Articles on Medical Diseases and Conditions

Tag: Neurologic Disorders

  • Peripheral Nerve Sensory Syndromes

    Sulfatide antibody syndrome (idiopathic sensory polyneuropathy). Sulfatide is a glycolipid found in greatest quantity in CNS and peripheral nerve myelin. Some patients develop antibodies against sulfatide, leading to destruction of peripheral nerve axon myelin sheaths. These changes are greater in sensory nerves than motor nerves, producing paresthesias with symptoms of numbness and burning as well as impairment of touch and temperature perception. An ELISA-method test has been described to detect antisulfatide antibodies. Only high titers are considered diagnostic. The test is available only in a few large reference laboratories and university medical centers. Besides idiopathic sensory polyneuropathy, elevated titers of antibody against sulfatide have also been reported in about 85% of patients with idiopathic chronic inflammatory demyelinating polyradiculoneuropathy and 19%-65% of patients with the Gullain-Barrй syndrome.

    Familial amyloidotic polyneuropathy (FAP). This is the most common form of hereditary amyloidosis. Familial amyloidotic polyneuropathy (FAP) comprises about one third of cases involving small fiber neuropathy. Amyloid is deposited in autonomic system ganglia and peripheral nerve fibers, both myelinated and nonmyelinated. Symptoms usually begin in the third and fourth age decade. About 50% of cases begin with sensory impairment that begins in the legs and eventually involves the arms, hands, and body trunk in a symmetrical distribution. After sensory loss begins, motor loss may follow some time later. In about 40% of cases, autonomic nervous system symptoms predominate, with diarrhea, constipation, vomiting, loss of sphincter control, and impotence. FAP is also associated with a genetic abnormality in one of the plasma proteins called transthyretin (TTR). Detection of the abnormal transthyretin molecule is useful as an indirect test for the presence of FAP. TTR is currently detected by nucleic acid probe with PCR amplification.

    Other syndromes. Both Hu antibody syndrome (previously described) and IgM (MAG) antibody syndrome (previously described) are predominantly motor nerve dysfunction syndromes that can have a sensory component.

  • Idiopathic or Paraneoplastic Autoimmune Sensory, Motor, or Mixed Sensory-Motor Disorders

    Primary motor or encephalitic syndromes

    Paraneoplastic cerebellar degeneration. This syndrome is caused by generalized loss of many cerebellar Purkinje cells, producing ataxia, which is also frequently accompanied by nystagmus and dysarthria. This is most commonly found in postmenopausal women with breast or ovarian carcinoma and less frequently with other adenocarcinomas. A few cases are associated with lung small cell carcinoma. About 5% of cases have no detectable cancer. Paraneoplastic cellular degeneration due to ovarian or breast cancer is accompanied in 50%-87% of patients by serum antibodies against Purkinje cell cytoplasm, known as Yo antibodies. In some cases appearance of the Purkinje cytoplasmic antibody may precede symptoms. Those cases due to lung small cell carcinoma are usually accompanied by antibodies against nuclei of CNS neurons called Hu antibodies. About one third of patients with Hu autoantibodies have CNS encephalopathy due to lung small cell carcinoma with or without cerebellar involvement. Hu and Yo antibodies are currently only available in some medical centers and large reference laboratories.

    Antineuronal antibody associated with sensory or encephalitic disease. Besides cerebellar degeneration, another third of patients with Hu autoantibodies have sensory neuropathy without encephalopathy and about 10% of patients have a special type of encephalopathy that involves the CNS limbic area, with memory loss, behavioral abnormality, and partial seizures. A few cases with Hu antibodies have nonpulmonary neoplasms such as prostate carcinoma. However, the great majority of patients with Hu autoantibodies have lung small cell carcinoma.

    Lambert-Eaton myasthenic syndrome (LEMS). Patients with Lambert-Eaton myasthenic syndrome (LEMS) have symptoms similar to those of MG; but weakness tends to be symmetrical in LEMS and asymmetrical in MG; weakness improves with exercise in LEMS and improves after rest in MG; tendon reflexes decrease in LEMS and increase in MG; ocular muscles often are not involved in LEMS but usually are involved in MG; and edrophonium test results are usually negative in LEMS but positive (correcting the weakness) in MG. The defect occurs presynaptically in LEMS and postsynaptically in MG. About 60% of patients with LEMS have a lung small cell carcinoma; therefore, LEMS is often considered a paraneoplastic disease. About 10%-15% of MG patients have a thymoma (which is a benign tumor) and another 60%-65% have benign thymus hyperplasia. Therefore, it is less certain that MG is a true paraneoplastic syndrome, at least in the way that the term “neoplastic” is ordinarily used. A test using Western blot technique has been described for LEMS antibody; this antibody attacks voltage-gated calcium channel antigen (myasthenia syndrome B antigen), which is used in the test in the form of recombinant antigen to assay LEMS antibody. About 45% of patients with LEMS have detectible LEMS antibody with this test method. LEMS antibody testing is only available in some research centers and a few large reference laboratories.

