Intrathecal Immunoglobulin Synthesis Research Articles

Evidence of Intrathecal Immunoglobulin Synthesis in Stroke

Immune mechanisms are included in stroke pathophysiologic factors, but the frequency and role of intrathecal antibodies is unclear and diagnostic tests are not routinely performed on cerebrospinal fluid (CSF). To determine the frequency of intrathecal immunoglobulin synthesis in a well-characterized cohort of patients who experienced “noninflammatory”acute stroke. Retrospective cohort study. University hospital neurology department. Patients (n=318) with stroke who were undergoing lumbar puncture during diagnostic workup and 79 control patients. Cerebrospinal fluid–specific immunoglobulin(IgG, IgM, and IgA) synthesis was significantly(P.001) more frequent after stroke (24.8%) compared with the incidence in age- and sex-matched controls(2.5%). Furthermore, 31.3% of stroke patients demonstrated blood-brain barrier dysfunction and 18.1% displayed pleocytosis. The strong association between CSF-specific immunoglobulin synthesis and stroke suggests a role in the development of cerebral ischemia and might constitute an immunologically defined stroke subgroup.

Immunological Markers of Optimal Response to Natalizumab in Multiple Sclerosis

To explore cell subsets and molecules that changed specifically in patients with multiple sclerosis (MS) who had an optimal response to natalizumab. Natalizumab is a monoclonal antibody that inhibits the migration of activated immune cells to the central nervous system. It shows high efficacy in modifying the natural history of MS and induces freedom of disease activity in about 40% of treated patients with MS. Prospective study of intrathecal immunoglobulin synthesis and cerebrospinal fluid lymphocyte subsets in patients with MS before and 1 year after beginning treatment with natalizumab. We monitored clinical and magnetic resonance imaging activity during a median time of 2 years. Two tertiary hospitals from the Spanish National Health Service. A total of 23 patients with MS. The differences between patients free of disease activity and patients with active disease during treatment. Of the 23 patients, 10 (43.5%) remained free of disease activity during follow-up. The remaining 13 patients (56.5%) had relapses or new lesions despite natalizumab therapy. We did not find differences in demographic variables or clinical data between both groups prior to natalizumab therapy. All patients showed a decrease in cerebrospinal fluid CD4(+) cells regardless of their response to treatment. Conversely, only patients free of disease activity showed a decrease in local IgM and, to a lesser extent, in IgG synthesis. They also showed lower percentages of B cells, particularly of CD5(+) and plasmablast subsets that virtually disappeared after treatment with natalizumab. These data indicate that inhibition of intrathecal antibody synthesis is associated with a complete therapeutic response to natalizumab in patients with aggressive MS.

A Case of Amyloid-β-Related Angiitis: Histology, CSF-Findings and Treatment

Amyloid- β -related angiitis (ABRA) is characterized by vasculitis and accumulation of amyloid- β in vessel walls. In this case report we describe findings of cranial MRI, brain biopsy and cerebrospinal fluid in a patient with Amyloid- β -related angiitis. The cranial MRI displayed extensive multifocal white matter lesion and brain biopsy revealed amyloid angiopathy as well as granulomatous angiitis. In the cerebrospinal fluid our patient showed normal cell count, slightly elevated protein and intrathecal immunoglobulin synthesis which recovered during steroid therapy. We illustrate that detailed CSF analysis including tests for intrathecal immunoglobulin synthesis is very useful in monitoring the efficacy of therapy and disease activity in ABRA since cranial MRI and histology are not suitable for this purpose. In addition we propose that CSF findings may be very helpful in diagnosing ABRA and starting early immunosuppressive therapy. J Neurol Res. 2012;2(4):168-171 doi: https://doi.org/10.4021/jnr123w

Disappearance of cerebrospinal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients

Intrathecal immunoglobulin synthesis in an oligoclonal pattern is the most common immunologic abnormality detected in MS patients. Various treatments, such as immunomodulators and immunosuppressors, have not been found to modify it. Natalizumab hinders migration of encephalitogenic T-cells into the central nervous system (CNS), reducing inflammatory response. Its impact on CSF oligoclonal bands (OCBs) has not been demonstrated. This report describes its effect in four out of six patients with multiple sclerosis after a mean of 10 infusions: the CSF was negative for OCBs at the second lumbar puncture. In conclusion, natalizumab treatment can reduce CSF OCBs to undetectable levels, although the clinical significance of this observation is not yet known.

