Cerebrospinal Fluid Immunoglobulin Research Articles

Detecção de imunoglobulinas IgG, IgM e IgA anti-Toxoplasma gondii no soro, líquor e saliva de pacientes com síndrome da imunodeficiência adquirida e neurotoxoplasmose

We studied 55 patients with acquired immunodeficiency syndrome (AIDS) and neurotoxoplasmosis (group 1), 37 patients with AIDS and neurological involvement due to another etiology (group 2) and 18 anti-HIV-negative individuals with neurological manifestations, by searching for anti-T. gondii IgG, IgA and IgM immunoglobulins in serum, cerebrospinal fluid (CSF)and saliva, using ELISA. The negative predictive value of the test for IgG in serum was 100% and in CSF, 92.4%. There was no difference among the three groups studied regarding IgA in serum. For IgA, in CSF the test reached 72.7% specificity (p<0.05). In saliva, only the detection of IgG was found to be correlated with a diagnosis of neurotoxoplasmosis. We emphasize that the absence of anti-T. gondii IgG antibodies in serum and CSF strongly indicates the absence of a diagnosis of neurotoxoplasmosis and that specific IgA immunoglobulins in CSF and IgG in saliva may represent two auxiliary markers for the differential diagnosis of toxoplasmic encephalitis in AIDS.

Dual impairment of GABA A- and GABA B-receptor-mediated synaptic responses by autoantibodies to glutamic acid decarboxylase

Anti-glutamate decarboxylase autoantibodies (GAD-A) are associated with a group of patients with progressive cerebellar ataxia. We reported previously that cerebellar GABA A-mediated synaptic transmission was presynaptically depressed by GAD-A in the cerebrospinal fluid (CSF). Using whole-cell recording of rat cerebellar slices, we found in the present study that CSF immunoglobulins from ataxic patients reduced gamma-aminobutyric acid (GABA) release from cerebellar interneurons, thereby attenuating presynaptic inhibition on neighboring excitatory synapses through GABA B receptors (GABA BRs). Our results suggest that in in vitro slices, GAD-A elicited the pathophysiological action of reduction in GABA release, which subsequently resulted in dual synaptic impairment in the cerebellar circuit, by depression of GABA A receptor (GABA AR)-mediated inhibitory synaptic transmissions, and attenuation of GABA B receptor-mediated inhibition of excitatory transmissions.

Detection of Oligoclonal Immunoglobulins in Cerebrospinal Fluid by an Immunofixation-Peroxidase Method

The detection of intrathecal synthesis of immunoglobulins is used in the diagnosis of multiple sclerosis (MS). We tested the semiautomated immunofixation-peroxidase (IFPOD) technique, which uses high-resolution agarose gel electrophoresis (HRAGE) directly followed by immunofixation with a peroxidase-labeled anti-IgG antiserum to detect oligoclonal immunoglobulins in cerebrospinal fluid (CSF). We analyzed 230 consecutive matched serum/CSF pairs that arrived in the laboratory over a 6-month period with both IFPOD and our routine techniques, immunofixation electrophoresis (IFE) and HRAGE. For IFPOD, CSF samples were not concentrated before testing. Among the 230 samples were 12 clinically definite MS, 33 clinically probable, and 20 clinically possible MS samples. IFPOD and HRAGE + IFE each detected oligoclonal IgG in CSF in 10, 16, and 7 cases of these respective groups. For clinically definite MS, sensitivity and specificity (95% confidence intervals) were, respectively, 83% (51-97%) and 79% (73-84%). The IFPOD technique performs comparably to other analytical methods, without the requirement for sample concentration, and may represent an attractive alternative in testing for intrathecal immunoglobulin synthesis.

