Cerebrospinal Fluid IgA Research Articles

Successful surgical and medical treatment of a severe, acute epidural bleed in a young dog due to steroid responsive meningitis-arteritis

BackgroundSteroid responsive meningitis-arteritis (SRMA) is an immune-mediated disease of the leptomeninges and its associated blood vessels, typically responsive to corticosteroids. Clinically relevant haemorrhage is a rare finding in such patients and for this reason surgical decompression of the spinal cord is normally not considered. The diagnosis of SRMA is supported by serum C-reactive protein (CRP) increase, cerebrospinal fluid (CSF) examination, including cytology (polymorphonuclear pleocytosis in the acute form), nucleated cell-, red blood cell- and protein count, as well as by evaluating CSF and serum IgA concentrations. D-dimer concentrations in serum and CSF should be elevated as well and therefore can be also evaluated as a further diagnostic tool.Case presentationA 1.5-year-old mixed breed dog was presented with pyrexia, cervical pain and acute tetraparesis. Magnetic resonance imaging revealed an extradural mass lesion at the level of the sixth cervical vertebra, consistent with a subacute epidural haemorrhage, causing severe compression of the spinal cord. Based on the dog’s signalment, clinical history and results of the blood and CSF analyses (incl. D-dimer determination), SRMA with secondary epidural haemorrhage was suspected. Decompressive surgery was performed through a right sided partial dorsal laminectomy. Post-surgical immunosuppressive treatment was started with cytarabine and then continued with prednisolone after completion of wound healing.ConclusionsThis is the first report in which medical and surgical treatment were combined in a patient with SRMA and it highlights the possibility of performing a successful surgical intervention despite the need for immunosuppressive therapy. Moreover, while SRMA diagnosis is normally based on CSF analysis and CSF and serum IgA concentrations, D-dimer concentrations in serum and CSF were also useful in this patient.

P03-76 - Mild encephalitis inflammation subgroups in affective and schizophrenic disorders

ObjectivesLow level inflammatory Mild Encephalitis (ME) mechanisms were suspected in a subgroup of treatment resistant hospitalised affective and schizophrenic spectrum disorder patients.MethodsWe analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in paired cerebrospinal fluid (CSF) and serum samples from patients with affective (n=24) or schizophrenic spectrum disorders (n=39). Numerical and graphical interpretation of CSF protein data was performed by Reibergrams with reference to a large control group (n= 4100).ResultsIn 41% of the psychiatric patients (n=63) we observed CSF pathologies: 14% displayed intrathecal humoral immune responses, 10% slightly increased CSF cell counts (5-8/μL) and 29% had moderate blood-CSF barrier dysfunctions, in 24% as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF (p= 0.9 testing the null hypothesis for intrathecal synthesis with reference to Qmean of the reference group). In the affective (n= 24) spectrum 20% displayed a systemic immune reaction as detected by oligoclonal IgG. In probable 6% of virusspecific, bacterial or autoimmune associated disorder with CNS involvement. Elevated CSF neopterin concentration in 34% of the patients was interpreted as an increased release from astrocytes or from other glia cells.ConclusionThe low level immune response and barrier dysfunctions are discussed on the base of a ME pathomechanism in subgroups of psychiatric patients. CSF analysis is shown to be a useful diagnostic tool for differential diagnosis in psychiatric diseases.

Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: Identification of subgroups with immune responses and blood–CSF barrier dysfunction