Intrathecal synthesis of IgM measured after a first demyelinating event suggestive of multiple sclerosis is associated with subsequent MRI brain lesion accrual

Background: Previous studies have demonstrated that intrathecal synthesis of IgM is observed in multiple sclerosis (MS) and correlates with a worse disease course. These results suggest that IgM participates in the formation of MS lesions. Objective: The aim of the present study was to assess the potential association between the level of intrathecal synthesis of IgM measured after a clinically isolated syndrome (CIS) and the subsequent formation of brain lesions. Methods: Fifty seven patients with a CIS and a high risk developing MS were enrolled in a longitudinal study. Examination of cerebrospinal fluid was performed after the CIS and included measures of intrathecal IgM and IgG synthesis. Patients were assessed with the same 1.5 Tesla magnetic resonance imaging (MRI) system at baseline and after a mean follow-up period of 49 months (range 36–60). Spearman Rank correlation was used to assess the potential correlations between levels of intrathecal immunoglobulin synthesis and MRI data. Results: The level of intrathecal IgM synthesis was correlated with the number of gadolinium-enhancing lesions at baseline (p = 0.01) and with accrual of brain lesions during the follow-up period (p = 0.02). By taking into account brain sub-regions, we demonstrated that the level of intrathecal IgM synthesis was only correlated with the increased number of lesions in the periventricular regions (p = 0.004). The level of intrathecal IgG synthesis was not correlated with any MRI data. Conclusion: The present longitudinal study demonstrates that the level of intrathecal IgM synthesis measured after a CIS is associated with subsequent lesion accrual during the first years of MS. This result emphasizes the involvement of IgM in plaque formation.

Cerebrospinal fluid findings in adults with acute Lyme neuroborreliosis

Presence of BB-specific antibodies in the cerebrospinal fluid (CSF) with evidence of their intrathecal production in conjunction with the white cell count in the CSF and typical clinical symptoms is the traditional diagnostic gold standard of Lyme neuroborreliosis (LNB). Few data are available on the CSF lactate concentration in European adults with the diagnosis of acute LNB. The objective of the study was to investigate the CSF changes during acute LNB. Routine CSF parameters [leukocyte count, protein, lactate and albumin concentrations, CSF/serum quotients of albumin (QAlb), IgG, IgA and IgM, and oligoclonal IgG bands] and the Borrelia burgdorferi (BB)-specific antibody index were retrospectively studied in relation to the clinical presentation in patients diagnosed with acute LNB. A total of 118 patients with LNB were categorized into the following groups according to their symptoms at presentation; group 1: polyradiculoneuritis (Bannwarth’s syndrome), group 2: isolated facial palsy and group 3: predominantly meningitic course of the disease. In addition to the CSF of patients with acute LNB, CSF of 19 patients with viral meningitis (VM) and 3 with neurolues (NL) were analyzed. There were 97 patients classified with definite LNB, and 21 as probable LNB. Neck stiffness and fever were reported by 15.3% of patients. Most of these patients were younger than 50 years. Polyradiculoneuritis was frequently found in patients older than 50 years. Lymphopleocytosis was found in all patients. Only 5 patients had a CSF lactate ≥3.5 mmol/l, and the mean CSF lactate level was not elevated (2.1 ± 0.6 mmol/l). The patients with definite LNB had significantly higher lactate levels than patients with probable LNB. Elevated lactate levels were accompanied by fever and headache. In the Reiber nomograms, intrathecal immunoglobulin synthesis was found for IgM in 70.2% followed by IgG in 19.5%. Isoelectric focussing detected an intrathecal IgG synthesis in 83 patients (70.3%). Elevated BB AIs in the CSF were found in 97 patients (82.2%). Patients with VM showed lower CSF protein concentration and CSF/serum quotients of albumin than LNB patients. In acute LNB, all patients had elevated cerebrospinal fluid (CSF) leukocyte counts. In contrast to infections by other bacteria, CSF lactate was lower than 3.5 mmol/l in all but 5 patients. The CSF findings did not differ between polyradiculoneuritis, facial palsy, and meningitis. The CSF in LNB patients strongly differed from CSF in VM patients with respect to protein concentration and the CSF/serum albumin quotient.

