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Petzold 2013
Petzold 2013
Petzold 2013
Journal of Neuroimmunology
journal homepage: www.elsevier.com/locate/jneuroim
Review article
a r t i c l e i n f o a b s t r a c t
Article history: The diagnosis of multiple sclerosis is based on dissemination in time and space. Before 2010 lack of evidence
Received 4 April 2013 for dissemination in space could be substituted by a paraclinical test, cerebrospinal fluid (CSF) oligoclonal
Received in revised form 2 June 2013 bands (OCBs). The present meta-analysis (13,467 patients) shows that the diagnostic specificity of OCB
Accepted 30 June 2013
drops from 94% to 61% if inflammatory etiologies are considered. Importantly, this was not caused by poor
laboratory practice. This review on CSF OCB further illustrates the conceptional problem of substituting
Keywords:
Diagnostic criteria
dissemination in space with a biomarker. The potential prognostic value of intrathecal OCB will need to be
Cerebrospinal fluid tested prospectively.
Multiple sclerosis © 2013 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Search strategy and selection criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.2. Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. What is intrathecal oligoclonal IgG synthesis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. What are the target antigens for intrathecally-produced IgG? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
5. Is the pattern of intrathecally-produced oligoclonal IgG preserved in MS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
6. How specific is intrathecal oligoclonal IgG for MS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
7. Poor analytical quality triggers the development of international guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
8. Analytical aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
9. Quality control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
10. What are the OCB patterns? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
10.1. Interpretation of the OCB pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
11. What happens to CSF monoclonal bands? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
12. CSF bands: to count or not to count? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
13. What information can CSF light chains add? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
14. What information can CSF IgM add? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
15. What is the diagnostic value of intrathecally-produced IgG in MS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
15.1. Meta-analysis — part I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
15.2. Meta-analysis — part II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
15.3. Potential sources of bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
15.4. What is the influence of ethnicity on the diagnostic value of CSF OCB? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
16. What is the prognostic value of intrathecally-produced IgG in predicting conversion from CIS to MS? . . . . . . . . . . . . . . . . . . . . . 7
16.1. Optic neuritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
16.2. Other CIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
17. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
⁎ VU Medical Center, Department of Neurology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel.: +31 204445292.
E-mail address: a.petzold@vumc.nl.
0165-5728/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jneuroim.2013.06.014
2 A. Petzold / Journal of Neuroimmunology 262 (2013) 1–10
1. Introduction characteristic (HSROC) model in SAS (version 9.3) (Rutter and Gatsonis,
2001).
Evidence of intrathecally-produced immunoglobulin G (IgG) was
used from around 1954 as an additional diagnostic test for multiple
sclerosis (MS) (Stangel et al., 2013). Stringent brain imaging criteria 3. What is intrathecal oligoclonal IgG synthesis?
can demonstrate dissemination in space (DIS) with such accuracy
that an additional CSF examination is not necessary (Polman et al., The immune system requires B-cells to produce IgG. In the central
2011). A debate followed on the value of cerebrospinal fluid (CSF) nervous system (CNS) B-cells reside in the meninges and parenchyma
analysis in general (Galea et al., 2011; Polman, 2011; Tumani et al., (Harp et al., 2007; Lovato et al., 2011). Importantly, only a small num-
2011; Stangel et al., 2013). Two aspects of this debate have to be ber of B-cell clones are present in the CNS (Racke, 2008). Therefore any
considered, one is focused on the potential utility of CSF analysis in intrathecally-produced IgG can only ever be oligoclonal. Clonally-
general and the other on the specific value of OCB for a set of diagnos- expanded B-cells from the CSF were shown to be the source of
tic criteria aimed to optimise early sensitivity and specificity. The matching CSF IgG (Monson et al., 2005; Obermeier et al., 2008). Readily
relevance of a state-of-the-art general CSF analysis for the differential distinguishable IgG bands seen on IEF are called “oligoclonal bands”
diagnosis of MS has been extensively reviewed (Tumani et al., 2011; (OCB) (Lowenthal et al., 1960). The practical points to remember
Stangel et al., 2013). In contrast, the present review and meta- about OCB are summarised in Synopsis 1.