Immune and inflammatory mechanisms are detected in a subgroup of treatment resistant hospitalized affective and schizophrenic spectrum disorder patients. We analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in paired cerebrospinal fluid (CSF) and serum samples. Numerical and graphical interpretation of CSF protein data was performed by Reibergrams with a new CSF statistics tool for nonlinear group analysis with reference to a large control group ( n = 4100). In 41% of the psychiatric patients ( n = 63) we observed CSF pathologies: 14% displayed intrathecal humoral immune responses, 10% slightly increased CSF cell counts (5–8/μL) and 29% had moderate blood–CSF barrier dysfunctions, in 24% as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF ( p = 0.9 testing the null hypothesis for intrathecal synthesis with reference to Qmean of the reference group). In the group of affective ( n = 24) spectrum disorders 20% displayed a systemic immune reaction as detected by oligoclonal IgG. CSF analysis and interdisciplinary clinical approach revealed 6% of psychiatric patients likely to represent a virusspecific, bacterial or autoimmune associated disorder with CNS involvement. Elevated CSF neopterin concentration in 34% of the patients was interpreted as an increased release from astrocytes or from other glia cells. The low level immune response and barrier dysfunctions are discussed on the base of a mild encephalitis pathomechanism in subgroups of psychiatric patients. CSF analysis is shown to be a useful diagnostic tool for differential diagnosis in psychiatric diseases.

Intrathecal production of measles-specific IgA in subacute sclerosing panencephalitis.

We measured measles-specific IgA in matched pairs of cerebrospinal fluid (CSF) and sera of patients with subacute sclerosing panencephalitis (SSPE), multiple sclerosis (MS), other central nervous system (CNS) infectious diseases (INF) and other neurological diseases (OND) by using enzyme linked immunosorbent assay. CSF and sera from 23 patients with SSPE, 15 with MS, 14 with INF, and 15 with OND were included in the study. The ratios of measles-specific IgA in CSF to serum were increased in SSPE patients compared to patients with MS, INF or OND. The data indicate a local production of measles-specific IgA in the CNS of SSPE patients.

Measurement of reference values for certain proteins in cerebrospinal fluid.

Reference values are presented for certain cerebrospinal fluid proteins and related indexes, based on determinations carried out on 46 patients with diffuse lower back pain using radial immunodiffusion and electroimmunoassay. A sex difference was noted in total protein and albumin values. The electroimmunoassay method with its sensitivity enhanced by the use of Coomassie Blue staining and optimal antiserum concentrations enabled a reference value to be determined for IgA in cerebrospinal fluid.

Central nervous system meningeal myelomatosis: a biochemical approach to a haematological disorder

Introduction Neurological complications occur in up to 50% of multiple myeloma (MM) cases, least commonly due to direct CNS involvement by meningeal myelomatosis (CNS MM), isolated cerebral plasmacytoma or localised intraparenchymal lesions. CNS MM occurs in 1% of cases. We report on the biochemical features of one such uncommon presentation. Aim To describe the role of cerebrospinal fluid (CSF) biochemical markers in the diagnosis, treatment monitoring and disease progression in CNS MM. Case history A 56-year-old female presented with a short history of bone pains, anaemia, hypercalcaemia, hyperglobulinaemia and lytic bone lesions. She was diagnosed with IgA (kappa) MM stage 2A. Despite chemotherapy, she developed pleural effusions, ascites and subsequently neurological manifestations over 12 months. Spinal magnetic resonance imaging (MRI) showed extensive myelomatosis with demonstration of CSF monoclonal plasma cells. She received intrathecal chemotherapy and cranial radiotherapy with partial improvement but died 6 weeks after recognition of CNS involvement. CSF analysis demonstrated evidence of intrathecal immunoglobulin synthesis. IgA intrathecal fraction and absolute levels of CSF IgA, free kappa light chains, ferritin and β 2 microglobulin were initially elevated and later dropped with treatment. Importantly, this drop coincided with symptomatic improvement. Conclusion CSF biochemical markers may be useful in diagnosing and monitoring CNS MM.

Prognostic value of cerebrospinal fluid IgA and IgG in multiple sclerosis.