Tratamiento intravenoso con inmunoglobulinas en síndromes epilépticos de difícil control

Several mechanisms have been found to be involved in the development of malignant epileptic syndromes in childhood and an immunological component has been shown in experimental studies of epilepsy. The effect of intravenous immunoglobulin (IgIV) has been reported in various cases of epilepsy which were difficult to control. To show the usefulness of IgIV in West s syndrome (WS) and Lennox Gastaut syndrome (LGS) which were difficult to control. We selected five patients who fulfilled the criteria for WS and LGS which were difficult to control. They were given IgIV for five days and subsequently six fortnightly doses of 0.5 g/kg/day. We recorded data on sex, age, onset of the disorder and laboratory investigations, including blood and cerebrospinal fluid (CSF) immunoglobulin levels. Four girls with symptomatic WS and one boy with LGS as a symptom of a neuro infection. Treatment was started at the age of 8 14 months. The spasms varied between 204 and 1,074 in 24 hours, and were markedly reduced after IgIV was given. The IgG in the CSF rose as the number of spasms fell (p< 0.05). There was a satisfactory response to treatment, as reported in previous publications. It is a coadjuvant treatment for cases which are difficult to control and may also be useful in cases of symptomatic epilepsy where goods results are also obtained.

Detection of oligoclonal immunoglobulins in the cerebrospinal fluid by immunofixation electrophoresis.

Many disorders of the central nervous system are associated with increased concentration of cerebrospinal fluid protein due to either an increase in the permeability of blood-brain barrier or the synthesis of immunoglobulins within the central nervous system. Immunofixation electrophoresis was used to detect the immunoglobulins in sera and cerebrospinal fluid in patients with different central nervous system disorders. A strong oligoclonal band, or a single weak monoclonal band, observed in the cerebrospinal fluid but not in the serum, indicates the endogenous immunoglobulin synthesis. In 17 cases of non-infectious central nervous system diseases, we diagnosed one case of progressive multifocal leukoencephalopathy, one case of multiple sclerosis, one case of Guillain-Barre syndrome, and one case of epilepsy. A weak band was observed in both serum and cerebrospinal fluid samples in two cases of cerebral trauma. Out of 25 cases of infectious central nervous system diseases, two cases of nervous system syphilis were positive only in cerebrospinal fluid samples, and 23 cases were negative in both samples. Compared with the standard immunofixation, the application of an enzyme-labeled antibody can significantly increase the sensitivity of the method.

Long-term treatment of dogs with steroid-responsive meningitis-arteritis: clinical, laboratory and therapeutic results.

Steroid-responsive meningitis-arteritis is an immunopathological disease in dogs characterised by neck pain, pleocytosis of the cerebrospinal fluid (CSF) and increased serum and CSF immunoglobulin (Ig) A levels. A long-term treatment protocol (four to 20 months) with prednisolone was applied in 10 dogs with the condition. Clinical side effects, changes in blood and CSF values and long-term outcome were evaluated retrospectively. Eight of the 10 dogs were without clinical signs up to 29 months after the treatment was terminated. Long-term glucocorticosteroid treatment appears to result only in mild clinical side effects, such as polyuria/polydipsia, polyphagia and weight gain. All clinical and laboratory changes were reversible after the therapy was discontinued. Elevated serum and CSF IgA levels did not decrease to normal values during prednisolone treatment and were still slightly increased after the therapy was discontinued. A marked decrease in the cell count of the CSF was observed after therapy was initiated, although pleocytosis increased again during relapses of the disease. Monitoring of CSF cell count in dogs with this condition seems to be a sensitive indicator of success of treatment. In addition, older dogs with high IgA levels in the CSF and frequent relapses seem to require a longer duration of therapy and have a less favourable prognosis long term. The reason for high systemic and intrathecally produced IgA levels remains unknown, but seems not to be influenced by prednisolone treatment.

Neuroblastoma associated with seizures and arrested development

Two unrelated cases of childhood peripheral neuroblastoma associated with infantile seizures and developmental problems (but without opsoclonus-myoclonus) are presented. The considerable body of evidence supporting the view that the opsoclonus-myoclonus syndrome associated with neuroblastoma has an immunologic basis is reviewed. Patients with neuroblastoma and opsoclonus-myoclonus syndrome commonly have subsequent developmental problems and, rarely, may have seizures. The authors postulate that the seizures and developmental problems in their two patients may result from an immunologic mechanism similar to that suggested for the opsoclonus-myoclonus syndrome of neuroblastoma. The only laboratory evidence to support an immunologic mechanism in these two patients was the presence of raised cerebrospinal fluid immunoglobulins in Patient 2. Specific antineuronal antibody tests in Patient 2 were negative. It is therefore possible that the association reported in these two unrelated cases is coincidental. However, reasonably extensive investigations did not uncover an alternative etiology for the presence of the seizures and developmental delay.

