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Prevalence of cerebrospinal fluid oligoclonal IgG bands in Greek patients with clinically isolated syndrome and multiple sclerosis

Clinical Neurology and Neurosurgery, 10, 115, pages 2094 - 2098

Abstract

Lower prevalence of cerebrospinal fluid oligoclonal IgG bands (IgG-OCBs) has been reported in multiple sclerosis (MS) patients from Southern Europe compared to other western countries.

Objectives

We aimed to determine the prevalence of CSF OCBs in Greek MS patients and to examine their relation with some selected clinical and demographical features.

Methods

Included patients fulfilled the 2005 McDonald criteria for definite MS (CDMS) or clinically isolated syndrome (CIS) and had a spinal tap performed between 2006 and 2010. Paired CSF and plasma samples were analyzed using isoelectric focusing followed by IgG-specific immunofixation. A pattern of two or more bands present only in the CSF was defined as positive. OCB status was correlated with age at disease onset, initial symptomatology, relapse rate, disease subtype, disease duration, medication, EDSS score and MSSS.

Results

Of the 231 included patients (53.2% with CDMS and 48.6% with CIS) 67.5% had OCBs. The prevalence of positive patterns did not differ between CIS and CDMS patients (67.6% vs. 67.5%, respectively). OCB-positive patients were younger than OCB-negative patients (35.2 ± 10.3 vs. 38.7 ± 11.8 years respectively,p = 0.022) and had more frequently cervical spinal cord lesions (x2 = 7.08,p = 0.008). No difference was observed between the two subgroups in the other studied disease parameters.

Conclusion

Despite the lower frequency of positive IgG-OCB patterns in our patients, both subgroups were mostly similar with regard to their clinical and demographic characteristics suggesting that the OCB status lacks prognostic significance in MS.

Keywords: Multiple sclerosis, Oligoclonal bands, Cerebrospinal fluid, Isoelectric focusing.

1. Introduction

There is evidence that multiple sclerosis (MS) patients in southern European countries show positive cerebrospinal fluid (CSF) restricted oligoclonal IgG bands (IgG-OCBs) less frequently compared to MS patients from Northern Europe. According to previous reports, the prevalence of IgG-OCBs in CSF from MS patients in the Czech Republic is 81%, in Portugal 82.6%, in Spain 87.7% and in Turkey 85.7%, while in Scandinavian countries, the UK and Canada is more than 90%[1] and [2]. Moreover, it is unclear whether the CSF antibodies have prognostic significance in MS and whether OCB-negative patients constitute a different disease subtype. In literature the association of disease severity with the presence of CSF OCBs is controversial. Several researchers have reported that the prognosis of OCB-positive patients with MS is worse than that of OCB-negative patients[3], [4], and [5]. Other investigators found no differences with respect to disease severity, disease course, or age at onset between OCB-positive and OCB-negative subgroups[6], [7], and [8]. In a Turkish study, patients with CSF OCBs were found to have female predominance, better clinical course with less disability and better prognosis [2] . Female predominance in OCB-positive MS patients was also found by Nakashima and co-workers [6] .

There are no data regarding the presence of OCBs in the CSF of MS patients from Greece. Thus, we aimed to determine the prevalence of IgG-OCBs in Greek MS patients and to investigate the correlation between the presence of OCBs and some selected clinical and demographic characteristics.

2. Methods

2.1. Patients

We included 231 patients. Included patients fulfilled the revised McDonald criteria [9] for definite MS or clinically isolated syndrome (CIS) and had a spinal tap performed between 2006 and 2010. All patients were screened for other conditions that could mimic early MS, including connective tissue diseases, other autoimmune diseases, sarcoidosis or infections. The clinical data of all patients were reviewed retrospectively from the clinical notes and records of the MS clinic. The following parameters were recorded: sex, age at disease onset, age at lumbar puncture (LP), initial symptomatology, subtype of MS, disease duration from onset to the time of LP, annualized relapse rate and time to secondary progressive MS (SPMS). Disability was assessed using the Expanded Disability Status Scale (EDSS) [10] at the time of LP and also with the MS Severity Score (MSSS) [11] .

2.2. Determination of the intrathecal IgG production

The CSF samples were obtained by LP with simultaneous serum sampling, and were stored at −80 °C.