IgA antibodies do not activate complement and may compete with and protect against myelin degradation caused by IgM and IgG in multiple sclerosis (MS). We retrospectively evaluated cerebrospinal fluid (CSF) IgA and IgG (as indices and extended indices) from 1980 to 1988 in 68 patients with definitive MS. Sixty-one of them had survived since the time of sampling (11-19 years). IgA Extended Index was significantly higher for surviving patients (median 0.65) than for the dead patients (median 0.33). CSF IgA or IgG indices did not correlate with disability, walking distance, or time from onset of symptoms to the need of walking aid. The retrospective experimental design allowed an unusually long follow-up time, but it also had the disadvantages of such a study. Thus the results warrant a prospective study to verify the prognostic vale of CSF IgA in MS.

Patrones de síntesis intratecal de inmunoglobulinas en epidemia de meningoencefalitis por echovirus 9

Epidemics of meningoencephalitis due to echovirus 9 were commonly occurred when a children population become susceptible for the first time in front the virus. To present the intrathecal synthesis pattern of immunoglobulins of the epidemic that affected Cuba in 1999 and to probe the usefulness of reibergram and antibody index in the diagnostic and characterization of the outbreak. 23 pediatric patients suffering from viral meningoencephalitis due to echovirus 9 were studied in the income moment. Serum and cerebrospinal fluid IgA, IgM, IgG, albumin and glucose were quantified. Cerebrospinal fluid total protein content and lactate were quantified. Titles of antibodies against echo 9 and Coxsackie A9 and differential cell count were performed. A mean of 555 cells/10 6 L mainly lymphocytes were obtained. Glucose in cerebrospinal fluid was over 50%, serum glucose and lactate levels below 2.1 mmol/L. In the reibergram an absence of intrathecal synthesis was predominant (15/23), IgM synthesis (6/23) and IgM+IgA (2/23). Blood cerebrospinal fluid dysfunction was observed in 15 patients. The mean antibody index was 1,8 for echo 9 and 0,9 for Coxsackie A9. The intrathecal synthesis pattern of immunoglobulins was different from other enterovirus and from echovirus 9 in non epidemic situations before this epidemic, probably with alteration of viral genome.

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.

Eosinophilia and intracranial worm recovery in interleukin-5 transgenic and interleukin-5 receptor α chain-knockout mice infected with Angiostrongylus cantonensis

We infected interleukin-5 (IL-5)-transgenic (IL-5-Tg) and IL-5 receptor alpha knockout (IL-5R alpha -/-) mice with Angiostrongylus cantonensis to determine the possible roles of IL-5 and eosinophils in A. cantonensis infection in mice. IL-5-Tg mice demonstrated significantly higher eosinophilia in bone marrow, blood and cerebrospinal fluid (CSF), lower intracranial worm recovery and smaller female worms than naive C3H/HeN mice. Both IL-5-Tg and C3H/HeN mice evoked antigen-specific serum and CSF IgA antibody responses as early as days 5 and 7 postinfection, respectively. Prominent eosinophil infiltration was noted around intracranial worms in the subarachnoid spaces of the mouse brains; eosinophils adhering to the worm surface were degranulated. In contrast, IL-5R alpha -/- mice yielded a higher worm recovery than wild-type or heterozygous mice at day 20 postinfection and failed to provoke CSF eosinophilia. These findings indicate that A. cantonensis infection in the mouse causes IL-5 production and subsequent CSF eosinophilia, the latter probably being involved in the killing of intracranial worms.

External quality assessment in clinical neurochemistry: survey of analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients

Participants (230) from Germany and 20 laboratories in 11 European countries took part in a newly designed cerebrospinal fluid (CSF) survey distributed by INSTAND. Conventional proficiency testing for albumin, IgG, IgA, and IgM in CSF and serum, for total protein in CSF, and for oligoclonal IgG in CSF and serum was combined with evaluation and interpretation of CSF/serum quotients in quotient diagrams. The correct detection of a blood-CSF barrier dysfunction and the pattern of intrathecal immunoglobulin synthesis was judged. The accuracy of CSF/serum quotients and their clinically relevant interpretation was given first priority as a new concept in quality assessment. The main result of the surveys was to confirm that CSF/serum quotients of proteins represent method-independent values approaching the quality of reference values. This finding has consequences for internal quality control of CSF analysis and for accreditation bodies. The sensitivity of the methods for quantifying IgA and IgM in CSF and for detecting oligoclonal IgG fractions is discussed.

