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Background: It is unclear whether the prevalence of oligoclonal IgG bands (OCBs) in multiple sclerosis (MS) is different between northern and southern regions of Asia. Objective: This study aimed to compare the prevalence of OCBs and positive cerebrospinal fluid (CSF) findings between northern and southern regions of Japan and to investigate the association of these CSF findings with HLA-DRB1 alleles. Methods: The study included 180 MS patients from Hokkaido (northern Japan) and 184 patients from Kyushu (southern Japan). The IgG index was defined as increased if it was >0.658. Presence of CSF OCBs and/or increased IgG index was defined as positive CSF findings. Results: Positive CSF findings and OCB positivity were significantly higher in MS patients from Hokkaido than in those from Kyushu ( p < 0.0001 for both). Logistic regression analysis revealed that after adjusting for covariates that can be related to abnormal CSF IgG production, the geographic region (Hokkaido) showed odds ratios (ORs) of 4.08 and 2.57, whereas the HLA-DRB1*04:05 allele showed ORs of 0.36 and 0.30 for positive CSF findings and OCB positivity, respectively. Conclusions: The results indicate that latitude and HLA-DRB1 alleles independently affect the emergence of CSF IgG abnormalities in Japanese patients with MS.

Objectives – To investigate the significance of oligoclonal bands (OCBs) and intrathecal IgG fractions (IgGIF) for the diagnosis of multiple sclerosis (MS) in northern China. Materials and methods – OCBs in cerebrospinal fluid from 30 patients with MS, 34 with other inflammatory neurological diseases (IND) and 22 with non-inflammatory neurological diseases (NIND) were detected using isoelectric focusing. IgGIF was calculated based on corresponding formula. Results – There was no significant difference in the frequencies of positive OCBs and elevated IgGIF between the MS group and the IND group. Compared with NIND, the MS and IND groups had a significantly higher incidence of OCBs and elevated IgGIF. The sensitivity, specificity and positive result likelihood ratio of OCBs for the diagnosis of MS were 63.3%, 74.2% and 2.5 respectively; those of IgGIF were 36.7%, 84.5% and 2.4. Conclusions – The two parameters, OCBs and IgGIF are of less diagnostic value for MS in China.

An article in this issue (1) reopens an old question: Is qualitative or quantitative testing of immunoglobulins in cerebrospinal fluid (CSF) more diagnostically useful? The short answer is that each has pros and cons. In the diagnosis of multiple sclerosis, it can be misleading to perform only quantitative analysis, but it is much less problematic to perform only qualitative analysis (2). To detect IgG synthesis within the brain/CSF, a recent International Consensus has reaffirmed that qualitative is better than quantitative analysis and has gone further to state that there must be isoelectric focusing followed by immunofixation (Freedman et al., submitted for publication). The study of “free” light chains (Bence Jones proteins) has been rekindled by the report by Fischer et al. (1) in this issue, in which the authors examine commercially available antibodies in the hope that they will provide a better test for intrathecal antibody synthesis. Several specific issues can be considered as individual questions, although some may be rhetorical. I will examine clinical aspects before chemical issues. Is the assertion by Consensus neurologists, that isoelectric focusing is equivalent to the IgG index (3), correct? Yes and no. The latter (quantitative) test is not sufficient to make the diagnosis because it is only ∼75% sensitive vs >95% for the focusing (qualitative) test (3). How often should we repeat the lumbar puncture to get the correct diagnosis? It would be best to get the right answer on the first (and thus the only) occasion. However, …

The relationship between human immunoglobulin administration, and human and experimental epilepsy was investigated by reviewing the literature as well as the authors' clinical and experimental studies. The focus was: 1) the possible efficacy of IVIg; 2) the possibility that IVIg significantly increases CSF IgG and could reach the brain, and 3) the interaction between the IVIg preparation and epilepsy. There is still no formal proof of efficacy of IVIg treatment in epilepsy. However, the clinical data presented suggests that IVIg is likely to be effective in a subgroup of patients with intractable and epilepsy, and may be considered as a safe add-on medication in various types of idiopathic and symptomatic intractable epilepsy. From the authors' study on cerebrospinal fluid IgG concentrations before and after IVIg treatment in patients with epilepsy, it is concluded that the main component of the IVIg preparation (the IgG molecule) crosses the blood-CSF barrier, significantly increases CSF IgG concentration, and may reach the brain and act centrally. From a review of previous reports and two immunological studies carried out by the authors it is concluded that immunogenetic mechanisms may play a role in triggering or maintaining some types of epilepsy. In view of this, IVIg could act on epilepsy by its broad immunomodulatory mechanism of action. In addition, preliminary data are reported that contribute to the hypothesis that IVIg may have a direct neuromodulating effect.

