Clinical correlates of abnormal brain-stem auditory evoked responses in multiple sclerosis

Brain-stem auditory evoked responses (BAERs) were examined in 178 patients with multiple sclerosis (MS) and compared to the frequency of abnormalities in visually evoked responses (VERs) and in CSF electrophoresis. In clinically definite MS, BAERs were abnormal in 61% and a significant relationship was noted between disability due to MS and the frequency and severity of BAER abnormalities. In suspected MS, BAERs showed evidence of a second lesion in 14% whereas VERs indicated a second lesion in 24%. Abnormal BAERs in patients with suspected MS with brain-stem signs were significantly associated with the presence of truncal and limb ataxia. In progressive possible MS, abnormal BAERs were found in 49% but indicated a second lesion in 35% of patients and were significantly related to the duration of illness. In progressive possible MS, abnormal VERs but not abnormal BAERs, were significantly associated with the presence of CSF oligoclonal IgG banding. Normal BAERs in association with clinical brain-stem abnormalities were found in 24% of patients with clinically definite MS, 50% with suspected MS and 33% with progressive possible MS.     

Suspected and clinically definite multiple sclerosis: the relationship between CSF immunoglobulins and clinical course.

CSF immunoglobulins were examined in 103 patients with clinically definite multiple sclerosis, 106 patients with either suspected or progressive possible multiple sclerosis and 72 patients with other neurological diseases. Raised CSF IgG index and oligoclonal banding were found in 71% and 75% of clinically definite multiple sclerosis patients respectively and both tests were abnormal in 11% of patients with other neurological diseases. The CSF IgG index and the presence of oligoclonal IgG did not relate to the severity or duration of established disease in these patients. In patients with suspected and progressive possible multiple sclerosis, both a raised IgG index and the presence of oligoclonal banding were found significantly more frequently than in the OND group. Abnormalities of these parameters were significantly correlated with the presence of an abnormal evoked response in these patients (chi 2 = 10.16 p less than 0.01). When 47 patients with suspected multiple sclerosis were studied prospectively the presence of oligoclonal banding at presentation was associated with development of further disease activity.     

Clinical and CSF findings in multiple sclerosis patients with or without IgG oligoclonal bands at isoelectric focusing examination of CSF and serum proteins

The IgG oligoclonal bands in CSF can be found in high percentage of MS patients but the existence of a limited number of cases with CSF normal IgG profile is known as well. In the present study 63 out of 70 patients with definite MS and 24 out of 35 with probable MS had oligoclonal bands in the CSF at the isoelectric focusing examination. The 18 patients with normal CSF IgG pattern did not show any statistically significant difference as concerns the age at onset and the duration of the disease, the functional disability, the course of the disease and the quantitative CSF parameters (IgG index, IgG synthesis and serum/CSF albumin quotient). The oligoclonal pattern does not seem of value to discriminate different groups of MS patients but it remains essentially of great diagnostic importance in this disease.     

IgG ratios and oligoclonal IgG in multiple sclerosis and other neurological disorders

The findings are reported of various CSF abnormalities, including IgG indices and oligoclonal IgG, in 160 patients with multiple sclerosis of differing diagnostic certainty and 146 patients with other neurological disorders.

An abnormal IgG index, defined as the ratio of IgG/albumin in CSF to that in serum, has been found in 77.7% of definite MS cases, falling to a figure of 32.1% in the single lesion group. A tendency, reported previously, for IgG levels to be higher in disabled patients, particularly those with a short history or early onset, has been confirmed.

Oligoclonal IgG, on the other hand, has been found in 56% of definite MS cases, less frequently than in most other reported series. Analysis of the literature suggests considerable variability in the finding of oligoclonal IgG in other than definite MS, and in other neurological disorders. The possibility that subjective factors are partly responsible for this variability, rather than discrepancies in patient selection requires consideration, and suggests that CSF electrophoresis and IgG estimations are complementary aids in the diagnosis of multiple sclerosis.

Differences have been expressed regarding the relationship of oligoclonal IgG to clinical parameters of the disease. Further sequential analysis of the development and variability of the oligoclonal pattern in MS is required.     

