Cerebrospinal Fluid Gamma Globulin Research Articles

Electrophoretic morphology of gamma globulins in cerebrospinal fluid of multiple sclerosis and other diseases of the nervous system

Electrophoretic morphology of gamma globulins in cerebrospinal fluid of multiple sclerosis and other diseases of the nervous system

Clinical and CSF cyto-proteic findings in 23 patients with CSF eosinophilia.

Clinical diagnosis and cerebrospinal fluid (CSF) protein pattern were studied in 23 patients who had eosinophilic granulocytes in the CSF. Clinical data revealed that an inflammatory disorder of the central nervous system (CNS) was evident in 20 cases. A lymphoid reaction and elevated CSF total protein were found in most of the cases, but the most important finding was an increase of CSF gamma-globulin in 12 patients, of whom 10 had oligoclonal patterns. Our results may give support to a relationship between intrathecal eosinophilic reaction and inflammatory diseases of the CNS with subacute or chronic course accompanied by intrathecal synthesis of immunoglobulins.

Glutaraldehyde-enhanced immunofixation: a sensitive new method for detecting oligoclonal immunoglobulin M

A new, specific and economical method with enhanced sensitivity for rapid detection of IgM oligoclonal bands in unconcentrated cerebrospinal fluid (CSF) is presented. It is based on the use of c glutaraldehyde during immunofixation of electrophoresed specimens and utilizes peroxidase-conjugates F(ab') 2 fragment of anti-IgM antibody to avoid cross-reactivity with other CSF gamma globulins. It is able to detect 1 ng of IgM banded protein in electrophoresed CSF. Using this method, oligoclonal IgM was mainly detected in inflammatory and infectious conditions of the central nervous system.

Localized CNS brucellosis: report of 7 cases.

Seven patients with brucellar infection localized in the central nervous system (CNS) are reported. This series represent 3.5% of all brucellosis cases in our hospital. There was a conspicuous absence of systemic signs and symptoms. The clinical course was characteristically protracted. Meningitis (acute, chronic, transient and recurrent) and progressive myeloradiculopathy were the 2 clinical patterns. Cranial nerve neuropathy was frequent, eight nerve involvement being present in 4 cases; transitory ischemic attacks and subarachnoid haemorrhage occurred in 2. Routine laboratory determinations were negative or non-specific. Cerebrospinal fluid (CSF) findings included hypoglycorrhachia, lymphocytic pleocytosis and hyperproteinorrhachia. There was also a remarkable increase in the gamma-globulin and IgG values with morphology of oligoclonal bands in CSF electrophoresis. Brucella agglutination titers were low or absent in serum and/or CSF. By contrast, Coombs tests were always positive and higher titers were found in serum and CSF. After treatment a persistent CSF positive Coombs test at low titers together with an isolated increase in CSF gamma-globulin and IgG values were detected in cured patients. Brucella blood cultures were negative, but CSF cultures were positive in four cases. Rifampin and doxycycline seems to be the treatment of choice. These agents must be maintained at least for 4 months in order to avoid relapses. Corticosteroids may be helpful at the beginning of treatment. Outcome is generally favourable in this disorder. We conclude that clinical and biological characteristics of localized CNS brucellosis are in accordance with those already described in other types of localized brucellosis.

A review of systemic nonspecific immunosuppressive treatment of multiple sclerosis

This article is a critical review of the literature about the effects of systemic immunosuppression on patients with multiple sclerosis. Azathioprine (or 6-mercaptopurine), chlorambucil, cyclophosphamide, levamisole, melphalan, podophyllin and other drugs by themselves and in combination therapies with adrenocortical steroids, thoracic duct drainage, and antilymphocyte sera or globulins are discussed. A decrease in frequency of relapses, rate of progression, cerebrospinal fluid gamma globulin and oligoclones, and in cerebrospinal fluid pleocytosis can be achieved, at least temporarily, by certain treatments. Lack of appropriate controls makes it difficult to evaluate these results. Therefore, immunosuppressive therapy of multiple sclerosis should be considered highly experimental. Systemic immunosuppression is difficult to achieve and maintain, has a high incidence of side effects, and the long-term consequences are not well established. More studies of drug combinations, with stratification of patients and with follow-up observations for at least 5 years, will be necessary before firm conclusions can be reached. Controlled studies of cyclophosphamide or azathioprine might be started now but other modalities also might be used in exploratory or pilot studies. These studies will require a significant investment by patients, biomedical personnel, and funding agencies, and should not be entered into casually.