analysis is solely focused on intrathecal oligoclonal IgG synthesis in
MS. The review starts with a discussion of the basic biology and path-
4. What are the target antigens for intrathecally-produced IgG?
ophysiology of intrathecal oligoclonal IgG synthesis. This short and
pragmatic neuroimmunological review prepares the ground for a
Intrathecally-produced IgG has been used in an attempt to identify
meta-analysis on the diagnostic value of CSF oligoclonal bands
aetiologically relevant antigens, but to date this has not been successful
(OCBs) in MS. The review closes with a revision of the potential
in MS.
prognostic value of the test.
Of the many candidate antigens studied, myelin-associated lipids
have been found to be present most consistently (Villar et al.,
2. Methods
2005a; Lambracht-Washington et al., 2007) (and references therein).
Analysis of recombinant IgG1 antibodies from single CSF plasma blast
2.1. Search strategy and selection criteria
clones suggests that about 27% of the antibodies are directed against
lipid complexes which frequently contain sulfatide (Brennan
A systematic review of the literature was conducted on all CSF
et al., 2011). The pathological significance of this finding re-
studies in MS since publication of the first consensus report rec-
mains speculative.
ommending the use of IEF for qualitative analysis of intrathecally-
produced IgG in MS (Andersson et al., 1994) between 1994 and
October 2011, including manuscripts published ahead of print and 5. Is the pattern of intrathecally-produced oligoclonal IgG
conference abstracts irrespective of language using PubMed, EMBASE, preserved in MS?
Medline, Web of Science and the Cochrane Register of Diagnostic Test
Accuracy Studies using the search terms: multiple sclerosis, MS, cere- Most studies report that the OCB pattern in MS, once established,
brospinal fluid and CSF. From 2164 studies identified, 2115 were ex- remains stable over time (Confavreux et al., 1986; Correale et al.,
cluded either because they were reviews, did not include a control 2002; Link and Huang, 2006; Yu et al., 2011) (and references therein).
group, were not performed in adult humans, did not perform analyses Only a minority of studies reported sequential changes of the OCB
of oligoclonal bands or IEF as recommended in the original consensus pattern such as more bands, less bands or change of band intensity
guidelines (Andersson et al., 1994), did not specify how a diagnosis of during the course of MS (Mattson et al., 1980; Thompson et al.,
MS was made or because missing data could not be obtained from the 1983; Axelsson et al., 2011; Glehn et al., 2012). A very recent report
authors by email contact. A total of 49 studies were included (Link et demonstrated that OCB disappeared in 12/73 (16%, p b 0.003) of pa-
al., 1994; Morrissey et al., 1995; Sellebjerg et al., 1995; Sellebjerg and tients between a baseline lumbar puncture and a later lumbar punc-
Christiansen, 1996; Xiao et al., 1996; Kaiser et al., 1997; Krakauer et ture after treatment with natazilumab was started (Harrer et al.,
al., 1998; Petersen et al., 1998; Tumani et al., 1998; Zhou et al., 1998; 2012).
Hampel et al., 1999; Heard et al., 1999; Haghighi et al., 2000; Lunding
et al., 2000; McMillan et al., 2000; Falip et al., 2001; Losy and
Niezgoda, 2001; Yao et al., 2001; Petzold et al., 2002; Silber et al., 6. How specific is intrathecal oligoclonal IgG for MS?
2002; Fortini et al., 2003; Malmeström et al., 2003; Bourahoui et al.,
2004; Bednárová et al., 2005; Caudie et al., 2005; Franciotta et al., Any process triggering a B-cell response may lead to the presence of
2005; Sá et al., 2005; Stoevring et al., 2005; Villar et al., 2005b; Li et IgG in the CSF. Diseases known to produce an intrathecal oligoclonal
al., 2007; Mygland et al., 2007; Zadro et al., 2007; Di Filippo et al., IgG response are summarised in Table 1.