Multiple sclerosis: diagnostic usefulness of cerebrospinal fluid.

Early, atypical, or progressive cases of multiple sclerosis (MS) may be hard to diagnose. Until recently, assays of the most common abnormalities in cerebrospinal fluid were not available in clinical diagnostic laboratories, but now they can be done with relative ease and adequate standardization. With the newer techniques the CSF is abnormal in more than 90% of clinically definite cases of MS, and determination of such changes can be a major aid in diagnosis. The most common CSF abnormalities are discussed: elevation of immunoglobulin G(IgG), expressed as percentage of total protein; elevation of the IgG/albumin index; and presence of oligoclonal IgG bands. Not only does assessment of these CSF proteins provide an improved aid to diagnosis, but their study may furnish important clues to the cause and pathogenesis of MS as well.     

Value of oligoclonal IgG fractions in the cerebrospinal fluid and blood in neurologic diseases

CSF and serum from 700 patients were analysed by isoelectric focusing (IEF). Oligoclonal bands in the high alkaline range were detected in 156 cases. Ninety-five patients were diagnosed as having multiple sclerosis (MS), 38 various CNS inflammatory disorders, 18 vascular, neoplastic or degenerative and 5 patients other neurological diseases. IEF was positive in 98% of clinically definite and 85% of clinically probable MS cases and was found to be more sensitive as compared to intrathecal IgG production and evoked potentials. Neither the presence of oligoclonal IgG nor the banding distribution pattern is specific for any disease. Further characterization may be obtained by immunofixation if the antigen is known.     

Intrathecal synthesis of free immunoglobulin light chains in multiple sclerosis

Objective – The detection of oligoclonal immunoglobulin free light chains (FLC) in the diagnosis of multiple sclerosis (MS) was compared to IgG isoelectric focusing. Material and methods – Cerebrospinal fluid and serum samples from 69 patients with possible first attacks of MS, 50 patients with clinically definite MS (CDMS), and 118 patients with other neurological diseases (OND) were analyzed. IgG and FLC oligoclonal bands were detected by isoelectric focusing and immunoperoxidase staining. Results – Intrathecal synthesis of IgG, kappa FLC, and lambda FLC oligoclonal bands, respectively, was seen in 92%, 92%, and 86% of MS patients; in 61%, 62%, and 64% of patients with possible first attacks of MS; and in 3%, 3%, and 8% of the patients with OND. In control patients without IgG synthesis intrathecal lambda FLC synthesis was more common than kappa FLC synthesis ( P =0.03). Conclusion – Kappa FLC detection proved as useful as IgG analysis for the laboratory diagnosis of MS whereas the presence of intrathecal lambda FLC synthesis was less specific.     

Free light chains in the CSF in multiple sclerosis

Summary The presence of free light chains (FLC) was investigated in 32 patients with clinically definite or laboratory supported definite multiple sclerosis (MS), 2 patients with neurosyphilis and 10 normal controls. The detection of FLC in unconcentrated cerebrospinal fluid (CSF) was performed by means of agarose isoelectric focusing, followed by transfer of proteins to nitrocellulose membranes, double immunofixation, avidin-biotin amplification and peroxidase staining. Bands due to FLC were clearly demonstrated in the CSF of 28 MS patients; 3 of them showed only kappa FLC, 10 only lambda FLC, while 15 had both kappa and lambda FLC. The CSF of 4 MS patients was FLC negative. In both cases of neurosyphilis FLC bands were observed. FLC were never found in normal CSF. Among the indexes of intrathecal immunological activity (IgG oligoclonal bands, FLC, IgG index, intra-blood-brain barrier IgG synthesis rate, pleocytosis) the FLC proved to be the second most frequent abnormality in MS CSF, the presence of IgG oligoclonal bands being the first. In one MS case an FLC band was found, while all the other indexes of intrathecal IgG production were negative. A high correlation was found between an elevated number of FLC and pleocytosis. The presence of FLC in MS CSF seems to indicate a recent immunological stimulation leading to increased synthesis of FLC within the CNS.     