The association of intrathecal immunoglobulin synthesis and cortical lesions predicts disease activity in clinically isolated syndrome and early relapsing–remitting multiple sclerosis

Background: The intrathecal production of immunoglobulin (Ig) is a major biological feature of multiple sclerosis (MS), and immunopathological studies have suggested a primary role of the humoral immune response in causing irreversible brain damage. Objective: To evaluate whether, in the early phases of MS, intrathecal Ig synthesis correlates with the presence of cortical lesions (CLs), and if their association could predict the clinical course of the disease. Methods: Eighty-six patients presenting with symptoms and signs suggestive of MS underwent a diagnostic work-up that included magnetic resonance imaging and cerebrospinal fluid examination. The risk ratios (RR) for conversion to MS and for a new disease activity were calculated. Results: Patients with clinically isolated syndromes (CIS) having CLs and intrathecal synthesis of Ig had the highest risk of conversion to MS (RR = 3.4; Wald 95% CI = 1.7–7.0, p < 0.001) whereas CIS patients without CLs and intrathecal synthesis of Ig had the lowest risk of conversion to MS (RR = 0.1, Wald 95% CI = 0.02–0.7, p < 0.001). The highest risk of having disease-related activity during the follow-up was observed in CIS and relapsing–remitting MS patients showing CLs and intrathecal Ig synthesis (RR = 2.1; Wald 95% CI = 1.5–3.1, p < 0.001) while the lowest in CIS and relapsing–remitting MS patients without CLs and intrathecal Ig synthesis (RR = 0.3; Wald 95% CI = 0.1–0.7, p < 0.001). Conclusion: We observed that the association of intrathecal immunoglobulin synthesis and CLs was highly predictive of an earlier CIS conversion to MS as well as of a higher disease activity.

Clinical, diagnostic and immunological characteristics of patients with possible neuroborreliosis without intrathecal Ig-synthesis against Borrelia antigen in the cerebrospinal fluid.

The diagnosis of neuroborreliosis is not always straightforward. Intrathecal immunoglobulin (Ig) synthesis against Borrelia antigen may not be detected, at least early in the disease course. Also other neurological and infectious diagnoses have to be considered. We have studied patients with clinical possible neuroborreliosis without intrathecal Ig synthesis against Borrelia antigen in the cerebrospinal fluid (CSF) (n=17). Diagnosis was based on typical clinical history and at least one of the following findings; mononuclear leucocytosis in the CSF (n=4); typical erythema migrans >5 cm in diameter in relation to debut of symptoms (n=8); prompt clinical response to antibiotic teratment (n=14). Also other possible diagnoses had to be excluded. Seventeen patients first investigated because of suspected neuroborreliosis but later confirmed with other diagnoses were used as controls. All patients had a lumbar puncture. Borrelia specific IFN-γ and IL-4 secretion was investigated in peripheral blood (PBL) and CSF with an ELISPOT assay. Polymerase chain reaction (PCR) was used to reveal any Borrelia antigen in the CSF. Six of 17 patients with possible neuroborreliosis showed high IFN-γ secretion in peripheral blood, otherwise we found no statistically significant differences between the groups. PCR did not reveal any Borrelia antigen in CSF. The diagnosis and treatment of possible but not confirmed neuroborreliosis is a clinical challenge. The clinical response to treatment may be the best option in these cases.

Comparison of Major Immunoglobulins Intrathecal Synthesis Patterns in Ecuadorian and Cuban Patients with Angiostrongyliasis

Angiostrongylus cantonensis meningitis was first reported in Cuba in 1981, and it was recently reported in South America. The aim of this paper is to evaluate the intrathecal immunoglobulin synthesis patterns from Cuba's and Ecuador's patients with angiostrongyliasis; 8 Ecuadorian patients from two different outbreaks and 28 Cuban patients were studied. Simultaneous blood and cerebrospinal fluid samples were taken. Immunoglobulin (Ig) A, IgM, IgG, and albumin were quantified by radial immunodiffusion. Corresponding Reibergrams were applied. A three-Ig pattern was the most frequent in the two groups, but IgM was presented in all Ecuadorian young mature patients; however, in the Cuban children, only 12 of 28 patients had intrathecal IgM, but about 90% had an IgA and IgG synthesis at time of later puncture. This indicates that, with a larger amount of parasites ingested, clinical symptoms are more severe, and a higher frequency of intrathecal IgM synthesis could be observed. This is discussed as a similarity with the intrathecal IgM synthesis in African trypanosomiasis.