2008; Presslauer et al., 2008; Sarchielli et al., 2008; Arneth and
Birklein, 2009; Gama et al., 2009; Vogt et al., 2009; Zipoli et al., 2009;
Brettschneider et al., 2010; Chalbot et al., 2010; Klawiter et al., 2010; Synopsis 1
Piazza et al., 2010; Verbeek et al., 2010; Franciotta et al., 2011; Five keys to intrathecally-produced IgG.
Haghighi et al., 2012; Khademi et al., 2011; Komori et al., 2012; Kuhle
et al., 2011). • In normal CSF all IgG comes from the blood by passive
diffusion
2.2. Statistical analysis • In normal CSF and serum IgG is polyclonal
• Oligoclonal bands in blood give a mirror pattern in CSF
The data analysis used the Cochrane Collaboration's Review Manager • Intrathecal (local) IgG synthesis is present when there are
software package (RevMan5) following the guidance of the Diagnostic bands in the CSF that are not visible in the serum
Test Accuracy (DTA) Working Group. The meta-analysis of the diagnostic • Oligoclonal bands are (generally) a sign of pathology
accuracy was performed using a hierarchical summary receiver-operating
A. Petzold / Journal of Neuroimmunology 262 (2013) 1–10 3
9. Quality control
Fig. 2. Forest plot of the analytical accuracy of reporting CSF OCB from 114 laboratories participating in an external quality control scheme (data kindly provided by UK NEQAS,
12.10.2011).
patterns be designated as “Type 1” to “Type 5” (Freedman et al., 11. What happens to CSF monoclonal bands?
2005). For didactic reasons, mnemonics are used in Synopsis 3 to sum-
marise these patterns. Monoclonal CSF bands are rare. The differential diagnosis includes
clinically-definite MS, probable MS, CIS, SLE, paraneoplastic syndrome,
vascular disease, encephalitis, peripheral neuropathies, superficial
10.1. Interpretation of the OCB pattern siderosis, torsion dystonia, lymphoma and lymphomatoid granuloma-
tosis within or adjacent to the nervous system (McCombe et al.,
A normal test result (Type 1) does not always exclude pathology 1991; Ben-Hur et al., 1996; Davies et al., 2003). In one study, a repeat
and may be found very early in the disease course, as illustrated in lumbar puncture demonstrated that all patients who developed
Fig. 4. At the first lumbar puncture this patient fulfilled the diagnostic clinically-definite MS also showed evidence of intrathecal IgG synthesis
criteria for a CIS and at the second lumbar puncture for clinically in the second CSF sample (Davies et al., 2003).
definite MS.
Local synthesis: oligoclonal bands are present in the CSF but not in
the serum (Type 2). This pattern is observed in patients with MS. As 12. CSF bands: to count or not to count?
mentioned above, OCBs are also seen in a number of other diseases,
with Table 1 likely to be incomplete. The hypothesis behind counting bands is that a higher number of
The interpretation of the mirror patterns (Types 3, 4 and 5) is more bands may be of prognostic or diagnostic value. Some investigators
complex and relies on additional information from the general CSF ex- found more than 10 bands in the CSF to be of high diagnostic specificity
amination (Synopsis 2). One needs to consider systemic inflammation for MS (Bourahoui et al., 2004). Others found that the absence of OCBs
with or without additional local IgG synthesis (Freedman et al., in the CSF of patient with MS was a good prognostic sign (Zeman et al.,
2005). Mirror steps (Type 5) indicates the presence of a monoclonal 1996; Lechner-Scott et al., 2012) (and references therein). In contrast,
gammopathy. two studies did not find any relationship between the presence and
number (or absence) of CSF OCB bands and either disease progression
or MS subgroups (RR, SP, PP disease) (Imrell et al., 2006; Koch et al.,
2007).
There are conceptional and methodological problems to be con-
sidered in counting bands. Firstly, the number of bands may not be
a true reflection of the number of relevant B-cell clones. In order to
address the biological relevance of OCBs, the number of clones pro-
ducing the bands may turn out to be more relevant than the number
of bands present. Secondly, clonally-expanded intrathecal B cells can
appear before OCBs. This may explain why some patients only
Synopsis 3
Classification of CSF OCB patterns.
dominant light chain in the human body. Therefore the kappa light
chain (free and bound) is found more frequently in the CSF than
lambda. In practice, immunoblotting for kappa/lambda light chains
is helpful in the following situations:
develop OCBs during the course of their disease (see reference 14. What information can CSF IgM add?