Anterior lumbosacral radiculopathy after intrathecal methotrexate treatment

Intrathecal chemotherapy with methotrexate or cytosine arabinoside is the standard approach to prophylaxis and treatment of central nervous system leukemia in children. Progressive paraplegia, one of the devastating neurologic complications related to this mode of treatment, has been attributed to spinal cord toxicity. Reported are three children who developed progressive paraparesis after intrathecal methotrexate administration followed by complete or partial recovery. Gadolinium enhancement of anterior lumbosacral spinal nerve roots was demonstrated in all three patients, and an elevation of cerebrospinal fluid immunoglobulin G synthesis was evident in two patients with more severe symptoms. The clinical data suggest that anterior lumbosacral radiculopathy is also a type of neurologic complication associated with intrathecal methotrexate treatment.

Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis

Our identification of Chlamydia pneumoniae in the cerebrospinal fluid (CSF) of a patient with multiple sclerosis (MS) led us to examine the incidence of this organism in the CSF from 17 patients with relapsing-remitting MS, 20 patients with progressive MS, and 27 patients with other neurological diseases (OND). CSF samples were examined for C pneumoniae by culture, polymerase chain reaction assays, and CSF immunoglobulin (Ig) reactivity with C pneumoniae elementary body antigens. C pneumoniae was isolated from CSF in 64% of MS patients versus 11% of OND controls. Polymerase chain reaction assays demonstrated the presence of C pneumoniae MOMP gene in the CSF of 97% of MS patients versus 18% of OND controls. Finally, 86% of MS patients had increased CSF antibodies to C pneumoniae elementary body antigens as shown by enzyme-linked immunosorbent assay absorbance values that were 3 SD greater than those seen in OND controls. The specificity of this antibody response was confirmed by western blot assays of the CSF, using elementary body antigens. Moreover, CSF isoelectric focusing followed by western blot assays revealed cationic antibodies against C pneumoniae. Infection of the central nervous system with C pneumoniae is a frequent occurrence in MS patients. Although the organism could represent the pathogenetic agent of MS, it may simply represent a secondary infection of damaged central nervous system tissue. A therapeutic trial directed at eliminating C pneumoniae from the central nervous system may provide additional information on its role in MS.

Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis

Our identification of Chlamydia pneumoniae in the cerebrospinal fluid (CSF) of a patient with multiple sclerosis (MS) led us to examine the incidence of this organism in the CSF from 17 patients with relapsing–remitting MS, 20 patients with progressive MS, and 27 patients with other neurological diseases (OND). CSF samples were examined for C pneumoniae by culture, polymerase chain reaction assays, and CSF immunoglobulin (Ig) reactivity with C pneumoniae elementary body antigens. C pneumoniae was isolated from CSF in 64% of MS patients versus 11% of OND controls. Polymerase chain reaction assays demonstrated the presence of C pneumoniae MOMP gene in the CSF of 97% of MS patients versus 18% of OND controls. Finally, 86% of MS patients had increased CSF antibodies to C pneumoniae elementary body antigens as shown by enzyme-linked immunosorbent assay absorbance values that were 3 SD greater than those seen in OND controls. The specificity of this antibody response was confirmed by western blot assays of the CSF, using elementary body antigens. Moreover, CSF isoelectric focusing followed by western blot assays revealed cationic antibodies against C pneumoniae. Infection of the central nervous system with C pneumoniae is a frequent occurrence in MS patients. Although the organism could represent the pathogenetic agent of MS, it may simply represent a secondary infection of damaged central nervous system tissue. A therapeutic trial directed at eliminating C pneumoniae from the central nervous system may provide additional information on its role in MS. Ann Neurol 1999;46:6–14