Monosymptomatic sensory symptoms and cerebrospinal fluid immunoglobulin levels in relation to multiple sclerosis

Of 53 patients with monosymptomatic paresthesiae, 55% had oligoclonal bands and 28% an elevated cerebrospinal fluid (CSF) IgG index. Over a mean observation period of 64 months, nine patients developed clinically definite multiple sclerosis (MS); all of these patients had IgG bands, illustrating the prognostic importance of this CSF aberration. Two lumbar punctures more than one year apart were performed in 31 of the patients, of whom 20 had oligoclonal bands. This abnormality was constant between the time of punctures in all subjects except one, thus behaving as in MS. Similarly, the CSF findings in the 11 patients without oligoclonal bands remained normal over the observation period. The majority of patients with oligoclonal bands had cells in their CSF producing immunoglobulin of one or more of the three main classes, while none of those without oligoclonal bands displayed immunoglobulin-producing cells in CSF. Occurrence of oligoclonal bands in CSF is common in patients with paresthesiae and increases the risk for future development of MS.     

Oligoclonal IgA bands in multiple sclerosis and subacute sclerosing panencephalitis

CSF oligoclonal IgG bands are often found in MS or cerebral diseases in which there is chronic antigenic stimulation. Using agarose isoelectric focusing followed by immunoblotting, we found oligoclonal IgA bands in CSF from 16 of 20 randomly selected patients with MS, 7 of 7 with subacute sclerosing panencephalitis (SSPE), and 0 of 10 with noninflammatory neurologic or psychiatric disease. IgA bands did not correlate with the course or stage of MS. Serial samples from two patients with MS and one with SSPE demonstrated only minor changes in IgA banding pattern. One MS patient without oligoclonal IgG bands had oligoclonal IgA bands, indicating that the latter test may be helpful in the diagnosis of MS.     

The cerebrospinal fluid in multiple sclerosis. Quantitative assessment of intrathecal immunoglobulin synthesis by empirical formulae

Intrathecal synthesis of IgG occurs in more than 90% of patients with clinically definite multiple sclerosis. The prevalence and significance of intrathecal synthesis of IgA and IgM are, however, less thoroughly characterized. We estimated intrathecal synthesis of IgG, IgA and IgM with various empirical formulae. The concentrations of albumin, IgG, IgA and IgM and the presence of IgG oligoclonal bands were determined in CSF and serum from 350 patients, including 97 with clinically definite multiple sclerosis. Intrathecal synthesis of IgG oligoclonal bands was detected in 95% of patients with multiple sclerosis (95% confidence interval 88–98%). The IgG-index, an extended IgG-index, and a hyperbolic IgG formula performed approximately equally in identifying patients with MS, but they were all inferior to the detection of IgG oligoclonal bands. In quantitative measurements, the extended immunoglobulin indices appeared to perform well; studies comparing the extended IgA- and IgM-indices to qualitative analyses (electrophoresis or isoelectric focusing) are, however, needed to confirm this. Detection of intrathecal synthesis of IgA of IgM was of little value in the diagnosis of multiple sclerosis.     

Optic neuritis: findings on MRI,CSF examination and HLA class II typing in 60 patients and results of a short-term follow-up

Optic neuritis (ON) is a common first manifestation of multiple sclerosis (MS), and examination of patients with ON provides opportunities to study the early clinical stages of MS. This prospective study compares results of brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) examinations and HLA-Dw2 phenotyping in 60 consecutive patients with ON. At a median of 17 days after the onset of ON, 69% had oligoclonal IgG bands, and at a median on 79 days after onset, 53% had multiple ( 3) white matter lesions on MRI. Subgroup analyses revealed that MRI abnormalities and oligoclonal IgG bands were equally common in patients examined early or late after the onset of ON. Strong correlations were found between the presence of MRI abnormalities and oligoclonal IgG bands. The HLA-Dw2 phenotype was significantly increased in ON patients compared with controls, but also significantly different from a group of MS patients from the same geographical area. A significant relation was found between Dw2 phenotype and oligoclonal IgG bands. During a mean follow-up time of about 2 years, the diagnosis in 17 of the patients changed to clinically definite MS. Initially, 16 of them had oligoclonal IgG bands and 12 had three or more MRI lesions. Both MRI and CSF studies are important diagnostic tools in the work-up of ON patients.     