We analyzed the cerebrospinal fluid (CSF) IgG profiles of 46 Japanese patients with relapsing and remitting types of multiple sclerosis (MS). There were 12, 13 and 21 patients, with inactive, active and both clinical conditions, respectively. The values for IgG, IgG/Alb ratio, IgG index and IgG synthesis rate were significantly higher during active than during inactive stages, but the patients with high values for these IgG profiles during active stages tend to also have high values during inactive stages. None of 33 (0%) and 2 of 34 patients (5.9%) exhibited abnormal IgG levels, 3 (9.1%) and 8 (23.5%) an abnormal IgG/Alb ratio, 9 (27.3%) and 18 (52.9%) an abnormal IgG index, and 5 (15.2%) and 14 (41.2%) an abnormal IgG synthesis rate, during inactive and active stages, respectively. Some of HLA antigen frequencies were significantly different between the patients with and without abnormal CNS IgG profiles. Increased CSF IgG was of lesser diagnostic value for MS in Japan, and seemed to be a function of immunogenetics rather than clinical activity.

In Reply. —In agreement with Baumhefner et al, we find it important that both studies, theirs and ours, came to the same conclusion: they have shown positive correlation between cerebrospinal fluid IgG concentration with the extent of cerebral lesions as measured by magnetic resonance imaging; also both of these correlate well with visual-evoked potential latencies. The fact that these results were obtained through distinctly differing methods can only add to their significance, also decreasing vulnerability caused by artifacts. Referring to the first point, please note that our global magnetic resonance imaging score incorporates both regions of hyperintensic changes, the intraparenchymatous focus, and the periventricular bright zones. If we independently calculate correlations between these two cerebral regions and the changes of the immunoglobulin content in cerebrospinal fluid, the value for the periventricular changes ( r =.43) is slightly better than for the intracerebral plaque ( r =.40), and both are highly significant. We

MS is one of the most common neurologic disorders encountered in the United States. An increase in the CSF IgG index or IgG synthesis rate within CNS, and the presence of CSF oligoclonal bands, now serve as important tools for the diagnosis of MS. Although IEF shows better identification of a number of distinct oligoclonal bands compared to AGE, the latter appears to be a more convenient system for the average hospital's clinical laboratory. These findings are not specific to MS, and similar CSF abnormalities occur in other, more rarely neurologic diseases. It is generally easy to distinguish MS from these other diseases when a thorough clinical and laboratory evaluation is carried out. However, the detection of these CSF IgG abnormalities in non-MS patients may offer an important clue to the presence of a previously unsuspected chronic infection or inflammatory process involving the CNS.

A simple, rapid and sensitive method of determining cerebrospinal fluid IgG is presented. The procedure depends upon the fact that spinal fluid gamma globulin, and two of its components (IgG and IgM) will precipitate latex particles in proportion to their concentration, and that the optical density of the supernatant solution containing unprecipitated latex particles after centrifugation is inversely proportional to the concentration of these immunoglobulins. The method is sensitive to 50 nanograms, is inexpensive, requires 0.1 ml. or less of spinal fluid, and can be performed in minutes. Preliminary studies show that it compares favorably with results obtained by radial immunodiffusion.

A retrospective analysis of quantitative and qualitative immunoglobulin G (IgG) results from 253 children who were either medically and neurologically normal or highly unlikely to have abnormalities of CSF IgG is reported. Normal values in this reference population vary with age for CSF/albumin IgG ratio and CSF/serum IgG index and are significantly different from the adult reference values. The rate of false positivity is lower for quantitative values than for qualitative IgG determinations (oligoclonal bands).

• The value of various parameters of reporting quantitative cerebrospinal fluid (CSF) IgG levels to indicate disease activity in 34 patients with clinically definite multiple sclerosis was examined. IgG alone correlated significantly with increasing degree of disability and increasing number of clinical central nervous system lesions. There was also a trend toward higher mean IgG levels when the course was relapsing and progressive as opposed to progressive or relapsing. For the IgG index, the relationships were the inverse of that noted with IgG alone. IgG-albumin ratio and IgG synthetic rate did not correlate significantly with course, number of CNS lesions, or degree of disability, and there was no statistically significant relationship between any parameter of reporting quantitative CSF IgG and age, duration of diesase, history of recent exacerbation, or area of first involvement in the nervous system. We conclude that although newer methods of reporting CSF IgG elevations in multiple sclerosis are more sensitive and some of them, more specific, in confirming a diagnosis than CSF IgG alone, this parameter remains the best marker of disease activity in individual patients.