(Zeman et al., 1996) and Fig. 4).
As in any immune-response, IgM levels increase in the serum and
CSF before IgG develops. Detection of CSF oligoclonal IgM bands is
13. What information can CSF light chains add? possible using IEF (Villar et al., 2001). An analytical drawback is that
the pentameric IgM antibodies need to be dissociated for IEF and
A single B-cell clone can only express either kappa or lambda light the association to single-cell clones is therefore lost. As with IgG,
chains. Because kappa is rearranged first, it is quantitatively the IgM is not specific for MS but is also found in other inflammatory
Fig. 5. Forest plot of the sensitivity and specificity of CSF OCB in patients diagnosed with MS according to consensus criteria (Poser et al., 1983; McDonald et al., 2001; Polman et al.,
2005). The controls comprise healthy patients, patients with non-inflammatory and inflammatory CNS disorders and patients with non-neurological conditions.
6 A. Petzold / Journal of Neuroimmunology 262 (2013) 1–10
CNS diseases (Villar et al., 2002). It has been suggested that those patients with MS or other inflammatory conditions (Sellebjerg
oligoclonal CSF IgM is of prognostic relevance in MS (Villar et al., and Christiansen, 1996; Xiao et al., 1996; Heard et al., 1999; Falip et
2003). al., 2001; Yao et al., 2001; Fortini et al., 2003; Bourahoui et al., 2004;
Bednárová et al., 2005; Caudie et al., 2005; Franciotta et al., 2005; Sá
et al., 2005; Villar et al., 2005b; Li et al., 2007; Mygland et al., 2007;
15. What is the diagnostic value of intrathecally-produced IgG in
Presslauer et al., 2008; Arneth and Birklein, 2009; Gama et al., 2009;
MS?
Vogt et al., 2009; Piazza et al., 2010; Franciotta et al., 2011) (2,331 pa-
tients) shows a reduced diagnostic specificity of 61% (Fig. 6). The
15.1. Meta-analysis — part I
change of the specificity level is best appreciated by the rightward
shift of the red dot in the HSROC plots (Fig. 7A & B).
The diagnostic sensitivity of CSF OCB using state-of-the-art
methods is reported by pioneering experts in the field to be above
95% (Freedman et al., 2005; Link and Huang, 2006). This estimate is 15.3. Potential sources of bias
consistent with the present meta-analysis of 49 studies (Link et al.,
1994; Morrissey et al., 1995; Sellebjerg et al., 1995; Sellebjerg and A number of potential biases need to be considered which will in-
Christiansen, 1996; Xiao et al., 1996; Kaiser et al., 1997; Krakauer et fluence the accuracy of a test. An index test bias may be introduced if
al., 1998; Petersen et al., 1998; Tumani et al., 1998; Zhou et al., subjects were solely to be included depending on the result of an
1998; Hampel et al., 1999; Heard et al., 1999; Haghighi et al., 2000; index (reference) test (Bossuyt et al., 2003). This is to be distin-
Lunding et al., 2000; McMillan et al., 2000; Falip et al., 2001; Losy guished from a double gold standard bias were different reference
and Niezgoda, 2001; Yao et al., 2001; Petzold et al., 2002; Silber et standards are used based on the results of the index test. Next,
al., 2002; Fortini et al., 2003; Malmeström et al., 2003; Bourahoui et there is the scenario of an inclusion bias if the reference standard
al., 2004; Bednárová et al., 2005; Caudie et al., 2005; Franciotta et and index test are dependent.