Relation between benign course of multiple sclerosis and low-grade humoral immune response in cerebrospinal fluid.

The prognosis in multiple sclerosis (MS) is related to the presence of an abnorma humoral immune response within the central nervous system: 14/17 MS patients (82%) without oligoclonal CSF IgG displayed no or slight disability after a mean duration of MS of 17 years, while 53% of 88 patients with oligoclonal CSF IgG had a benign course after a mean duration of 13 years (p less than 0.05). A benign course also was more often accompanied by a normal CSF IgG index. MS patients without oligoclonal CSF IgG had elevated CSF/serum ratios of albumin in 6%, and of the complement factors C3 in 0% and C4 in 6%, as against 20%, 27% and 37%, respectively, in MS patients with oligoclonal CSF IgG.     

Discontinuos distribution of IgG oligoclonal bands in cerebrospinal fluid from multiple sclerosis patients

To test the effect of sampling on the detection of immunoglobulin (Ig) cerebrospinal fluid (CSF) abnormalities, we analyzed the first and last 1 ml fraction of 10 ml obtained during a single CSF removal from 27 multiple sclerosis (MS) patients and six patients with other neurological diseases. IgG index, hyperbolic function, and IgG synthesis rate decreased between the first and the last CSF aliquot. Discordant results were found in (15%) MS patients. In (7.5%) clinically definite MS patients, the number of CSF oligoclonal bands (OCB) decreased between the first and the last fraction. In one of the two patients, the three OCB visualized in the first fraction were not found in the last. We conclude that fractionated sampling may partially account for the absence of OCB in the CSF of some definite MS patients.     

Discontinuous distribution of IgG oligoclonal bands in cerebrospinal fluid from multiple sclerosis patients

To test the effect of sampling on the detection of immunoglobulin (Ig) cerebrospinal fluid (CSF) abnormalities, we analyzed the first and last 1 ml fraction of 10 ml obtained during a single CSF removal from 27 multiple sclerosis (MS) patients and six patients with other neurological diseases. IgG index, hyperbolic function, and IgG synthesis rate decreased between the first and the last CSF aliquot. Discordant results were found in 4/27 (15%) MS patients. In 2/27 (7.5%) clinically definite MS patients, the number of CSF oligoclonal bands (OCB) decreased between the first and the last fraction. In one of the two patients, the three OCB visualized in the first fraction were not found in the last. We conclude that fractionated sampling may partially account for the absence of OCB in the CSF of some definite MS patients.     

Detection of oligoclonal free kappa chains in the absence of oligoclonal IgG in the CSF of patients with suspected multiple sclerosis

BACKGROUND: Oligoclonal free kappa bands are present as frequently as oligoclonal IgG bands in the cerebrospinal fluid (CSF) from patients with definite multiple sclerosis (MS) and can even occur in the absence of oligoclonal IgG. As such, they too are markers of an ongoing intrathecal immune process. OBJECTIVES: To determine how frequently oligoclonal free kappa bands are detectable in the CSF from patients with clinical signs and symptoms suggestive of MS in the absence of CSF restricted oligoclonal IgG. METHODS: An immunoaffinity mediated immunoblotting technique specific for free kappa chains was used, after isoelectric focusing of paired CSF and serum samples from 33 patients with clinical signs and symptoms suggestive of MS but without CSF oligoclonal IgG. CSF data were correlated with MRI results in the context of the new diagnostic criteria from McDonald et al. RESULTS: Eighteen CSF samples contained oligoclonal free kappa bands (54%), mainly from patients with motor dysfunction (83%) and optic neuritis (64%). All patients with a positive MRI according to Barkhof's criteria (n = 6) had free kappa bands in their CSF. CONCLUSIONS: (1) Oligoclonal free kappa bands in the CSF are related to the dissemination of MS lesions; (2) such bands should be looked for in oligoclonal IgG negative CSF, and (3) the presence of free kappa bands in the CSF may be a substitute for oligoclonal IgG in the McDonald's criteria for diagnosis of MS.     