Antibodies to antigen A60 in cerebrospinal fluid from patients with tuberculous meningitis.

Cerebrospinal fluid (CSF) anti-mycobacterial antigen 60 (A60) IgM, IgG and IgA in patients affected by meningitis of different etiologies were assayed as a rapid diagnostic test in cases of tuberculous meningitis. A commercial EIA was used to test 127 CSF samples classified as follows: tuberculous meningitis (n = 27 CSF samples from 16 patients, 6 of them with AIDS), pyogenic meningitis (n = 13), non-tuberculous aseptic meningitis (n = 43) and 44 normal CSF samples (16 of them from HIV-positive patients, 8 of whom had extraneurological tuberculosis). Anti-A60 IgM was positive only in two cases (1 tuberculous meningitis and 1 self-resolving aseptic meningitis). Positive CSF anti-A60 IgG and IgA were observed in eight and nine out of 16 patients with tuberculous meningitis, but only in four and five out of 13 samples studied prior to or in the first ten days of treatment, respectively. Most of the patients with false-positive IgG and IgA (16%) had pyogenic meningitis, but without intrathecal synthesis of antibodies. In patients with aseptic meningitis, the finding of CSF anti-A60 IgG plus IgA, initially or during follow-up, can be used as a diagnostic criterion for tuberculous meningitis, with a specificity of 100%, a positive predictive value of 1, and a negative predictive value of 0.81. However, its sensitivity is only 50% in immunocompetent patients and 16% in patients with AIDS.

Detection of oligoclonal IgA in cerebrospinal fluid samples by an isoelectric focusing procedure.

An isoelectric focusing procedure for the detection of oligoclonal IgA in cerebrospinal fluid (CSF) samples is presented. CSF IgA bands were found in 69% of patients with various inflammatory neurological diseases, in 22% of patients with other neurological diseases, but in none of the patients with non-neurological diseases. In patients with inflammatory neurological diseases we examined the relationship between an intrathecal synthesis of oligoclonal IgA and an intrathecal IgA synthesis as proved by a formula recently described by Reiber and Felgenhauer: 83% of patients with an intrathecal IgA synthesis according to the formula of Reiber and Felgenhauer also showed CSF IgA bands whereas 59% of patients without an intrathecal IgA synthesis displayed an intrathecal synthesis of oligoclonal IgA. Seventeen percent of patients with inflammatory neurological diseases were characterized by an intrathecal synthesis of oligoclonal IgA but did not show either an intrathecal IgA synthesis or an intrathecal synthesis of oligoclonal IgG, the detection of oligoclonal IgA therefore being the only evidence of an intrathecal humoral immune response in these patients.

Improved Formulae for the Judgement of Intrathecal Produced IgA and IgM in the Presence of Blood CSF Barrier Damage

In order to discriminate between transsudated and intrathecally produced IgA and IgM in patients with blood cerebrospinal fluid (CSF) barrier (BCB) damage, we developed extended indices (IgA-EI and IgM-EI) for these immunoglobulins according to the general formula for extended index of a component X in CSF: X-EI = (CSF-X/serum-X)/(CSF-albumin/serum-albumin)a where a is a parameter specific for X. For IgA parameter a was found to be 1.15 and for IgM 1.9. A preliminary evaluation of IgA-EI and IgM-EI indicated lower false positive rates as compared to CSF IgA and IgM concentrations as well as 'conventional' IgA and IgM indices in cases with BCB damage, and essentially the same rates as for the hyperbolic formulae of Reiber and Felgenhauer. The importance of reliable sampling and analytical technique for IgM in CSF is discussed.

