidiously from onset, with or without occasional plateaus and minor improvements. Secondary progressive MS develops in about 50% of relapsing MS patients about 10 years into the disease. Progressive relapsing is the rarest form of the disease. Patients begin with primary progression but subsequently experience one or more relapses.

Diagnostic Methods. Magnetic resonance imaging (MRI) is a key imaging modality for establishing a diagnosis of MS. No single laboratory test confirms a diagnosis, but appropriate laboratory test results must be evaluated carefully. Conditions that need to be excluded include collagen vascular disease, vita min B12 deficiency, and endocrine disorders (e.g., thyroid and adrenal gland disease). It is also important to rule out infectious diseases (e.g., Lyme disease, syphilis, human T lymphotropic virus type 1[HTLV-1] infection). CSF analysis may identify the following:

• Oligoclonal IgG band pattern by CSF electrophoresis

 • Quantification of CSF IgG and albumin concentrations

• Interpretation of CSF indices (e.g., albumin index, IgG index, IgG synthesis rate, local IgG synthesis)

Immunologic Manifestations. Box 2 presents immunologic manifestations of MS suggestive of its autoimmune nature. Antimyelin antibodies directed against components of the myelin sheath of nerves or myelin basic protein can be demonstrated in patients with MS or other neurologic dis eases. However, myelin antibodies are not detectable in the CSF of MS patients.

Box2. Immunologic Manifestations of Multiple Sclerosis

Detection of Oligoclonal Bands. Oligoclonal immunoglobulins may be seen in serum and CSF. An oligoclonal immunoglobulin pattern consists of multiple, homogeneous, narrow, and probably faint bands in the gamma zone on electrophoresis.

Electrophoresis on cellulose acetate will rarely resolve an oligoclonal pattern. Therefore, electrophoretic media with greater resolution, such as agar or agarose gel, are required, and both require the use of concentrated CSF. It is important to perform electrophoresis on a serum specimen concurrently with the CSF specimen to ensure that the demonstrated homogeneous bands are present only in the CSF, which implies endogenous synthesis rather than a serum band that might appear secondarily in the CSF. Infrequently, if a prominent CSF band is present, it may appear in the serum as a homogeneous band. This is most often encountered in subacute sclerosing panencephalitis.

High-resolution electrophoresis attempts to achieve better resolution of proteins beyond the classic five-band pattern. The primary reason for performing high-resolution protein electrophoresis is to detect oligoclonal bands in CSF to increase the diagnostic usefulness of protein patterns. About 80% of CSF proteins originate from the plasma. The electrophoretic pattern of normal CSF is similar to a normal serum protein pattern; however, several differences are detectable, including a prominent prealbumin band and two transferrin bands.

Immunofixation has been used in some research studies to show that the oligoclonal bands seen in CSF protein patterns are made up primarily of IgG. Although this may be of aca demic interest, characterization of the immunoglobulin bands does not significantly improve the diagnostic usefulness of the procedure. Isoelectric focusing, however, is becoming the method of choice for oligoclonal band detection.

Significance of Oligoclonal Bands. If oligoclonal bands are present in CSF but not in the serum, they are the result of increased production of IgG by the CNS. CNS production of IgG occurs in the subarachnoid space of the brain in conjunction with local accumulation of immunocytes. Each has its own specificity that gives rise to oligoclonal bands. Although the immunoglobulin is IgG, it is polyclonal in nature, with several groups of cells producing it. Oligoclonal bands are therefore defined as discrete populations of IgG, with restricted heterogeneity demonstrated by electrophoresis.

One procedure for confirming local CNS production of oligoclonal IgG is to test a matched serum specimen diluted 1:100 concurrently with a nonconcentrated CSF sample. Oligoclonal bands present in CSF, but not in the serum, indicate CNS production. This matched sample procedure is especially useful if damage to the blood-brain barrier is suspected because of acute or chronic inflammation, such as meningitis, intracranial tumor, or cerebrovascular disease.

Serum oligoclonal bands may represent immune complexes and are associated with diseases such as Hodgkin’s disease or a nonspecific early immune response to other diseases (Box 3). Clinical Findings. Total CSF protein in patients with MS is usually normal or slightly elevated. In general, patients with no neurologic disease have an IgG concentration of less than 10% of total CSF proteins. Almost 70% of MS patients typically have IgG concentrations of 11% to 35% of total CSF proteins.

Box3. Conditions Associated With Oligoclonal Cerebrospinal Fluid Gamma Globulins

Oligoclonal bands in serum are not absolutely indicative of MS; their presence should be used in conjunction with the clinical evaluation and other diagnostic procedures. Although oligoclonal bands can occur in more than 90% of MS patients at some time during the course of their disease, the presence of bands does not correlate with the activity of the disease. The exact number of bands present in MS varies; some studies have demonstrated 7 to 15 bands.

Treatment. Corticosteroid therapy (e.g., methylprednisolone, prednisone) is a common symptomatic treatment for disease relapses. The relapsing form of MS can be treated with immunomodulators such as interferon beta-1b (Betaseron), interferon beta-1a (Avonex), and glatiramer acetate (Copaxone). All these drugs have been approved by the U.S. Food and Drug Administration (FDA). The newest medication for MS is fingolimod (Gilenya), which was approved by the FDA in September 2010. This is the first oral drug available for the long-term treatment of MS. Possible future therapeutic strategies may include combination treatments using existing therapies, standard immunosuppressive drugs, and new immunomodulating agents. Autologous bone marrow transplantation, plasma exchange, TCR peptide vaccine, and gene therapy are other possibilities.

The Myelin Project Cell Culture Units at the University of Wisconsin-Madison and at Sweden’s University of Lund have been developing an immortal line of human cells, oligodendrocyte precursors, to repair myelin lesions in MS and the leukodystrophies. Studies have demonstrated that myelin produced as a result of transplantation is capable of restoring nerve con duction. The feasibility of transplanting glial cells derived from human tissue into the CNS is being explored.

French researchers have demonstrated that progesterone promotes remyelination by activating genes that control the synthesis of important myelin proteins.

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