The intrathecal IgG production was determined by calculation of the IgG-index in the CSF. First the total IgG fraction and the albumin concentrations were measured in serum and CSF, by means of a commercially available immunonephelometric assay using an automatic immunonephelometer (reagents and equipment provided by Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany). For the evaluation of the blood-brain barrier permeability the albumin index (Qalb) was calculated as the quotient of the albumin concentration in CSF to the concentration in serum multiplied by 103. Values >10 were considered as positive for a disruption of the blood-brain barrier and increased permeability. For the assessment of the intrathecal IgG production, the IgG-index was calculated as the quotient of the quotient IgGCSF/IgGserto the quotient AlbCSF/Albser. Values ≥0.65 were considered as indicative for a local IgG production in CSF.

2.3. Immunoelectrophoretic detection of OCBs in CSF

Detection of the OCBs in the CSF was performed using a commercially available system including reagents and equipment (SEBIA, Evry Cedex, France). The methodology referred to the isoelectric separation of the CSF and serum proteins in an agarose gel in paired specimens of serum and unconcentrated CSF, after setting up equivalent IgG concentrations, through serum dilution. The assay was carried out in two stages: (1) isoelectric focusing on agarose gel to fractionate the proteins and (2) immunofixation with peroxidase labelled anti-IgG antiserum and subsequent incubation with the chromogenic substrate TTF3, to detect IgG oligoclonal bands and to demonstrate the difference, or lack of, in the distribution of IgG in the CSF and serum.

Paired serum and CSF samples were processed side-by-side and compared for the presence of any banding present in the CSF but not in the serum sample. A pattern of two or more bands present only in the CSF was evaluated as indicative for intrathecal IgG production (positive).

2.4. Statistics

Statistical analysis was performed with SPSS (version 17.0). All variables were checked for normality by the Shapiro-Wilks and for homogeneity of variances by the Levene test. Continuous variables were compared using independent samplest-test and categorical data using Chi-square test. Nonparametric tests (Mann–Whitney test) were used for comparison of albumin and IgG index, disease duration, EDSS, MSSS and annualized relapse rate, due to deviations from normal distribution. All analyses were two-tailed and the level of statistical significance was set to 5%.

3. Results

The clinical, demographic characteristics and laboratory findings of the included patients are summarized inTable 1 and Table 2. Of the 231 patients, 53.2% had clinically definite MS (CDMS) and 46.8% CIS. The most common initial symptoms were sensory (32.5%), followed by brainstem–cerebellar (26.4%) and optic neuritis (22.5%). The female to male ratio was 2. Mean annualized relapse rate [for patients with relapsing–remitting MS (RRMS)] was 0.79 ± 0.63 and mean time to SPMS was 9.9 ± 6.5 years. A minority of patients were receiving treatment for MS at the time of CSF examination (11.8%).

Table 1 Demographic and clinical data of the patients.

    CIS RRMS SPMS PPMS-PRMS
%   46.8% 39.8% 6.5% 6.9%
  N (males/females) 108 (41/67) 92 (26/66) 15 (3/12) 16 (7/9)
Age (years)   34.0 ± 9.2 34.7 ± 10.1 45.7 ± 9.6 52.8 ± 8.2
Age at disease onset (years)   33.6 ± 9.2 27.8 ± 8.1 30.7 ± 11.2 47.1 ± 10.6
Initial symptom Optic neuritis 27 22 3 0
  Sensory 37 30 5 3
  Motor 4 3 3 9
  Brainstem-Cerebellar 28 27 3 3
  Multifocal 12 10 1 0
  Other 0 0 0 1
Disease duration (years)   0.0 (0.0–0.0) 6.0 (2.0–10.0) 14.0 (8.0–24.0) 2.5 (2.0–8.8)
EDSS   1.5 (1.0–2.0) 2.0 (1.0–3.0) 4.0 (3.0–6.0) 4.0 (3.0–6.0)
MSSS   2.0 (0.6–4.1) 2.7 (1.3–5.3) 5.8 (2.4–6.8) 7.6 (5.9–9.0)
Relapse rate     0.6 (0.4–1.0)    
Treatment No treatment 97 72 9 9
Cortizole 3 0 1 0
Immunomodulating 0 14 3 0
Immunosuppresive 0 0 1 2
Natalizumab 0 1 0 0
Brain MRI Negative 5 1 2 1
  Positive 103 90 13 15
Gd-enhancement Absent 55 48 11 13
  Present 48 41 4 2
Cervical MRI Negative 32 10 0 2
  Positive 62 71 15 12
Thoracic MRI Negative 5 7 1 1
  Positive 12 19 3 4
VEP Negative 45 27 4 5
  Positive 49 47 8 5
OCBs Negative 35 26 7 7
  Positive 73 66 8 9
IgG nominal Negative 38 24 8 7
  Positive 70 68 7 9
IgG index   0.8 (0.6–1.2) 0.8 (0.6–1.1) 0.6 (0.6–1.3) 0.7 (0.6–0.8)
OCB-IgG category OCB− IgG− 31 18 6 7
  OCB+ IgG+ 66 60 6 9
  OCB+ IgG− 7 6 2 0
  OCB− IgG+ 4 7 1 0
albumin index   4.4 (3.1–5.5) 4.7 (3.4–6.3) 3.8 (2.9–4.8) 5.5 (4.2–7.4)