Immunoglobulin and albumin content of cerebrospinal fluid in schizophrenic patients: Relationship to negative symptomatology

Alterations of the cerebrospinal fluid (CSF) protein contents and the blood brain barrier (BBB) in schizophrenia have been observed by several authors but no relationship to clinical characteristics like psychopathology, the course or the duration of the disease could be described until now. We have studied 27 schizophrenic patients upon each of whom a lumbar punction had been carried out for clinical reasons. The average values of the patients were within the normal range. Nine patients (33%) showed the total protein content to be >45 mg% and 6 (22%) >50 mg%. In the latter 6 patients an impaired BBB (raised albumin CSF/serum quotient) and in 4 patients (15%) a raised CSF immunoglobulin (IgG) were observed. No relation to the patient's age and the duration of the disease was found but correlations with the Scale for the Assessment of Negative Symptoms (SANS) showed significant results in the subscores “affective flattening/affective blunting”, “alogia/paralogia” as well as in the total score with respect to the CSF contents of albumin and IgG ( p=0.009−0.02). These correlations suggest that the CSF albumin and the CSF IgG are related to the negative symptomatology in schizophrenia and that patients with these CSF alterations may have a higher risk of developing negative symptoms.

Tonic “Seizures” in a patient with brainstem demyelination: MRI study of brain and spinal cord

Tonic seizures are a poorly understood manifestation of demyelinating disease, first reported in 4 patients with multiple sclerosis. We describe a patient with tonic extension of the left limbs caused by a right-sided brainstem lesion as the first manifestation of demyelinating disease. A 19-year-old man was referred with a 4-month history of spontaneous attacks of mild paresthesias of the left arm and leg, followed by 15–45 s of rigid extension of the left limbs, occurring up to 25 times per day. Two months after onset, an MRI scan revealed areas of T 2 abnormality in the lateral right cerebral peduncle and deep frontal white matter. The EEG was normal, including during hyperventilation which induced a typical episode. All attacks were successfully suppressed by carbamazepine, phenytoin, and valproate monotherapy. Serologic testing for toxoplasmosis, cytomegalovirus, Epstein-Barr virus, Lyme disease, and HIV was negative. Cerebrospinal fluid oligoclonal bands were absent but cerebrospinal fluid immunoglobulin G was mildly elevated (4.2 mg/dl). Over the next 30 months, serial MRIs revealed a normal spinal cord and persistence of the midbrain lesion, with resolution of some of the white matter lesions but reappearance of others. At 46 months, the midbrain lesion resolved on MRI, and the spasms no longer occurred spontaneously, nor could they be elicited by hyperventilation. While two previous reports have shown internal capsule lesions to underlie the tonic spasms in demyelinating disease, this is the first report in which a brainstem lesion has been causative.

Cerebrospinal Fluid lnterleukin-6, Prostaglandin E2 and Autoantibodies in Patients with Neuropsychiatric Systemic Lupus Erythematosus and Central Nervous System Infections

Cerebrospinal fluid (CSF) from patients with a variety of central nervous system (CNS) disorders was assayed for cytokines, prostaglandins, and autoantibodies. CSF interleukin-6 (IL-6) in patients with CNS infection (374.24 +/- 92.61 pg/mL) and neuropsychiatric systemic lupus erythematosus (NP-SLE) (71.40 +/- 5.89 pg/mL) were significantly higher than in patients with CNS inflammation (33.92 +/- 29.36 pg/mL) or controls (non-inflammatory CNS diseases) (4.35 +/- 3.00 pg/mL). Interleukin-1 beta, interferon alpha, and tumor necrosis factor alpha were undetectable in these samples: CSF prostaglandin E2 (PGE2) also exhibited similar patterns as IL-6. CSF immunoglobulin G (IgG) in patients with NP-SLE (8.84 +/- 1.80 mg/dL) was much higher than in patients with CNS infection (4.65 +/- 3.09 mg/dL), CNS inflammation (2.54 +/- 1.24 mg/dL), or controls (2.11 +/- 1.03 mg/dL). CSF autoantibodies against calf thymus antigens were present in patients with NP-SLE but not in patients with CNS infection as demonstrated by immunoblot. These results suggest that high IL-6 and PGE2 in CSF favors the diagnosis of CNS infection, while modestly elevated IL-6, high IgG, and autoantibodies against calf thymus antigens in CSF are the features of NP-SLE.