al., 2005; Sá et al., 2005; Stoevring et al., 2005; Villar et al., 2005b; Finally, a selection bias may suggest impressive levels of the sensitiv-
Li et al., 2007; Mygland et al., 2007; Zadro et al., 2007; Di Filippo et ity and specificity of a particular test, but be based on the comparison of
al., 2008; Presslauer et al., 2008; Sarchielli et al., 2008; Arneth and a hyper-normal control group with a clearly diseased group. This would
Birklein, 2009; Gama et al., 2009; Vogt et al., 2009; Zipoli et al., for example be the comparison of CSF samples from patients with defi-
2009; Brettschneider et al., 2010; Chalbot et al., 2010; Klawiter et nite MS with CSF samples from a healthy, non-inflammatory control
al., 2010; Piazza et al., 2010; Verbeek et al., 2010; Franciotta et al., group. The results of the meta-analysis suggest that the high diagnostic
2011; Haghighi et al., 2012; Khademi et al., 2011; Komori et al., sensitivity and specificity levels of CSF OCB for MS may, at least in part,
2012; Kuhle et al., 2011) (11,136 patients) which calculates a pooled be caused by a selection bias. Future studies in the field would need to
diagnostic sensitivity for MS of 93% with a specificity of 94% (Fig. 7A) be careful to consider potential sources of bias.
(Petzold, 2012). The forest plot (Fig. 5) illustrates that the sensitivity
of individual studies ranges from 1.0 (95%CI 0.88–1.00) (Yao et al.,
15.4. What is the influence of ethnicity on the diagnostic value of CSF
2001) to 0.53 (95%CI 0.44–0.63) (Zipoli et al., 2009).
OCB?
Of note, the majority of studies included healthy controls, patients
without neurological diseases or patients with non-inflammatory
Most studies reporting a diagnostic sensitivity above 95% were
neurological conditions. In reality, MS is frequently in the clinical dif-
performed on patients with a predominantly Caucasian background.
ferential diagnosis of those conditions listed in Table 1.
A much lower diagnostic sensitivity (7%–63%) was reported for Asian
patients from China, Japan, and Taiwan (Fukazawa et al., 1998; Chang
15.2. Meta-analysis — part II et al., 2006; Li et al., 2007) and Brazilian patients (Gama et al., 2009).
In addition, there was an association between latitude (thought to be
What is the influence of other inflammatory conditions on the di- related to ethnic distribution) and the proportion of MS patients with
agnostic value of CSF OCB? A repeat meta-analysis only considering evidence of intrathecally-produced IgG in a large (n = 4481) multicentre
Fig. 6. The specificity of CSF OCB is 61% if patients diagnosed with MS according to consensus criteria (Poser et al., 1983; McDonald et al., 2001; Polman et al., 2005) are compared to
patients with inflammatory neurological conditions.
A. Petzold / Journal of Neuroimmunology 262 (2013) 1–10 7
study (Lechner-Scott et al., 2012). Together, this data suggests that the di- 17. Conclusion
agnostic sensitivity of CSF OCB may be less in non-Caucasian patients.
Over the past 50 years multiple sclerosis has been considered to
16. What is the prognostic value of intrathecally-produced IgG in be a disease in which DIS and DIT needed to be demonstrated in
predicting conversion from CIS to MS? order to make a diagnosis (Schumacher et al., 1965; McAlpine,
1972; Poser et al., 1983; Polman et al., 2011). Brain imaging is an
At first presentation, patients fulfilling radiological DIS but not DIT ideal tool to show DIS and DIT and consequently became the corner-
are classified as clinically-isolated syndrome (CIS), and some will go stone of MS diagnosis with the introduction of the McDonald criteria
on to develop MS. The question is whether the presence of in 1998 (McDonald et al., 2001). In the face of clinical assessment and
8 A. Petzold / Journal of Neuroimmunology 262 (2013) 1–10
brain imaging it seems rather challenging to demonstrate DIS and DIT Brettschneider, Johannes, Czerwoniak, Anne, Senel, Makbule, Fang, Lubin, Kassubek,
Jan, Pinkhardt, Elmar, Lauda, Florian, Kapfer, Tamara, Jesse, Sarah, Lehmensiek,
based on evidence for intrathecally-produced oligoclonal IgG. Having Vera, Ludolph, Albert C., Otto, Markus, Tumani, Hayrettin, 2010. The chemokine
said this, in the past CSF OCBs were regarded as a diagnostic test CXCL13 is a prognostic marker in clinically isolated syndrome (CIS). PLoS One 5,
which could substitute for radiological DIS (McDonald et al., 2001; e11986.