Data are presented as mean ± SD or median (25th–75th percentile). CIS: clinically isolated syndrome; RRMS: relapsing–remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; PPMS: primary progressive multiple sclerosis; PRMS: progressive relapsing multiple sclerosis; EDSS: Expanded Disability Status Scale; MSSS: multiple sclerosis Severity Score; VEP: visual evoked potentials; OCBs: Oligoclonal bands.

Table 2 Demographic and clinical data of the patients according to OCB status.

  All patients CIS CDMS
    RRMS SPMS PPMS-PRMS
OCB+ OCB− OCB+ OCB− OCB+ OCB− OCB+ OCB−
N(males/females) 231 73 (27/46) 35 (14/21) 66 (17/49) 26 (9/17) 8 (2/6) 7 (1/6) 9 (4/5) 7 (3/4)
Age (years) 36.3 ± 10.9 32.8 ± 8.8 36.5 ± 9.7 34.6 ± 9.8 34.9 ± 11.1        
    34.0 ± 9.2   34.7 ± 10.1   45.7 ± 9.6   52.8 ± 8.2  
Age at disease onset (years) 32.1 ± 10.3 32.5 ± 8.8 36.1 ± 9.7 28.7 ± 8.3 25.7 ± 7.4        
    33.6 ± 9.2   27.8 ± 8.1   30.7 ± 11.2   47.1 ± 10.6  
Disease duration (years) 2.0 (0.0-6.0)                
    0.0 (0.0–0.0)   6.0 (2.0–10.0)   14.0 (8.0–24.0)   2.5 (2.0–8.8)  
Annualized relapse rate       0.6 (0.4–1.0) 0.6 (0.3–1.0)        
        0.6 (0.4–1.0)          
EDSS 2.1 ± 1.6 1.3(1.0–2.0) 1.5 (1.0–2.3) 2.0 (1.0–3.0) 2.0 (1.0–3.0)        
    1.5 (1.0–2.0)   2.0 (1.0–3.0)   4.0 (2.0–6.5)   4.0 (3.0–6.0)  
MSSS 3.6 ± 2.7 2.3 (0.6–4.1) 2.0 (0.6–3.8) 3.3 (1.3–5.4) 2.1 (1.2–3.5)        
    2.0 (0.6–4.1)   2.7 (1.3–5.3)   5.8 (2.4–6.8)   7.6 (5.9–9.0)  
IgG-index   0.9 (0.7–1.3) 0.5 (0.5–0.6) 0.9 (0.8–1.2) 0.6 (0.5–0.7) 0.6 (0.6–1.3)   0.7 (0.6–0.8)  

Data are presented as mean ± SD or median (25th–75th percentile). CDMS: clinically definite multiple sclerosis.

From all the patients, 67.5% had positive OCBs and 66.7% had a positive IgG-index (≥0.65) ( Table 3 ). OCB-positive patients were significantly younger than OCB-negative patients (35.2 ± 10.3 vs. 38.7 ± 11.8 years, respectively,p = 0.022). No differences were observed between OCB-positive and negative MS patients in initial symptomatology (p = 0.761), age at disease onset (p = 0.097), relapse rate (p = 0.625), disease subtype (p = 0.384), disease duration (p = 0.661), EDSS (p = 0.149) and MSSS (p = 0.547) scores. Furthermore all laboratory characteristics (MRI data and VEPs) were similar in the two patient groups, with the exception of more frequent positive cervical MRI (defined as the presence of ≥1 demyelinating lesion in the cervical spine) in OCB-positive patients (x2 = 7.08,p = 0.008).

Table 3 Comparison of clinical and laboratory characteristics of OCB+ and OCB− patients.