Prolonged dynamic clinico-immunological observation of 85 patients with definite multiple sclerosis: first steps towards monitoring process activity.

Prolonged clinico-immunological observation of 85 patients with definite multiple sclerosis (MS) was performed in order to elucidate the connections between the clinical and immune state. A battery of immunological investigations was performed, including estimation of T-cell subpopulations in blood and cerebrospinal fluid (CSF); proliferative responses of circulating lymphocytes to mitogens, recombinant interleukin-2 (rIL2) and myelin basic protein levels in different culture conditions; levels of immunoglobulin (Ig) in sera and CSF, and of Ig production in vitro; indices of IL2 synthesis and IL2 sensitivity; production of prostaglandin E2 and tumour necrosis factor (TNF) alpha by monocytes and levels of beta-endorphin in sera and supernatants phytohaemagglutinin of (PHA)-activated cells. Clinical observation was performed periodically using Kurtzke scales and was supplemented by repeated recording of evoked potentials and magnetic resonance imaging. Initial investigations showed specific differences between patients with MS and the control groups (donors and patients with other neurological disorders of the same age). Correlative and regressive analyses showed no association between immunological and clinical parameters at the initial investigation, although immunological indexes were inter-related, and indicated specific alterations in immunoregulation in MS. Retrospective analysis revealed associations between the clinical status of patients with MS and their previous immune status. Evidence of cell activation--including a decreased percentage of circulating cells with differential antigens, lower cell mitogen-induced proliferative responses in vitro, with restoration following the addition of autoserum, greater IL2 sensitivity, and increased TNF-alpha production by macrophages--often predicted the clinical manifestation of deterioration. It is proposed that the immunopathological process in MS has a number of stages with characteristic features, and that progression from one stage to another can be subclinical. No single immunological index can be used to determine stage. Only systemic alterations reflect the real situation, whilst every patient has some abnormalities. A system of clinico-immunological monitoring could severe as the basis for a new approach to the dynamic treatment of MS.

Cerebrospinal Fluid Analysis

Accurate interpretation of cerebrospinal fluid (CSF) changes can only be made in the context of the differential diagnosis for each case. The routine analysis of CSF cell number and type as well as CSF total protein can provide information that suggests a specific mechanism or disease, but is often inconclusive. Further information obtained from CSF protein electrophoresis and immunoglobulin determination and calculation of an albumin quota and IgG index can lend additional support for the suspected mechanism of disease. Paired serum and CSF antibody titers for specific organisms can be useful to confirm the presence of a systemic or nervous system infection. Current research on detecting antibodies against nervous tissue components in CSF should result in better diagnostic capabilities and understanding of the pathophysiology of certain disorders in the future.

The estimation of free light chains of immunoglobulins in biological fluids

Methods for the estimation of the free light chains of immunoglobulins in serum, urine and cerebrospinal fluid are divided into two groups, electrophoretic and immunological, and the analytical performance of each method described. The problems associated with the accurate and precise determination of free light chains by the different methods are discussed and their complementary clinical roles emphasized. It is proposed that an International Reference Preparation for free light chains is established.