Caudie, Christiane, Medhi Birouk, Al, Bancel, Julien, ele Claudy, Dani, Gignoux,
Polman et al., 2005). Laurence, Vukusic, Sandra, Confavreux, Christian, 2005. Cytoimmunological profile
Overall a state-of-the-art CSF examination should be used as an of cerebrospinal fluid in diagnosis of multiple sclerosis. Pathol. Biol. (Paris) 53,
extension of clinical reasoning to make optimal use of the added 68–74.
Chalbot, Sonia, Zetterberg, Henrik, Blennow, Kaj, Fladby, Tormod, Iqbal, Inge Grundke-,
value of the tests requested (Polman et al., 1985; Stangel et al., Iqbal, Khalid, 2010. Cerebrospinal fluid secretory Ca2+-dependent phospholipase
2013). An unselected request of CSF OCB on all patients will reduce A2 activity: a biomarker of blood-cerebrospinal fluid barrier permeability.
the diagnostic specificity. Taken together, there are four potential sce- Neurosci. Lett. 478, 179–183.
Chang, K.H., Lyu, R.K., Chen, C.M., Hsu, W.C., Wu, Y.R., Chen, S.T., Ro, L.S., 2006. Clinical
narios. First, if the clinical picture and MRI are non-specific, likelihood
characteristics of multiple sclerosis in Taiwan: a cross-sectional study. Mult. Scler.
is that CSF OCB may not be particularly helpful. Second, if the clinical 12, 501–506.
picture is highly suggestive for MS, but there is no evidence for radio- Confavreux, C., Chapuis-Cellier, C., Arnaud, P., Robert, O., Aimard, G., Devic, M., 1986.
logical DIS or DIT, CSF OCB may be of potential prognostic value. Oligoclonal “fingerprint” of CSF IgG in multiple sclerosis patients is not modified
following intrathecal administration of natural betainterferon. J. Neurol.
Third, if the clinical presentation is unspecific, but radiological DIS Neurosurg. Psychiatry 49, 1308–1312.
and DIT are present as are CSF OCB, one would be very suspicious Correale, Jorge, de los Milagros, María, Molinas, Bassani, 2002. Oligoclonal bands and
about a diagnosis of MS. Finally, given the high sensitivity of CSF antibody responses in multiple sclerosis. J. Neurol. 249, 375–389.
Davies, G., Keir, G., Thompson, E.J., Giovannoni, G., 2003. The clinical significance of an
OCB in patients with MS, one might be careful about making a diagno- intrathecal monoclonal immunoglobulin band: a follow-up study. Neurology 60,
sis of MS in a patient with a doubtful clinical history in whom CSF OCB 1106–1163.
are absent. Di Filippo, M., Pini, L.A., Pelliccioli, G.P., Calabresi, P., Sarchielli, P., 2008. Abnormalities
in the cerebrospinal fluid levels of endocannabinoids in multiple sclerosis.
Importantly, the present meta-analysis provides class I evidence J. Neurol. Neurosurg. Psychiatry 79, 1224–1229.
that CSF OCB can only be of low diagnostic specificity when other in- Dobson, Ruth, Leddy, Sara Geraldine, Gangadharan, Sunay, Giovannoni, Gavin, 2013.
flammatory conditions come into the differential diagnosis. This may Assessing fracture risk in people with MS: a service development study comparing
three fracture risk scoring systems. BMJ Open 3.
be regarded as an additional argument for no longer considering CSF Falip, M., Tintoré, M., Jardí, R., Duran, I., Link, H., Montalbán, X., 2001. Clinical usefulness
OCB as a substitute for non-specific MRI lesions, which fail the radio- of oligoclonal bands. Rev. Neurol. 32, 1120–1124.
logical criteria for DIS. In summary, one non-specific test result should Fortini, Alexandre S., Sanders, Elizabeth L., Weinshenker, Brian G., Katzmann, Jerry A.,
2003. Cerebrospinal fluid oligoclonal bands in the diagnosis of multiple sclerosis.
not be used to substitute for another non-specific test result.