Solid-phase immunofluorometric assay for quantification of CSF immunoglobulins: Determination of normal reference values

Because a highly sensitive method is required to quantify low concentrations of immunoglobulin (Ig) classes in cerebrospinal fluid (CSF), there have been a few papers reporting normal values of CSF IgG, IgA and IgM determined in the same samples. Enzyme immunoassay (EIA) is most frequently used, but has such drawbacks as susceptibility of enzyme to inhibition and denaturation and the requirement for additional incubation with a substrate. Therefore, solid-phase immunofluorometric assay was evaluated for quantification of CSF IgG, IgA and IgM in the nanogram range. We found this to be rapid and reproducible. The mean (SD) values of normal CSF samples obtained from 22 subjects with tension headache were 23.9 (7.6) μg/ml for IgG, 2.00 (0.90) μg/ml for IgA and 197 (87) ng/ml for IgM. The normal mean (SD) values of indexes were 0.51 (0.10) for IgG, 0.25 (0.05) for IgA and 0.044 (0.017) for IgM. These values agreed quite well with those determined by EIA. The values of CSF albumin correlated significantly with those of CSF IgG or IgA, but did not with those of CSF IgM. Levels of each of the three Ig classes in CSF and serum were significantly correlated. When CSF serum ratio was introduced, a significant correlation between the albumin ratio and each Ig ratio was found. These results suggest that the Ig content of normal CSF may depend upon that of serum and upon the characteristics of the Ig molecule.

Structural and functional relationships between the immune and central nervous systems in Alzheimer's disease

AbstractAn intact blood–brain barrier (BBB) is a prerequisite to maintaining functional compartmentalization between the neural and immune systems. Only small amounts of immunoglobulins access the internal milieu of the brain, probably via so‐called “functional leaks” existing in the region of the circumventricular organs. However, with aging and disease, globular and other proteins can be found within the cerebrospinal fluid (CSF) because of disruption of perhaps both the BBB and the blood–CSF barrier. There is an increase of lgG, IgA, albumin, and prealbumin in CSF of patients with Alzheimerapos;s disease. The presence of these proteins is taken to be pathognomonic for neuronal impairment, and they are believed to be associated with the amyloid deposits of senile plaques. Our studies have shown that albumins may occur naturally in some CNS neurons. Immunocytochemical studies with antibodies to rat serum albumin have shown the uptake of this serum protein by nerve endings with retrograde transport to perikarya of their cells of origin. Likewise, we have also shown than an endogenous albuminoid substance occurs in arcuate nucleus neurons of the hypothalamus that immunoreact with antibodies to bovine serum albumin. The arcuate nucleus neurons are neurosecretory and have neurohemal endings in contact with blood vessels of the hypothalamohypophysial vasculature. These neurohemal contacts are capable of taking up albumins from the blood for retrograde transport. We, therefore, hypothesize that immunoglobulins may be similarly incorporated by neurons having neurohemal contacts and access the CNS in this and several other ways. We have localized endogenous gammaglobulins in brains of both immunized and nonimmunized rabbits with antisera against rabbit lgG generated in sheep, goat, and mouse. However, serum proteins are also found in neurons without neurohemal contacts. Taken together, albumins, globulins, and other substances may reach the interior milieu of the CNS via: (1) endothelial transcytosis, (2) neurohemal contacts whereby neurons take up blood‐borne substances and retrogradely transport them to their perikarya, (3) circumventricular organs (inter‐ and intraependymal transport), (4) functional leaks at the interface of the circumventricular organs and the brain, (5) a nose–brain pathway, (6) a meningeal pathway, and (7) transsynaptic transport, i.e., substances passed from a neurohemal cell to other connecting neurons.

Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system

The cerebrospinal fluid (CSF)/serum concentration quotients of albumin and the immunoglobulins G, A and M have been determined for 396 patients with a normal blood CSF barrier function or a pure barrier impairment without a humoral immune response within the central nervous system. The ratios between the concentration quotients of the three immunoglobulins and that of albumin increase in a nonlinear fashion with progressive impairments of the blood CSF barrier, i.e. the molecular size dependent discrimination of the protein transfer (‘selectivity’) decreases. The upper reference values of the concentration quotients for the whole range of passive transfer comply with the hyperbolic function: Q( IgX) = a b √ Q(Alb) 2 + b 2 − c with different constants a b , b 2, c for IgG (0.8, 15 × 10 −6, 1.8 × 10 −3), IgA (0.72, 80 × 10 −6, 5.1 × 10 −3) and IgM (0.65, 150 × 10 −6, 7.5 × 10 −3). With these discriminatory functions the locally synthesized fractions IgX(loc) of IgG, IgA and IgM in CSF can be calculated by the general formula: IgX(loc) = [Q( IgX) − a b √Q( Alb) 2 + b 2 + c] . IgX(Ser).

Cerebrospinal fluid protein findings during prophylaxis and treatment of neuromeningosis in leukaemic patients

Methotrexate and Aracytin commonly employed in prophylaxis and treatment of leukaemic neuromeningosis, can induce neuromeningeal injury. Cerebrospinal fluid (CSF) protein disturbance may reflect the damage. In this study we have examined 141 CSF samples collected by lumbar puncture from 51 subjects: 15 normal controls and 36 leukaemic patients during the prophylaxis or the Central Nervous System (CNS) involvement treatment. In all the CSF samples, total proteins, IgG and IgA were examined. CSF total protein and albumin levels increased in the presence of leukaemic neuromeningosis and also after a prolonged CNS prophylaxis or therapy. The same behaviour was found in IgG levels. The IgA levels did not show any modification. We conclude that these parameters are not reliable indices of leukaemic CNS involvement.

Rapid diagnosis of central nervous systembrucellosis by ELISA

The diagnosis of central nervous system (CNS) brucellosis was made by determining Brucella-specific IgG, IgM and IgA in cerebrospinal fluid (CSF) specimens, using an enzyme-linked immunosorbent assay (ELISA) method. A total of 68 CSF specimens including 10 from patients with brucellosis of the nervous system, 4 with Brucella infection but without CNS involvement, 38 with meningitis other than due to Brucella and 16 with no meningitis were studied. Of the 10 CSF specimens from patients with CNS brucellosis, Brucella-specific IgG was detected in all 10, IgM in 7 and IgA in 8. The 10 patients were also seropositive for anti-Brucella IgG and IgM, and 9 were seropositive for IgA. No Brucella-specific IgG, IgM or IgA was detected in the CSF of 4 patients with brucellosis but without CNS involvement, even though the blood of these patients had high titres of anti-Brucella IgG, IgM and IgA. In addition, none of the CSF specimens from the 38 patients with meningitis other than due to Brucella, or from the 16 patients without meningitis, had detectable anti-Brucella antibodies. This study indicates that the Brucella ELISA on CSF is a reliable, rapid, sensitive and specific assay in the diagnosis of CNS brucellosis.

Cerebrospinal Fluid IgM, IgA, and IgG Indexes in Systemic Lupus Erythematosus

Paired serum and cerebrospinal fluid (CSF) specimens from 13 patients with systemic lupus erythematosus (SLE) and central nervous system involvement (CNS-SLE) were studied for CSF IgM, IgA, and IgG indexes (indicators of intrathecal immunoglobulin synthesis) and CSF-serum albumin quotient (Q albumin) (an indicator of blood-brain-barrier function). We also studied 20 patients with noninflammatory neurologic diseases and seven patients with SLE without CNS involvement for comparison. In addition to an increase in the CSF IgG index, IgM and IgA indexes also were elevated in patients with CNS-SLE. All three indexes decreased significantly when CNS manifestations subsided by successful treatment. The Q albumin was normal in most patients. The elevation of CSF immunoglobulin indexes may be a result of polyclonal B-lymphocyte activation within the CNS, rather than the leak of immunoglobulins from the systemic circulation into the CNS. Since these indexes reflect CNS disease activity in SLE, they may be a successful tool for the management of SLE.