Isoelectric focusing of gamma globulins in cerebrospinal fluid from patients with multiple sclerosis.

The technique of isoelectric focusing has been adapted for rapid clinical analysis for globulins in cerebrospinal fluid with use of commercially prepared horizontal-slab acrylamide gels. The globulin fraction is concentrated by ammonium sulfate precipitation, which allows more of the relevant protein to be applied, use of a wider range of total protein concentrations, and higher resolution than is true for previously described methods. Critical variables include a constant concentration and volume of IgG, a constant low temperature of the acrylamide gel, and sensitive staining with Coomassie Brilliant Blue G-250. The apparatus used is adaptable for other electrophoretic procedures in the clinical laboratory, and the use of commercially prepared gel slabs is more convenient, more reproducible, and requires less time than other methods.

The in vivo development of plasma cells

This is a case study of a patient with the clinical diagnosis of meningoencephalitis. It demonstrates the in vivo development of plasma cells in the central nervous system. All the stages of in vitro mitogen-induced lymphocyte transformation previously described by light and electron microscopy are recapitulated in this analysis of cerebrospinal fluid. It is postulated that this represents a local humoral immune reaction in the central nervous system and provides morphologic support for the concept that the gamma globulin in cerebrospinal fluid is produced locally in part, in addition to its origin from the plasma proteins.

Agarose electrophoresis of cerebrospinal fluid in multiple sclerosis. A simplified method for demonstrating cerebrospinal fluid oligoclonal immunoglobulin bands.

The gamma globulins in cerebrospinal fluid from almost all patients with multiple sclerosis migrate in agarose electrophoresis as abnormal discrete populations, so-called oligoclonal bands. Such bands have also appeared in cerebrospinal fluid from patients with other types of inflammatory pathology such as neurosyphilis, acute idiopathic polyneuropathy, and subacute sclerosing panencephalitis. The demonstration of cerebrospinal fluid oligoclonal bands may aid in the evaluation of patients with early or atypical multiple sclerosis. This report describes a simple method for demonstrating cerebrospinal fluid oligoclonal bands using readily available commercial reagents and apparatus. Oligoclonal bands were seen in cerebrospinal fluid from all patients with clinically definite multiple sclerosis, even though some had normal cerebrospinal fluid gamma globulin levels, and in most patients with presumptive multiple sclerosis or other inflammatory conditions of the nervous system. They were not seen in cerebrospinal fluid of control patients with a variety of other neurologic diseases.

The course of multiple sclerosis cases with extremely high gamma-globulin values in the cerebrospinal fluid.

40 selected cases of multiple sclerosis (MS) with extremely high gamma-globulin values in the cerebrospinal fluid (CSF) (over 25 rel%, upper normal limit 7.5 rel%) were matched with the same number of MS patients with normal CSF findings. Surprisingly, no definite relationship could be shown between the amount of CSF gamma-globulins and the various clinical criteria in MS, such as age, type of progression, duration of illness, remission, extent of plaques and gravity of the disease.