Isoelectric focusing with IgG immunoblotting compared with high-resolution
agarose gel electrophoresis and cerebrospinal fluid IgG index. Am. J. Clin. Pathol.
120, 672–675.
Acknowledgments
Franciotta, D., Zardini, E., Bergamaschi, R., Grimaldi, L.M., Andreoni, L., Cosi, V., 2005.
Analysis of Chlamydia pneumoniae-specific oligoclonal bands in multiple sclerosis
The MS Center VUmc is partially funded by a programme grant of and other neurologic diseases. Acta Neurol. Scand. 112, 238–241.
Franciotta, Diego, Stefano, Anna Luisa Di, Jarius, Sven, Zardini, Elisabetta, Tavazzi,
the Dutch MS Research Foundation. I am most grateful to Dr Dina
Eleonora, Ballerini, Clara, Marchioni, Enrico, Bergamaschi, Roberto, Ceroni,
Patel, Deputy Director of the UK NEQAS CSF programme for providing Mauro, 2011. Cerebrospinal BAFF and Epstein–Barr virus-specific oligoclonal
the data on inter-laboratory accuracy from the UK. I should also like bands in multiple sclerosis and other inflammatory demyelinating neurological
to thank Chris Polman and Geoff Keir for their critical comments on diseases. J. Neuroimmunol. 230, 160–163.
Freedman, M.S., Thompson, E.J., Deisenhammer, F., Giovannoni, G., Grimsley, G., Keir,
this manuscript. The meta-analysis was presented at the ECTRIMS G., Ohman, S., Racke, M.K., Sharief, M., Sindic, C.J., Sellebjerg, F., Tourtellotte,
meeting in Lyon, 10–13 October 2012. W.W., 2005. Recommended standard of cerebrospinal fluid analysis in the diagno-
sis of multiple sclerosis: a consensus statement. Arch. Neurol. 62, 865–870.
Fukazawa, T., Kikuchi, S., Sasaki, H., Hamada, K., Hamada, T., Miyasaka, K., Tashiro, K.,
References 1998. The significance of oligoclonal bands in multiple sclerosis in Japan: relevance
of immunogenetic backgrounds. J. Neurol. Sci. 158, 209–214.
Abraira, V., Alvarez-Cermeño, J.C., Arroyo, R., Cámara, C., Casanova, B., Cubillo, S., de Galea, Ian, Freedman, Mark S., Thompson, Edward J., 2011. Cerebrospinal fluid analysis
Andrés, C., Espejo, C., Fernández, et al., 2011. Utility of oligoclonal IgG band detec- in the 2010 revised McDonald's multiple sclerosis diagnostic criteria. Ann. Neurol.
tion for MS diagnosis in daily clinical practice. J. Immunol. Methods 371, 170–173. 70, 183–184 (author reply 184).
Andersson, M., Alvarez-Cermeño, J., Bernardi, G., Cogato, I., Fredman, P., Frederiksen, J., Gama, Paulo Diniz da, Dos Ramos Machado, Luís, Antonio Livramento, José, Rodrigues
Fredrikson, S., Gallo, P., Grimaldi, L.M., Grønning, M., 1994. Cerebrospinal fluid in Gomes, Hélio, Adoni, Tarso, Maria Martins Lino, Angelina, Eurípedes Marchiori,
the diagnosis of multiple sclerosis: a consensus report. J. Neurol. Neurosurg. Paulo, de Rizo Morales, Rogério, Aurélio Lana-Peixoto, Marco, Callegaro, Dagoberto,
Psychiatry 57, 897–902. 2009. Study of oligoclonal bands restricted to the cerebrospinal fluid in multiple
Arneth, B., Birklein, F., 2009. High sensitivity of free lambda and free kappa light chains sclerosis patients in the city of São Paulo. Arq. Neuropsiquiatr. 67, 1017–1022.
