Articles on Medical Diseases and Conditions

Tag: Summary

  • Multiple Sclerosis (MS)

    Multiple sclerosis is a chronic demyelinating disease that has a reputation for recurrent illness of unpredictable length and severity. A multifocal demyelinating process in cerebral hemisphere white matter results in various combinations of weakness, ataxia, vision difficulties, and parasthesias, frequently ending in paralysis. Thus, the clinical symptoms, especially early in the disease, can be mimicked by a considerable number of other conditions.

    Cerebrospinal fluid laboratory findings. Routine CSF test findings are nonspecific, and when abnormality is present, the standard CNS test results are similar to those of aseptic meningitis. The CSF total protein is increased in about 25% of cases (literature range, 13%-63%). The cell count is increased in about 30% of cases (literature range, 25%-45%), with the increase usually being mononuclear in type and relatively small in degree.

    The CSF gamma-globulin (IgG) level is increased in 60%-80% of cases (literature range, 20%-88%). Technical methods such as radial immunodiffusion produce more accurate results than electrophoresis. Problems have been recognized in interpretation of CSF gamma-globulin values because elevated serum gamma-globulin levels can diffuse into the CSF and affect values there. Many investigators analyze a specimen of serum as well as of CSF to see if the serum gamma-globulin level is increased. Several ratios have been devised to correct for or point toward peripheral blood protein contamination. The most widely used is the CSF IgG/albumin ratio. Albumin is synthesized in the liver but not in the CNS and therefore can be used to some degree as a marker for serum protein diffusion into the CSF or introduction into the CSF through traumatic lumbar puncture or intracerebral hemorrhage. The IgG/albumin ratio is based on the theory that if serum leaks or is deposited into spinal fluid, albumin and IgG will be present in roughly the same proportion that they have in serum; whereas a disproportionate elevation of IgG relative to albumin suggests actual production of the IgG within the CNS. The normal CSF IgG/albumin ratio is less than 25% (literature range, 22%-28%). About 70% of MS patients have elevated IgG/albumin ratios (literature range, 59%-90%). The IgG/albumin ratio is a little more specific for MS than increase of IgG by itself. However, many conditions produce increased IgG within the CNS, such as chronic CNS infections, brain tissue destruction, CNS vasculitis, systemic lupus erythematosus and primary Sjцgren’s syndrome involving the CNS, and various demyelinating diseases.

    Another way to estimate CNS production of IgG is the IgG index, which is (CSF IgG level/CSF albumin level) ч (serum IgG level/serum albumin level). This index is reported to be abnormal in about 85% (range, 60%-94%) of definite MS patients. A third method for estimating CNS IgG production is the IgG synthesis rate formula of Tourtellote. Sensitivity of this method is about 85% (range, 70%-96%). Consensus seems to be that the IgG index is slightly more sensitive and reproducible than the IgG synthesis rate. Both can be influenced by altered blood-brain barrier permeability or presence of blood in the CSF as well as the various conditions other than MS that induce CNS production of IgG antibody.

    Another useful test is based on the observation that patients with MS demonstrate several narrow bands (“oligoclonal bands”) in the gamma area when their spinal fluid is subjected to certain types of electrophoresis (polyacrylamide gel, high-resolution agarose, or immunofixation; ordinary cellulose acetate electrophoresis will not demonstrate the oligoclonal bands). Oligoclonal banding is present in 85%-90% of MS patients (literature range, 65%-100%. Some of this variation is due to different methods used). Similar narrow bands may be found in subacute sclerosing panencephalitis, destructive CNS lesions, CNS vasculitis, lupus or primary Sjцgren’s syndrome involving the CNS, diabetes mellitus, and the Guillain-Barrй syndrome. A similar but not identical phenomenon has been reported in some patients with aseptic meningitis.

    Antibodies have been produced against myelin components, and a radioassay for myelin basic protein (MBP) is available in some reference laboratories. The MBP level is reported to be increased in 70%-80% of patients with active MS (literature range, 62%-93%), depending to some extent on the status of active demyelination. Incidence is less if the disease is not active or if steroid therapy is being given. The various demyelinating conditions other than MS also produce abnormal MBP assay results. The MBP level may also be increased in destructive CNS lesions such as a CVA, in some patients with the Guillain-Barrй syndrome, and in some patients with CNS lupus erythematosus.

    Summary. Of the various laboratory tests for MS, the two most widely used are the spinal fluid IgG index and presence of oligoclonal bands. Of these, the best single test is probably oligoclonal banding. CT and MRI can often demonstrate focal demyelinized areas in the CNS, with CT reported to show abnormality in 40%-60% of patients with definite MS and MRI positive findings in about 90% (range, 80%-100%). Neither CT nor MRI is currently able to differentiate MS with certainty from other CNS demyelinizing diseases.