    Cancer-associated retinopathy (CAR). Some patients with occult or overt malignancies have rapid worsening of vision. The most commonly associated (but not the only) tumor is lung small cell carcinoma. A test has been devised using a recombinant form of the retinal photoreceptor protein Recoverin as antigen to detect cancer-associated retinopathy (CAR) antibody. The test is only available in some research centers and a few large reference laboratories.

    Paraneoplastic opsoclonus/myoclonus syndrome. The main clinical symptoms associated with this syndrome are opsoclonus (involuntary side-to-side eye motion) or truncal ataxia. There may also be myoclonus or motor weakness. Current diagnosis is based on detection of antibody to the Ri antigen, a neuron nuclear antigen. Most of the few patients to date found to have the Ri antibody had lung small cell carcinoma. The test is currently only available in a limited number of medical school research laboratories and a few large reference laboratories.

    IgM motor neuropathies. Currently there are two syndromes in this category, both involved with carbohydrate antigens shared by neuron glycolipids and glycoproteins, and both diagnosed by detection of IgM antibodies against the carbohydrate-glycolipid antigens. The first is a syndrome characterized by antibodies against ganglioside monosialic acid (GM1), consisting of predominantly lower motor neuron disease and distal muscle weakness (although there may be combined sensory and motor abnormalities). Occasionally GM1 antibodies have also been reported in patients with SLE having CNS involvement and IgM monoclonal gammopathies with neuropathy. Only high antibody titers of GM1 are considered diagnostic because low titers of GM1 have been reported in some clinically normal persons, as well as some patients wtih MS or ALS. Unfortunately, at present only about 20% of patients with lower motor neuron disease or sensory neuropathy have diagnostic GM1 titer levels. The test is only available in large commercial laboratories and some university centers. The other syndrome is a demyelinating condition associated with antibody against myelin-associated glycoprotein (MAG). This syndrome can have either motor or sensory components or both together. Anti-MAG antibody elevation has been reported in up to 50% of patients with IgM monoclonal gammopathies associated wtih peripheral neuropathy. Only high antibody titers are considered diagnostic because low levels of MAG have been reported in some clinically normal persons and some patients with rheumatoid-collagen diseases. MAG antibody tests are available only in some large reference laboratories and university centers.

  • Myasthenia Gravis

    Myasthenia gravis (MG) is manifested primarily by muscle weakness. Clinically, there is especially frequent involvement of cranial nerves, most commonly manifested by diplopia and ptosis. In more serious cases there is difficulty in swallowing. Peripheral nerve involvement tends to affect proximal muscles more severely than distal ones. In the most severe cases there is paralysis of chest respiratory muscles. The disease affects only the eyes in about 20% of cases. Whenever muscles are involved, the degree of muscle weakness may fluctuate over short or long periods of time. The basic problem is located at the neuromuscular junction area of striated muscle. In normal persons, acetylcholine is released at nerve terminals on the proximal side of the neuromuscular junction, and the acetylcholine crosses the nerve-muscle junction and acts on acetylcholine receptor sites in the muscle membrane to set off muscle contraction. In patients with MG, acetylcholine receptor antibodies are present that interfere with the binding of acetylcholine to the receptor sites. The classic test for MG used to be a “therapeutic trial” of drugs such as edrophonium (Tensilon). Assays are now available in reference laboratories for serum acetylcholine receptor antibodies. Current assays are positive in 85%-90% of acute MG patients. The test is less sensitive in congenital MG and MG localized to the eyes; also, test results may become negative with therapy. Definitely elevated levels of acetylcholine receptor antibody are fairly specific for MG, with only a few conditions known to produce false positive results (such as D-penicillamine therapy for rheumatoid arthritis).