Multiple Sclerosis: A New Hypothesis

MULTIPLE SCLEROSIS: A NEW HYPOTHESIS HUBERT S. MICKEL* Introduction "Despite a continuing advance in knowledge concerning many aspects of multiple sclerosis and the existence of several not entirely implausible aetiological theories, a number of experienced workers in this field have professed that they would not be too surprised if the final answer to the questions of causation and pathogenesis in multiple sclerosis involved entirely novel or hitherto unsuspected disease processes" [I]. Multiple sclerosis, as a clinical and pathological entity, was first described by Cruveilhier [2] and Carswell [3]. The term, "sclerose en plaques," appeared in the literature in 1866 in a report by Vulpian, in which two cases were described by Charcot [4]. Charcot called attention to mild cases andformes frustes, but further description of the disease —including the triad of nystagmus, scanning speech, and intention tremor—is also attributed to him [5-7]. Many different etiologies have been suggested for multiple sclerosis. A prominent consideration has been an infectious origin of the disease. In 1884, Marie stated that it might be a complication of a number of infectious illnesses [8]. Charcot suggested a relationship to an antecedent illness and cited cases that had followed cholera, smallpox, and typhoid fever. Bullock, in 1913 [9], and Gye, in 1921 [10], claimed to have transmitted multiple sclerosis from man to rabbits, using cerebrospinal fluid injections. In these and other such studies, the failure to identify a specific organism has been a stumbling block. Pette has pointed out the ?Departments of Neurology, Harvard Medical School and Children's Hospital Medical Center, 300 Longwood Avenue, Boston, Massachusetts 021 15. Supported by grants from the Office of Naval Research, Department ofthe Navy, NR 908-108; United Cerebral Palsy Research and Educational Foundation R224-69; National Institutes of Health Developmental Neurology grant NS-HD 09704; National Institutes of Health Children's Hospital Medical Center Mental Retardation and Human Development Research program HD-03773; and National Institutes of Health grant HE-10098. I express my gratitude to the following individuals for their comments and suggestions on reviewing the manuscript prior to its submission for publication: Dr. Charles Barlow, Children's Hospital Medical Center, Boston; Dr. Torben Fog, Kommunehospitalet, Copenhagen, Denmark; and Dr. Floyd Gilles, Children's Hospital Medical Center, Boston. I am also grateful to Lynn Gerrick for her assistance in typing the manuscript. Perspectives in Biology and Medicine · Spring 1975 I 363 absence of a preliminary phase in this disease, seen in most viral infections , as \vell as the predilection of most known neurotropic viral infections for gray matter [11-12]. The possibility of a latent viral infection causing multiple sclerosis is widely considered, as suggested by Gadjusek , Gibbs, and Alpers [13]. The hypothesis that the disease is associated with diffusion of a circulating myelinolytic toxin or enzyme was proposed by Marburg in 1906 [14], and again by Brickner in 1931 [15]. A vascular, thrombogenic etiology of multiple sclerosis was postulated by Putnam in 1933, by the observation of the close proximity of the plaques to small venules in both brain and spinal cord [16-17]. Torben Fog has elaborated on this hypothesis with extensive observations [18]. A dietary etiology of multiple sclerosis was proposed by Swank, who has claimed improvement by treating multiple sclerosis patients with low-fat diets, especially restricted in fats ofanimal origin [19-20]. Others have shown that there is a decrease in polyunsaturated fatty acids in plasma [21-24] and in brain [25-28] in patients with multiple sclerosis. These observations have been advanced as evidence for a dietary hypothesis for the disease. A diet relatively low in polyunsaturated fatty acids and high in saturated fatty acids is considered to predispose to the disease. The lack of confirmation of these decreases in linoleic acid in plasma and brain in cases of chronic multiple sclerosis has been advanced as evidence against the saturated fatty acid dietary hypothesis [29-30]. An autoimmune etiology is currently also considered possible. The accumulation oflymphocytes and plasma cells in areas ofdemyelination, as well as the deposition of gamma globulin in the same area, supports this view. However, there is no raised plasma gamma globulin level in multiple sclerosis. On the other hand, cerebrospinal fluid gamma globulin levels...

Effect of Pantopaque myelography on cerebrospinal fluid fractions.

✓ Cerebrospinal fluid (CSF) changes induced by Pantopaque myelography were determined by comparing samples of CSF from 47 patients with disc symptoms, obtained before and after myelography. Cell count, total protein, colloidal gold curve, and CSF protein electrophoretic patterns were compared. An immediate and persistent modest lymphocytosis was found. Total protein and CSF gamma globulin were elevated 3 weeks after myelography and throughout the remainder of the 80-day study period. This CSF profile characterizes a chronic inflammatory reaction induced by Pantopaque.