A prospective study on 61 previously healthy patients with acute mono-symptomatic optic neuritis is reported. Interest was focused on changes in the cerebrospinal fluid and the clinical course with possible development of multiple sclerosis. At the beginning of the disease, a mononuclear pleocytosis was noted in 51 per cent of the patients, an elevated IgG level in 18 per cent, and an oligoclonal IgG distribution in 41 per cent. These results are in sharp contrast to those in multiple sclerosis. Eleven patients have so far developed definite multiple sclerosis. At onset only five of these had cerebrospinal fluid findings indistinguishable from those in multiple sclerosis, with pleocytosis and bands on electrophoresis. In five more patients, who subsequently developed multiple sclerosis, the cerebrospinal fluid IgG was normal at onset, but an oligoclonal IgG appeared during the follow-up; there was no correlation in time between the appearance of new symptoms and cerebrospinal fluid changes. In six patients with normal cerebrospinal fluid and four patients with only mononuclear pleocytosis at the onset of disease, the IgG pattern became oligoclonal on electrophoresis during the follow-up period, although the patients had no further symptoms or signs of disease. It was concluded, therefore, that the cerebrospinal fluid was often normal in the first attack of what later proved to be multiple sclerosis, and that a normal fluid did not preclude a development into definite multiple sclerosis. Sometimes IgG bands appeared in previously normal cerebrospinal fluid, although the patients had not experienced new symptoms.

Isoelectric focusing of CSF and serum IgG followed by crossed immuno isoelectric focusing and direct immunofixation as well as quantitative assay of IgG and albumin were performed in 64 clinically definite multiple sclerosis patients. Intrathecal IgG synthesis was calculated according to the CSF IgG index and de novo CNS IgGsyn. Isoelectric focusing showed abnormal IgG fractions in CSF indicating increased intrathecal synthesis of oligoclonal IgG in 99% of patients. Only 62% and 70% of multiple sclerosis patients showed values of CSF IgG indices and de novo CNS IgGsyn higher than in controls. Increased intrathecal IgG synthesis was indicated more frequently by de novo CNS IgGsyn in patients with a normal CSF IgG index than by the CSF IgG index in patients with normal de novo CNS IgGsyn. All patients with blood CSF barrier damage had increased de novo CNS IgGsyn, but only 40% had an increased CSF IgG index. Isoelectric focusing seemed to be a more sensitive method to detect an increased intrathecal oligoclonal IgG synthesis than quantitative methods. Identification of abnormal IgG fractions can be performed easily and with more reproducible results by direct immunofixation than by crossed immuno isoelectric focusing. The formula for de novo CNS IgGsyn seemed more sensitive and less influenced by blood-CSF barrier damage than the CSF IgG index to detect increased intrathecal IgG synthesis in multiple sclerosis patients. No correlation was found between the CSF IgG pattern or amounts and age, duration, clinical course or therapy of the disease.

The binding of partially purified multiple sclerosis (MS) specific brain antigens (MSG2) and of the corresponding antigens of non-MS brains (KG2) to cerebrospinal fluid IgG of patients with MS and other neurological diseases was assayed employing sandwich enzyme linked immunosorbent assay (ELISA). Assay of the antigen-antibody binding revealed that the concentration of MSG2 required for the optimum binding to IgG in the undiluted MS CSFs was lower than that of KG2 in all cases. The index for IgG binding capacity of an antigen (IgBC) was expressed as a ratio of the optical density of the enzymic products in ELISA at the optimal antigen-antibody binding to the lowest concentration of the antigen required for the optimal binding. The IgBC of MSG2 was found to be linearly correlated with the IgG concentration in the CSF of MS patients. These results indicate that IgG with specificity to MSG2 may be present in the CSF of MS patients.

SummaryAntigenic analysis of γ-globulins in the CSF of controls and patients with multiple sclerosis showed no gross deficiency in Gm or Inv typing. Concordant typing for Gm and Inv factors from serum and CSF identifies the antigenic completeness of IgG in both control and multiple sclerosis CSF. No support was obtained for the possibility that individuals with multiple sclerosis differ from controls in Gm or Inv(a) serotypes.