679 Cerebrospinal Fluid Oligoclonal Bands and Igg in Children

Introduction: Cerebrospinal fluid examination may be an essential aid in the diagnostic process of many neurological diseases in children as well as in adult patients The detection of oligoclonal bands and the assessment of IgG index contribute to information about the intrathecal production of oligoclonal IgG that may possibly occur in many neurological diseases This includes mainly demyelinating and inflammatory diseases, but elevated IgG index and/or positive oligoclonal bands can be detected also in other conditions, such as neoplastic disorders or neurometabolic diseases/ progressive encephalopaties (PE) Intrathecal immunoglobulin synthesis can be measured either quantitatively, using the IgG index, or /and qualitatively by oligoclonal bands detection. Material and methods: Cerebrospinal fluid and serum samples from 287 patients hospitalized in Child Neurology Department Medical University of Silesia in Katowice in the years 2000-2009 were analyzed The established diagnoses in examined group of patients included: demyelinating diseases (including MS, ADEM), neuroinfections (also neuroboreliosis), Guilliain -Barre syndrome (GBS), progressive encephalopathies, epilepsy, tumours of the central nervous system Agarose gel electrophoresis was used for detection of CSF oligoclonal bands. Results: Oligoclonal bands were detected in 108 In 50 patients with PE, in 39 children with neuroinfections, Guilliain-Barre syndrome -13, tumours-2 patients. Conclusions: Oligoclonal bands are important additional marker in different neurological disorders and can be used to confirm primary diagnosis.

Intrathecal Synthesis of Immunoglobulins in Patients with Unexplained Intermediate Uveitis

Purpose: To assess the value of lumbar punctures in adult patients with unexplained intermediate uveitis (IU).Methods: Retrospective study of 17 patients with unexplained IU. All the patients underwent physical examination, complete laboratory tests, and cerebrospinal MRI.Results: Out of the 12 patients who underwent a lumbar puncture, six had oligoclonal bands and/or increased IgG index.Conclusion: Intrathecal synthesis of immunoglobulins is not rare in patients with unexplained IU. A longer follow-up is mandatory to determine whether intrathecal immunoglobulins synthesis has a predictive value for subsequent progression to multiple sclerosis.

Author’s Response to Professor Reiber’s second letter concerning our article: High sensitivity of free lambda and free kappa light chains for the detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid

Author’s Response to Professor Reiber’s second letter concerning our article: High sensitivity of free lambda and free kappa light chains for the detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid

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.

Intrathecal synthesis of immunoglobulin G in vascular dementia

Serum and CSF from 53 vascular dementia (VD) patients and 50 controls were analysed to investigate the possibility of an intrathecal synthesis of IgG, defined as an elevated IgG index (greater than or equal to 7) and/or presence of oligoclonal IgG in cerebrospinal fluid (CSF), but not in serum. Five (9%) patients and no controls exhibited an intrathecal synthesis of IgG. The IgG index increased with the degree of dementia (p less than 0.05). It was positively related to presence/absence of hypertension (p less than 0.05) and correlated positively with diastolic blood pressure (p less than 0.05). The findings suggest that immunological factors might be involved in the pathogenesis of VD.

Acute peripheral facial palsy: CSF findings and etiology

CSF and serum were examined in acute and convalescence phase from 56 patients with acute idiopathic peripheral facial palsy. CSF protein analysis, viral and borrelia serology were performed. Borrelia infection was found in 9/56 cases and was often associated with inflammatory CSF findings. One patient each had serological evidence for a recent or ongoing infection with herpes simplex, varicella zoster, adeno, influenza B, echo and Epstein-Barr virus, but none had specific intrathecal antibody synthesis; 11 patients had a serological pattern compatible with a reactivated Epstein-Barr virus infection. Eleven patients displayed mononuclear CSF pleocytosis. Four of them had a borrelia infection. A disturbed blood-brain barrier was observed in 19 patients. Intrathecal immunoglobulin synthesis as indicated by elevated IgM-indices was found in 16 patients and by IgG indices in three. Nine patients had oligoclonal IgG bands in serum and CSF, three exclusively in CSF. It is concluded that patients with facial palsy often have inflammatory CSF findings, indicating a generalised central nervous system affection, and not only a mononeuritis. The importance of viral infections in the pathogenesis is still obscure. Borrelia is the most common infectious cause of facial palsy.

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.

Intrathecal synthesis of IgE in children with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis

BackgroundEosinophilic meningoencephalitis caused by the helminth Angiostrongylus cantonensis, is an emerging infectious disease in America. The objective of this paper was to determine if the intrathecal synthesis of immunoglobulin E is produced during the acute phase of the disease.MethodsThirteen patients, mean age 4.5 years were studied; a diagnostic lumbar puncture was performed and serum samples taken. Immunoglobulin E (IgE) in serum and in cerebrospinal fluid (CSF) was quantified by nephelometry. Control patients had other infections or other neurological diseases.ResultsThe mean cell count in the CSF was 500 × 10-6 cells/L and of these 23% were eosinophils. In blood the eosinophils were 13%. The chief symptoms of the patients were migraine, vomiting and fever and 50% presented some meningeal signs. IgE intrathecal synthesis analyzed by the corresponding quotient diagram (Reibergram) was observed in all patients. No intrathecal IgE synthesis was seen in control patients.ConclusionIntrathecal synthesis of IgE demonstrates the participation of this immunoglobulin in the destruction of the third stage larvae of the parasite in the CSF. The test should be considered in our environment as a tool to aid diagnosis.