Central Nervous System Manifestations in Human Immunodeficiency Virus Infection Without AIDS

To characterize neurological and neuropsychological findings associated with human immunodeficiency virus type-I (HIV) infection, 77 seropositive homosexual or bisexual males with no or minor symptoms of HIV were compared prospectively to 44 HIV seronegative men by observers blinded to serological status of the subjects. Neurological symptoms and examination findings were not significantly different between seropositives and seronegatives except for cranial nerve findings, predominantly mild hearing impairment. Mean performance scores for a 15-test neuropsychological battery were within an unimpaired range for both groups, although for five tests, mean scores were significantly poorer in seropositives. After adjustment for vocabulary score, and demographic and psychosocial variables, the mean score of seropositives was significantly worse only for the Benton Visual Retention Test. Magnetic resonance (MR) images of brain were abnormal in 14 (27%) of 52 seropositives and one of 10 seronegatives (value was not significant). HIV was isolated from cerebrospinal fluid (CSF) in 31 (61%) of 51 seropositives. The only clinical or laboratory difference between CSF culture positives and negatives was a higher CSF immunoglobulin synthesis rate in the former subjects (medians of 10.3 versus 0.1 mg/day; p = 0.03). An additional 13 seropositive subjects had immunologic evidence of central nervous system HIV infection, defined by a serum-to-CSF HIV antibody ratio of less than 5.5. Intracranial abnormalities on MR imaging were associated with CSF immunologic responses to HIV. Nervous system involvement occurred in the vast majority of men with early HIV infection, but clinically significant impairment was uncommon.

The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system.

The antibody specificity index (ASI) indicates the cerebrospinal fluid (CSF)/serum difference of antibody amounts per weight unit IgG (normal less than 1.5). It has proven to be the most sensitive inflammation parameter in CSF analysis so far, more sensitive than the Western blot, the "oligoclonal" response, and the empirical differentiation of CSF immunoglobulins. By this diagnostic criterion, several benign viral meningitis cases were found to be caused by the varicella/zoster virus. The diagnostic relevance of local zoster antibody synthesis was greatest in ganglionitis cases, e.g., in zoster oticus sine herpete (facial paresis) and acute radicular syndromes of the elderly. The diagnostic significance of the local immune response against measles, rubella, and zoster antigens (MRZ response) was ascertained further. Together with oligoclonal gamma-globulin fractionation, there is now only 1 out of 100 multiple sclerosis (MS) patients left who has been found to have a normal CSF.

Brain-stem auditory evoked potentials in multiple sclerosis: the relation to VEP, SEP and CSF immunoglobulins

One hundred patients with multiple sclerosis (MS) were analysed retrospectively with respect to investigations of brain-stem auditory evoked potentials (BAEP), pattern reversal visual evoked potentials (VEP), somatosensory evoked potentials (SEP), and cerebrospinal fluid immunoglobulins (CSF-IG). BAEP were abnormal in 42% of those with normal VEP and SEP examinations, and in 38% of patients with normal CSF-IG. The chance of obtaining at least one abnormal EP was lower in patients with normal CSF-IG than in patients with abnormal CSF. When a "dispersion ratio" was included in the criteria for BAEP abnormality, the sensitivity increased compared with conventional BAEP criteria. We recommend that BAEP should still be included in the EP test battery for patients with suspected MS.

A rapid method for the direct identification of paramyxovirus in canine CSF by ultracentrifugation and negative staining as a rule out for distemper

Canine distemper is a multisystemic contagious viral disease having a worldwide distribution, a high mortality rate, and significant central neurologic system (CNS) complications. In its systemic manifestations, it is often presumptively diagnosed on the basis of clinical signs and history. Few definitive antemortem diagnostic tests exist, and most are limited to the detection of viral antigen by immunofluorescence techniques on tissues or cytologic specimens or high immunoglobulin levels in CSF (cerebrospinal fluid). Diagnosis of CNS distemper is often unreliable due to the relatively low cell count in CSF (&lt;50 cells/μl) and the binding of blocking immunoglobulins in CSF to cell surfaces. A more reliable and definitive test might be possible utilizing direct morphologic detection of the etiologic agent. Distemper is the canine equivalent of human measles, in that both involve a closely related member of the Paramyxoviridae, both produce mucosal inflammation, and may produce CNS complications. In humans, diagnosis of measles-induced subacute sclerosing panencephalitis is through negative stain identification of whole or incomplete viral particles in patient CSF.