    OCB N Mean or Median P-Value
Sex(M:F) Negative 29:46   0.233
Positive 48:108  
Age (years) Negative 75 38.7 ± 11.8 0.022
Positive 156 35.2 ± 10.3
Age at disease onset (years) Negative 75 33.7 ± 11.9 0.097
Positive 156 31.3 ± 9.3
Initial symptom Optic neuritis Negative 15   0.761
Positive 37  
Sensory Negative 26  
Positive 49  
Motor Negative 5  
Positive 14  
Brainstem-cerebellar Negative 19  
Positive 42  
Multifocal Negative 10  
Positive 13  
Other Negative 0  
Positive 1  
Disease subtype CIS Negative 35   0.384
Positive 73  
RRMS Negative 26  
Positive 66  
SPMS Negative 7  
Positive 8  
PPMS-PRMS Negative 7  
Positive 9  
Disease duration (years) Negative 75 2.0 (0.0–7.0) 0.661
Positive 156 2.0 (0.0–6.0)  
Albumin index Negative 75 4.9 (3.7–7.8) 0.002
Positive 156 4.3 (3.0–5.5)  
IgG index Negative 75 0.6 (0.5–0.6) 0.0001
Positive 156 0.9 (0.7–1.3)  
MSSS Negative 64 2.3 (1.3–5.7) 0.547
Positive 118 2.9 (1.1–5.7)  
EDSS Negative 72 2.0 (1.0–3.0) 0.149
Positive 149 2.0 (1.0–3.0)  
Annualized relapse rate Negative 23 0.7 (0.3–1.0) 0.625
Positive 64 0.6 (0.4–1.0)  
Time to SPMS (years) Negative 6 8.0 (6.5–12.8) 0.842
Positive 9 10.0 (5.0–15.5)  
MRI cervical (neg/pos) Negative 23/49   0.008
Positive 21/111  
Gd-enhancement (Absence/presence) Negative 44/28   0.415
Positive 83/67  

Data are presented as mean ± SD or median (25th–75th percentile). M: males, F: females.

Elevated IgG-index correlated with younger age (34.6 ± 10.3 vs. 39.7 ± 11.4,p = 0.001) and age at disease onset (30.9 ± 9.4 vs. 34.4 ± 10.3,p = 0.014). IgG-index was more frequently elevated in MS patients with lesions in cervical MRI (x2 = 13.3,p = 0.0001).

The same analyses were performed in the subset of patients with CDMS. The percentage of OCB-positive CDMS patients was unchanged (67.5%). Positive OCBs did not correlate with any of the demographic and disease characteristics, neither with positive cervical MRI (p = 0.438). Elevated IgG-index correlated with younger age (36.1 ± 10.9 vs. 42.4 ± 12.1,p = 0.003).

4. Discussion

In the present study, the incidence of OCB-positive patients fulfilling the diagnostic criteria for MS was found to be 67.5%. The prevalence of OCBs is higher than that reported in oriental populations [12] but lower than the frequency found in other Western countries, particularly in northern Europe and Canada, where have been reported rates of over 90% [1] . Moreover, the percentage of positive patterns is even lower than the values reported in other southern European and Mediterranean countries, where it ranges from 80% to 90%[2] and [4]. Interestingly, the prevalence of IgG-OCBs in our patient population is similar to that reported in MS patients from Western Australia, where it was found to be 66.4% [13] . In fact, we included a large proportion of patients with CIS. While it has been established that the OCB status (either positive or negative) does not alter during the course of MS, some CIS patients with initial absence of OCBs may later express OCBs [3] . Although a lumbar puncture was not repeated in our OCB-negative CIS patients, the prevalence of positive patterns did not differ between patients with CIS and those with CDMS (67.6 vs. 67.5%, respectively). Therefore, the inclusion of a high percentage of CIS patients in our study could not adequately explain this discrepancy. It has been suggested that the detection methods may play a role in the low prevalence of CSF OCBs. In the present study, OCB detection was performed by isoelectric separation in agarose gel, followed by ultrasensitive immunofixation, According to the International Consensus, this method is considered the “gold standard” for the detection of OCBs in the CSF[14] and [15]. However, in commercially available or in house prepared diagnostic kits, differences in the quality of the reagents and the technical performance conditions, can lead to differences in specificity and sensitivity[1] and [16]. In addition to that, in cases with only two or three weak OCBs in the CSF, there is always a factor of subjectivity in evaluating the results, either as positive or negative. Another factor that could be associated with this higher proportion of patients lacking OCBs is possible immunogenetic differences of the Greek MS population. It has been consistently reported that HLA-DRB1*15 antigen is more frequent among OCB-positive than OCB-negative patients[2], [7], [12], [17], [18], and [19]. Additionally, DRB1*15 patients were found to have a higher percentage of OCB positivity compared with patients carrying other alleles [18] . It is intriguing that although the carriage frequency of HLA-DRB1*15 allele in an Australian population with MS was similar to Northern European MS patients, higher than the frequency reported in Mediterranean MS populations (54.5% vs. 24–34%), the percentage of OCB positivity was comparable with that found in our study[2], [18], [19], and [20]. In Sweden, OCB-negative MS seems to be associated with HLA-DRB1*04, which is rare in Northern Europe but common in Asia and the Mediterranean countries[7], [21], and [22]. Although interdependence of HLA-DRB1 genotype and OCB status has been repeatedly suggested, interactions between HLA-DRB1 alleles that may vary in different populations were found to influence the frequency of OCBs [19] . The possible role of the immunogenetic basis in the emergence of positive or negative OCBs in the Greek MS population is a matter of further investigation [20] .