  • Cardiolipin Tests

    The first practical serologic test for syphilis (STS) was the complement fixation (CF) technique invented by Wassermann. He used extract from a syphilitic liver as the antigen that demonstrated the presence of antitreponemal antibodies. Subsequently it was found that the main ingredient of the substance he used actually had nothing to do with syphilitic infection and was present in other tissues besides liver. It is a phospholipid that is now commercially prepared from beef heart and therefore called cardiolipin. The reagent used in current screening tests for syphilis (as a group, sometimes called STS) is a mixture of purified lipoproteins that includes cardiolipin, cholesterol, and lecithin. Apparently, an antibody called “reagin” is produced in syphilis that will react with this cardiolipin-lipoprotein complex. Why reagin is produced is not entirely understood; it is not a specific antibody to T. pallidum. There is a lipoidal substance in spirochetes, and it is possible that this substance is similar enough to the cardiolipin-lipoprotein complex that antibodies produced against spirochetal lipoidal antigen may also fortuitously react with cardiolipin.

    The original Wasserman CF test was replaced by a modification called the Kolmer test; but this in turn was replaced by the much faster, easier, and cheaper flocculation tests. In earlier versions of the flocculation reaction the patient’s serum was heated; for unknown reasons, heating seemed to enhance the reaction. Then a suspension of cardiolipin antigen particles is added to the serum and mixed. In a positive (reactive) test result, the reagin antibody in the patient serum will combine with the cardiolopin antigen particles, producing a microscopic clumping or flocculation of the antigen particles. The reaction is graded according to degree of clumping. The current standard procedure for this type of test is the Venereal Disease Research Laboratory (VDRL) test. It was found that the preliminary heating step could be eliminated if certain chemicals were added to the antigen; this modification is called the rapid plasma reagin (RPR) test and gives results very similar to those of the VDRL.

    Drawbacks of the cardiolipin serologic tests for syphilis

    Variation in test modifications. Not all sera from known syphilitics gave positive reactions in these tests. It was discovered that the number of positives could be increased by altering the ratio of antigen ingredients. However, usually when the percentage of positive results increases significantly, more false positives are reported. One report indicates that about 2% of VDRL or RPR tests in primary and secondary syphilis are falsely negative due to antigen excess (prozone phenomenon).

    Effect of antibiotic therapy. A peculiarity of the STS exists when antibiotic treatment is given. If the patient is treated early in the disease, the STS will revert to nonreactive state. In patients with primary syphilis, one study found that the VDRL or RPR returned to nonreactive state in 60% of patients by 4 months and 100% of patients by 12 months. In secondary syphilis, the VDRL became nonreactive in 12-24 months. Another study of patients with primary and secondary syphilis reported that successful treatment usually produced a fourfold decrease in VDRL titer by 3 months and an eightfold decrease by 6 months. The VDRL decline may be slower if the patient had other episodes of syphilis in the past. However, the longer the disease has been present before treatment, the longer the VDRL takes to become nonreactive. In many cases after the secondary stage it will never become nonreactive, even with adequate treatment (this is called “Wassermann fastness”).

    Spontaneous loss of test reactivity. In tertiary syphilis, there is a well-documented tendency for a previously reactive VDRL/RPR test result to revert spontaneously to nonreactive, even if the patient is untreated. This is reported to occur in about 20%-30% (literature range, 5%-45%) of patients.

    Biologic false positive reactions. Some patients have definitely positive results on RPR but just as definitely do not have syphilis or any exposure to it. These are called biologic false positive (BFP) reactions. The major known causes of BFP reactions can be classified under three headings:

    1. Acute BFP reactions, due to many viral or bacterial infections and to many febrile reactions such as hypersensitivity or vaccination. These usually give low-grade or moderate (1 to 2 +) STS reactions and return to normal within a few weeks.
    2. Chronic BFP reactions, due to chronic systemic illness such as antiphospholipid antibodies (Chapter 8), rheumatoid-collagen diseases, malaria, or chronic tuberculosis. There is also an increased incidence of BFP reactions in old age. Whereas there is less than 2% incidence of BFP reactions in men before the age of 60 years, some studies report an incidence as high as 9%-10% after age 70.
    3. Nonsyphilitic treponemal diseases such as yaws, pinta, Borrelia (Lyme disease), or relapsing fever.

    Summary. The cardiolipin STS is cheap, easy to do, and suitable for mass testing. Its sensitivity and specificity are adequate, and positivity develops reasonably early in the disease. Reagents are well standardized and reproducibility is good. Disadvantages are relatively poor sensitivity in primary syphilis, the tendency in late syphilis for spontaneous reversion of a reactive test result to a nonreactive result, and the problem of BPF reactions. To add further to the confusion, some patients with BFP reactions may have syphilis in addition to one of the diseases known to give BFP reactions. Because of this, everyone hoped for a way to use T. pallidum organisms themselves as antigen rather than depend on the nonspecific reagin system.