Oligoclonal antibodies in the diagnosis of multiple sclerosis and other diseases of the nervous system

The detection of CSF oligoclonal IgG is one of the most useful laboratory tests to aid in the diagnosis of multiple sclerosis. Oligoclonal IgG is synthesized within the CNS and is usually detected in the CSF by agar and agarose gel electrophoresis or by isoelectric focusing. Oligoclonal IgG is present in about 90-95% in patients with clinically definite MS. There is a predominance of kappa light chains and IgG1 and IgG3 subclasses in oligoclonal IgG in MS. The specificity of oligoclonal IgG in this disease is still unknown, as antibodies, for instance against measles virus or myelin basic protein, represent only a minimal part of intrathecally synthesized IgG.     

The use and abuse of the cerebrospinal fluid IgG profile in the adult: A practical evaluation

Cerebrospinal fluid (CSF) samples from 150 patients with multiple sclerosis (MS) and 190 patients with other neurological disorders were examined with a battery of tests (the IgG profile) to detect quantitative and qualitative abnormalities in CSF IgG. The CSF IgG profile consisted of an IgG/albumin (IgG/alb) ratio, an IgG index, and examination by agarose gel electrophoresis (AGE) and isoelectric focusing (IF) to detect oligoclonal bands. The tests were compared for diagnostic accuracy, including false-positive results. The IgG/alb ratio was less reliable in confirming the diagnosis of MS, but no significant difference in accuracy was found among the other three methods. IF tended to identify more possible and probable MS cases than did AGE but gave a higher rate of false-positives. The IgG index and IgG synthesis rates showed no significant difference in their ability to identify MS patients. Steroid administration decreased the incidence of abnormal IgG/alb ratios and IgG indices, but not abnormal oligoclonal bands. Central nervous system (CNS) infections or immunological diseases involving the CNS produced a 28 to 40% incidence of abnormalities in the CSF. Neither the patient's age, sex, duration of illness, activity of disease, nor longitudinal course correlated with the CSF findings. A few (1%) control neurological patients had all components in the CSF IgG profile abnormal. For most routine clinical purposes the IgG index and AGE are sufficient for confirmation of diagnosis, and the IgG index was the best single test in our series.     

Oligoclonal bands in cerebrospinal fluid: a comparative study of isoelectric focusing, agarose gel electrophoresis and IgG index

OBJECTIVE: To compare the sensitivity and specificity of isoelectric focusing (IEF) with immunofixation, agarose gel electrophoresis (AGE) and the IgG index in detecting intrathecally synthesized IgG in multiple sclerosis (MS) and in other nervous system disorders. MATERIALS AND METHODS: Cerebrospinal fluid (CSF) and serum from 147 patients with various nervous system diseases, 20 of whom had MS, were compared with IEF, AGE and the IgG index. RESULTS: CSF-restricted oligoclonal bands (OCB) were found in 20 of 20 patients with MS using IEF and in 9 of 20 using AGE. OCB were found in 12 patients with other nervous system disorders (OND) using IEF and 4 using AGE. The mean IgG index was 0.50 in OND and 0.96 in MS (P< 0.0001). Of 20 MS patients, 9 had an IgG index above the defined cut-off value of 0.72. CONCLUSIONS: IEF is about twice as sensitive as AGE in detecting OCB in MS. IEF is also far superior to the IgG index in determining intrathecal IgG synthesis.     

IgG synthesis rate in evaluation of multiple sclerosis in a community hospital

We obtained CSF and serum from 21 patients with definite MS in a community hospital. Ninety percent of patients had an elevated IgG synthesis rate, comparable with the sensitivity of oligoclonal bands (0.95) or the IgG index (0.90) and better than the IgG% (0.47) in definite MS. We found that no area hospital routinely employs the IgG synthesis rate. The low-sensitivity IgG% and the dimensionless IgG index can be abandoned. The linear IgG synthesis rate and oligoclonal band scanning should be the CSF tests of choice.