To date there is no definite explanation for the absence of OCBs in a subgroup of MS patients. OCBs are immunoglobulins (IgG, IgM, or IgA) that are produced by specific B-cell clones, possibly long-lived plasma cells, within the CNS, reflecting an ongoing inflammatory response. Since no specific antigen has been detected hitherto to be recognized by the CSF IgG, the IgG-OCBs are considered by most researchers to target various types of nonspecific ubiquitous viral antigens and to be enhanced by a bystander response [23] . Thus, it could be hypothesized that the intra-CNS B-cell response may vary quantitatively, and that a subgroup of MS patients does not show evidence for an augmented local IgG response that is reflected in the CSF. On the other hand, the absence of OCBs might reflect a problem in sensitivity of OCB detection as an indicator of intrathecal immunoglobulin synthesis, at least in a subgroup of patients. Data supporting these speculations have been recently reported by Brecht and co-workers [24] . In their study, an intrathecal, polyspecific antiviral immune response was detected in a significant proportion of the 46 clinically definite OCB-negative MS patients that were investigated. Interestingly, the prevalence of antiviral antibodies was higher in chronic progressive forms of the disease compared with the relapsing-remitting forms, indicating broadening and strengthening of the antiviral immune response with increasing disease duration [24] .

Apart from the lack of explanation for the absence of OCBs in a proportion of patients, the clinical significance of their presence remains controversial. In our study, OCB-positive patients were significantly younger than OCB-negative patients. Although no statistically significant difference was observed between OCB-positive and negative MS patients in age at disease onset, OCB-positive patients had a trend towards a younger age of onset. This correlation of the presence of OCBs with younger age of the patients could be possibly attributed to the association of HLA-DRB1*15 both with a higher percentage of OCB positivity and a lower age of onset that have been consistently reported[25], [26], [27], and [28]. It is noteworthy that in a large Swedish study the effect of HLA-DRB1*15 on age at onset was evident only in OCB-positive patients [27] .

Another notable finding of our study is the higher frequency of cervical spinal cord lesions among OCB-positive patients. Although a correlation between OCB status and spinal cord lesions has not been previously reported, our observation might be related to the findings of previous studies in which OCB-positive MS patients were found to have a higher prevalence of infratentorial and a lower frequency of juxtacortical lesions compared to OCB-negative patients[29], [30], and [31]. Given that brainstem and spinal cord lesions are located closely to the CSF, their presence might affect the detection of OCBs.

In the present study, despite the younger age and the more frequent presence of spinal cord lesions in OCB-positive patients, disability assessments, i.e. EDSS and MSSS did not differ significantly between the two groups, perhaps because biological age is more strongly correlated with accumulated disability [27] . Interestingly, in the study of Imrell et al., although EDSS and MSSS did not differ significantly between OCB-positive and OCB-negative patients, OCB-positivity accelerated disability accumulation along with carriage of HLA-DRB1*15 [27] .

Nevertheless, in our study, no meaningful correlation was found between the presence of OCBs and any of the demographic and disease characteristics. Our findings support previous reports suggesting that the OCB status lacks prognostic significance in MS[6], [7], and [8].

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Footnotes

a Department of Neurology, Athens National University, “Aeginition” Hospital, Athens, Greece

b Department of Medical Biopathology, Athens National University, “Aeginition” Hospital, Athens, Greece

lowast Corresponding author at: Department of Neurology, “Aeginition” Hospital, 74, Vas. Sophia's Avenue, 11528 Athens, Greece. Tel.: +3210 72 89 277; fax: +3210 5739900.