    It is of interest that about 10% (range, 8.5%-15%) of MG patients have an associated thymoma, and about 50%-60% have hyperplasia of the thymus. Antistriated muscle (antistriational) antibodies have been reported in about 95%-99% of patients with MG plus thymoma and about 30% of patients with thymoma but without MG. Since the incidence of MG in patients with thymoma is about 35% (range, 7%-59%), the test results would be expected to be elevated in about 55% of all thymoma patients. Unfortunately, the test results are also elevated in about 25% of MG patients without thymoma. Therefore, absence of this antibody in a patient with MG is strong evidence against thymoma, but presence of antistriated muscle antibody does not prove that the patient has a thymoma.

  • Laboratory Tests in Neurology

    Most laboratory tests concerned with diagnosis or function of the CNS are discussed earlier in this chapter. The major condition affecting the peripheral nervous system which involves the laboratory is myasthenia gravis.

  • Cerebrospinal Fluid Artifacts

    During or after a lumbar puncture the question frequently arises whether blood has been introduced into the spinal fluid by the spinal needle, resulting in a traumatic tap. There are several useful differential points. Xanthochromia, if present, suggests previous bleeding. However, a nonxanthochromic supernatant fluid does not rule out the diagnosis, since xanthochromia may be absent even when subarachnoid bleeding has occurred many hours before. A second differential point utilizes the fact that the standard method for collecting CSF involves catching the specimen in three consecutively numbered tubes. If blood was introduced by a traumatic tap, more blood should appear in the first tube, less in the second, and even less in the third, as the bleeding decreases. Previous CSF bleeding should distribute the RBCs equally throughout the spinal fluid and characteristically shows approximately equal numbers of RBCs in each of the three tubes. Therefore, RBC counts can, if necessary, be requested for all three tubes. However, sometimes traumatic taps, if severe, can yield roughly equal numbers of RBCs in each tube. As noted previously, blood in the CSF may falsely alter the various chemical tests.

  • Lead Encephalopathy

    Lead poisoning is discussed elsewhere. Lead encephalopathy occurs mainly in children (adults are more likely to develop peripheral neuropathy), and it is more common in acute than in chronic poisoning. Clinical signs and symptoms include visual disturbances, delirium, convulsions, severe headaches, hypertension, and sometimes papilledema. CSF usually displays increased pressure. The cell count varies from normal to several thousand; the majority of patients have mild to moderate pleocytosis. Mononuclears usually predominate, but polymorphonuclears may occasionally be high, especially in patients with the more elevated cell counts. The CSF protein level may be normal or increased; the glucose level is normal. These findings may suggest a variety of conditions, such as meningitis or meningoencephalitis due to virus or fungus, or early bacterial meningitis.

  • 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.

  • Intracerebral Hemorrhage

    CSF findings depend on how close the hematoma is to the subarachnoid space. If penetration to the brain surface occurs, the CSF resembles that of subarachnoid hemorrhage; if situated relatively far from the brain surface, the CSF will be relatively normal. About 20% (literature range, 15%-25%) of cases are said to have clear CSF; the remainder are xanthochromic or contain blood. Cell count and protein values reflect the presence of spinal fluid blood and the closeness of the hematoma to the meninges. With bloody fluid, protein and cell count initially reflect the RBC count; after 12 or more hours, protein level and cell count may rise disproportionately to the number of RBCs, sometimes to moderately high levels (similar to effects of subarachnoid hemorrhage). CT and MRI are the best methods for diagnosis, with CT better than MRI in the first week.

  • Subarachnoid Hemorrhage

    In hemorrhage involving the subarachnoid space, the findings depend on the time interval following hemorrhage when the patient is examined. It takes about 4 hours (literature range, 2-48 hours) to develop xanthochromia. Therefore, CSF obtained very early may have a colorless supernatant. Initially, the WBC count and protein level are proportional to the amount of CSF blood (about 1 WBC/700 RBCs and 1 mg protein/1,000 RBCs). Later, the WBC count may rise, sometimes to levels greater than 1,000/cu mm, with predominance of segmented neutrophils. This may raise the question of intracranial infection. This rise is usually attributed to meningeal irritation by the blood. Protein also is initially correlated to RBC count but later may rise out of proportion to the number of RBCs as the WBCs increase and the RBCs lyse and disappear. Usually by 3 weeks after onset, xanthochromia has disappeared and both protein and cell count have returned to normal.

  • Cerebral Thrombosis

    In one series of fatal cerebral thrombosis, 90% had clear CSF and most of the remaining 10% had xanthochromia. WBC counts were usually normal; about 15% had a small increase in cell count (usually < 50/mm3). CSF protein level was normal in 50% of cases and usually less than 100 mg/ 100 ml in the remainder. CT or MRI is the best method of demonstrating the lesion. CT is better in the first week.