Electrophoretic morphology of gamma globulins in cerebrospinal fluid of multiple sclerosis and other diseases of the nervous system.

SUMMARYCSF protein electrophoresis in agar gel was performed in 2,043 patients. Among them, 323 patients were classified as having MS. The essential feature of the gamma globulins in CSF from MS patients and other inflammatory CNS diseases resided in their restricted heterogeneity distribution. This peculiar electrophoretic pattern occurs in 75.2 to 86.9% of MS patients, depending upon the diagnostic category (possible, probable, or definite). The differences were significant. In MS patients there was also a positive correlation between the degree of disability and the frequency of gamma pattern when Grade I and Grade III were compared, but no correlation was found between the duration and course of the disease on the one hand and the CSF gamma globulin changes on the other hand. In the other patients, this frequency varied between 2. to 5.1%, except for the group with inflammatory CNS diseases in which it reached 39.6%. The diagnostic value of the method employed is discussed and emphasized.

Eletroforese em papel das proteínas do líquido cefalorraqueano e seu valor prático em clínica neurológica

O presente trabalho é baseado no estudo dos perfis eletroforéticos das proteínas do líquido cefalorraqueano de 300 pacientes normais ou portadores de diversas entidades neurológicas. Analisando êste material, os autores verificaram que a gama-globulina é a fração protêica cuja variação tem grande importância na prática neurológica para o diagnóstico diferencial. A principal conclusão a que chegaram indica que há dois diferentes mecanismos que atuam na alteração do perfil eletroforético das proteínas do líquor: a) alteração da permeabilidade da barreira hêmato-encefálica; b) liberação intratecal de gama-globulina. Portanto, o método eletroforético não permite o diagnóstico de determinada entidade neurológica, mas indica o mecanismo fisiopatológico em atividade.

A COMPARISON OF THE MEASUREMENT OF GAMMA GLOBULIN IN CEREBROSPINAL FLUID BY ELECTROPHORETIC AND IMMUNOLOGICAL METHODS.

The results of measurement of gamma globulin in the cerebrospinal fluid by electrophoresis and by an immunological technique are compared. In some fluids marked discrepancies were found. Such discrepancies, when substantiated and better understood, may have diagnostic significance.

Cerebrospinal fluid gamma-globulin in multiple sclerosis. Observations on its nature.

Cerebrospinal fluid gamma-globulin in multiple sclerosis. Observations on its nature.

Progression of amaurotic family idiocy as reflected by serum and cerebrospinal fluid changes

Serial biochemical studies were performed in nineteen cases of amaurotic family idiocy (Tay-Sachs disease), one case of Niemann-Pick's disease (NPD) and one case of diffuse sclerosis, at monthly intervals for periods up to thirty months. An attempt was thus made to equate certain consistent changes in serum and cerebrospinal fluid with the clinical and pathologic evolution of these disorders. Serum aldolase, initially normal in the early phase of amaurotic family idiocy (AFI), became significantly elevated after approximately nine months of clinically evident illness, coincident with the emergence of skeletal muscle atrophy. The latter was believed to be caused by the observed acceleration of lower motor neuron breakdown. In the protracted phase of AFI, the serum aldolase generally regressed to normal values. A roughly similar pattern was obtained in the case of NPD, which is a disorder presenting a central nervous system anatomic component almost identical with AFI. No comparable changes in serum aldolase were seen in the case of diffuse sclerosis or other long tract or upper motor neuron diseases studied. Serum GO-transaminase (GO-T) was consistently and markedy elevated during the entire course of all cases of AFI and also in the case of NPD. The hypertransaminasemia tended to lessen during the protracted phase of these disorders. In contrast, the child with diffuse sclerosis (and patients with other neurologic disorders) showed normal or minimally elevated values. High GO-T levels were also noted in the cerebrospinal fluid of the AFI and NPD cases. The cerebrospinal fluid GO-T was depressed in the case of diffuse sclerosis. These data indicate that the extensive and continuing ganglionic disintegration of AFI is sensitively mirrored by elevated GO-T levels in these two biologic fluids. The total serum neuraminic acid was non-specifically elevated in the three neurologic disorders principally studied, in contradistinction to the singular elevation of this substance in the cerebral tissues of AFI. However, the serum protein-linkage distribution of this substance in these three diseases showed a distinctly abnormal pattern as indicated by the ratios formed by globulin neuraminic acid total neuraminic acid and globulin neuraminic acid globulin protein . A significant depression of serum and cerebrospinal fluid gamma globulin also was observed in AFI. The evidence presented seems to indicate the possibility that the pathophysiologic substrate of AFI may extend beyond the confines of ganglionic degeneration.