Cerebrospinal Fluid Studies in Kenyan Children with Severe Falciparum Malaria.

The pathogenesis of the neurological complications of Plasmodium falciparum malaria is unclear. We measured proteins and amino acids in paired plasma and cerebrospinal fluid (CSF) samples in children with severe falciparum malaria, to assess the integrity of the blood brain barrier (BBB), and look for evidence of intrathecal synthesis of immunoglobulins, excitotoxins and brain damage. METHODS: Proteins of different molecular sizes and immunoglobulins were measured in paired CSF and plasma samples in children with falciparum malaria and either impaired consciousness, prostrate, or seizures. RESULTS: The ratio of CSF to plasma albumin (Q(alb)) exceeded the reference values in 42 (51%) children. The CSF concentrations of the excitotoxic amino acid aspartate and many non-polar amino acids, except alanine, were above the reference value, despite normal plasma concentrations. IgM concentrations were elevated in 21 (46%) and the IgM index was raised in 22 (52%). Identical IgG oligoclonal bands were found in 9 (35%), but only one patient had an increase in the CSF IgG without a concomitant increase in plasma indicating intrathecal synthesis of IgG. CONCLUSIONS: This study indicates that the BBB is mildly impaired in some children with severe falciparum malaria, and this impairment is not confined to cerebral malaria, but also occurs in children with prostrate malaria and to a lesser extent the children with malaria and seizures. There is evidence of intrathecal synthesis of immunoglobulins in children with malaria, but this requires further investigation. This finding, together with raised level of excitotoxic amino acid aspartate could contribute to the pathogenesis of neurological complications in malaria.

High sensitivity of free lambda and free kappa light chains for detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid

So far, an inflammation of the central nervous system (CNS) is diagnosed by immunoglobulin measurement in cerebrospinal fluid (CSF) and serum as well as by determination of the oligoclonal bands. With the free kappa and lambda light chains, new markers to diagnose intrathecal synthesis are available. In addition to routine diagnostic tests and the assessment of standard parameters, free immunoglobulin light chains were measured in the CSF of patients with neurological disorders. A significant agreement was found between an increase in free kappa light chain CSF serum quotients and results of the currently widely applied method of oligoclonal band measurement for the detection of intrathecal immunoglobulin synthesis. A sensitivity of 95% and 100% specificity for free kappa light chain concentrations at a cut-off of 0.41 mg/l was determined for free kappa light chains compared with oligoclonal bands. However, the free lambda light chains in 20 out of the 110 investigated samples were characterized by inconsistent behaviour. These otherwise unremarkable samples yielded increased CSF quotients, leading to the assumption that free lambda light chains represent a highly sensitive measure of intrathecal immunologlobulin synthesis. Thirteen of the 20 samples described above were obtained from patients with cerebral infarction, 4 samples derived from patients with cerebral paresis (primarily facial paresis), one sample was from a patient with multisystem atrophy and two were obtained from patients with migraine and neuralgia. These findings suggest that the high sensitivity of lambda light chains for the detection intrathecal immunoglobulin synthesis may be of benefit in establishing clinical diagnoses.

Human cerebral malaria: characterization of malarial antibodies in cerebrospinal fluid

Anti-malarial antibodies were quantified in cerebrospinal fluid (CSF) of 17 cases of cerebral malaria, 16 presumptive cases (no demonstrable parasitaemia in peripheral blood but responding to i.v. quinine therapy) of cerebral malaria, and 15 controls. A schizont-enriched Plasmodium knowlesi antigen was used in an ELISA. Anti-malarial antibodies of IgA and IgM isotypes were not detectable in most of the CSF samples analysed, although serum antibody titres were high. However, 88% of CSF from cerebral malaria and 56% of presumptive cerebral malaria cases had significant levels of IgG anti-malarial antibodies in comparison to control CSF. The antibody levels did not correlate with the severity of coma but correlated well with the duration of coma. The CSF malarial antibody titres were independent of degree of parasitaemia. The possible role of CSF anti-malarial antibodies in cerebral malaria in the light of recent demonstrations of intrathecal synthesis of immunoglobulins and deposition of immune complex in cerebral tissues is discussed.