Cerebrospinal fluid gamma globulin as a diagnostic test for multiple sclerosis.

Neuronal degeneration represents a pathogenetic hallmark after different brain insults, such as ischemia and status epilepticus (SE). Excessive release of glutamate triggered by pathophysiologic synaptic activity has been put forward as key mechanism in this context. In response to pathophysiologic synaptic activity, multiple signaling cascades are activated that ultimately initiate expression of specific sets of genes, which may decide between neuronal survival versus death. Recently, a core set of genes [“activity-regulated inhibitor of death” (AID) genes] including the transcription factor (TF) NPAS4 (neuronal PAS domain protein 4) has been found to provide activity-induced protection against neuronal death caused by excitotoxic stimulation. However, the downstream targets of AID action mediating neuroprotection remained so far unknown. Here, we have identified synaptotagmin 10 (Syt10), a vesicular Ca²⁺ sensor, as the first neuroprotective effector protein downstream of the TF NPAS4. The expression of Syt10 is strongly upregulated by pathophysiologic synaptic activity after kainic acid (KA) exposure and its absence renders mouse hippocampal neurons highly susceptible to excitotoxic insults. We found NPAS4 as critical for the increase in Syt10 levels and in turn the ability of NPAS4 to confer neuroprotection against KA-induced excitotoxicity to be severely diminished in Syt10 knock-out neurons. In summary, our results point to an important role for signaling of the NPAS4–Syt10 pathway in the neuronal response to strong synaptic activity as a consequence of excitotoxic insults. <b>SIGNIFICANCE STATEMENT</b> Aberrant synaptic activity is observed in many neurological disorders and has been suggested as an important factor contributing to the pathophysiology. Intriguingly, pathophysiologic activity can also trigger signaling cascades mediating potentially compensatory neuroprotection against excitotoxic insult. Here, we identify a new neuroprotective signaling cascade involving the activity-induced transcriptional regulator NPAS4 and the vesicular Ca²⁺-sensor protein synaptotagmin 10 (Syt10). Syt10 is required for NPAS4 to protect hippocampal neurons against excitotoxic cell death. NPAS4 in turn controls the activity of the Syt10 gene, which is strongly induced by pathophysiologic activity. Our results uncover an entirely unexpected, novel function of Syt10 underlying the response of neurons to pathophysiologic activity and provide new therapeutic perspectives for neurological disorders.

The photometric microdetermination of gamma globulin in cerebrospinal fluid by a quantitative protein flocculation-ninhydrin reaction.

The photometric microdetermination of gamma globulin in cerebrospinal fluid by a quantitative protein flocculation-ninhydrin reaction.

Quantitative determination of gamma globulin in cerebrospinal fluid; its application in multiple sclerosis.

Quantitative determination of gamma globulin in cerebrospinal fluid; its application in multiple sclerosis.

Quantitative estimation of the albumin and gamma globulin in normal and pathologic cerebrospinal fluid by immunochemical methods

1. 1. An immunochemical method for the estimation of albumin and gamma globulin in cerebrospinal fluid is outlined. 2. 2. Normal values for albumin and gamma globulin are presented. 3. 3. In fifteen of sixteen cases of neurosyphilis, increases in gamma globulin were found. The highest values were found in those patients with active neurosyphilis and the lowest in patients who had shown a favorable response to therapy. 4. 4. Eight of fourteen patients with multiple sclerosis showed an increased spinal fluid gamma globulin. 5. 5. Data on cerebrospinal fluid albumin and gamma globulin in a variety of other diseases are presented.