for detection of intrathecal immunoglobulin synthesis in cerebrospinal fluid. Acta Glehn, Felipe von, Farias, Alessandro S., Penalva de Oliveira, Augusto C., Damasceno,
Neurol. Scand. 119, 39–44. Alfredo, Longhini, Ana Leda F., Oliveira, Elaine C., Damasceno, Benito P., Mb
Axelsson, M., Mattsson, N., Malmestrom, C., Nilsson, S., Haghighi, S., Rosengren, L., Santos, Leonilda, Otavio Brandao, Carlos, 2012. Disappearance of cerebrospinal
Zetterberg, H., Lycke, J. (Eds.), 2011. Change in number and pattern of CSF oligoclonal fluid oligoclonal bands after natalizumab treatment of multiple sclerosis patients.
bands in MS patients over time. Multiple Sclerosis Journal, vol. 17, p. P646 (S281. Mult. Scler. 18, 1038–1041.
ECTRIMS ACTRIMS). Gout, Olivier, Bouchareine, Annie, Moulignier, Antoine, Deschamps, Romain, Papeix,
Bednárová, J., Stourac, P., Adam, P., 2005. Relevance of immunological variables in Caroline, Gorochov, Guy, Héran, Françoise, Bastuji-Garin, Sylvie, 2011. Prognostic
neuroborreliosis and multiple sclerosis. Acta Neurol. Scand. 112, 97–102. value of cerebrospinal fluid analysis at the time of a first demyelinating event.
Ben-Hur, T., Abramsky, O., River, Y., 1996. The clinical significance of a single abnormal Mult. Scler. 17, 164–172.
immunoglobulin band in cerebrospinal fluid electrophoresis. J. Neurol. Sci. 136, Haghighi, S., Andersen, O., Rosengren, L., Bergström, T., Wahlström, J., Nilsson, S., 2000.
159–161. Incidence of CSF abnormalities in siblings of multiple sclerosis patients and
Bossuyt, Patrick M., Reitsma, Johannes B., Bruns, David E., Gatsonis, Constantine A., unrelated controls. J. Neurol. 247, 616–622.
Glasziou, Paul P., Irwig, Les M., Lijmer, Jeroen G., Moher, David, Rennie, Haghighi, S., Lekman, A., Nilsson, S., Blomqvist, M., Andersen, O., 2012. Myelin
Drummond, CWde Vet, Henrica, Standards for Reporting of Diagnostic Accuracy, glycosphingolipid immunoreactivity and CSF levels in multiple sclerosis. Acta
2003. Towards complete and accurate reporting of studies of diagnostic accuracy: Neurol. Scand. 125, 64–70.
the STARD initiative. BMJ 326, 41–44. Hampel, H., Kötter, H.U., Padberg, F., Körschenhausen, D.A., Möller, H.J., 1999.
Bourahoui, A., De Seze, J., Guttierez, R., Onraed, B., Hennache, B., Ferriby, D., Stojkovic, Oligoclonal bands and blood–cerebrospinal-fluid barrier dysfunction in a subset
T., Vermersch, P., 2004. CSF isoelectrofocusing in a large cohort of MS and other of patients with Alzheimer disease: comparison with vascular dementia, major de-
neurological diseases. Eur. J. Neurol. 11, 525–529. pression, and multiple sclerosis. Alzheimer Dis. Assoc. Disord. 13, 9–19.
Brennan, Kathryn M., Galban-Horcajo, Francesc, Rinaldi, Simon, O'Leary, Colin P., Harp, Christopher, Lee, Jane, Lambracht-Washington, Doris, Cameron, Elizabeth, Olsen,
Goodyear, Carl S., Kalna, Gabriela, Arthur, Ariel, Elliot, Christina, Barnett, Sue, Gregory, Frohman, Elliot, Racke, Michael, Monson, Nancy, 2007. Cerebrospinal
Linington, Christopher, Bennett, Jeffrey L., Owens, Gregory P., Willison, Hugh J., fluid B cells from multiple sclerosis patients are subject to normal germinal center
2011. Lipid arrays identify myelin-derived lipids and lipid complexes as prominent selection. J. Neuroimmunol. 183, 189–199.
targets for oligoclonal band antibodies in multiple sclerosis. J. Neuroimmunol. 238, Harrer, A., Tumani, H., Niendorf, S., Lauda, F., Geis, C., Weishaupt, A., Kleinschnitz, C., Rauer,
87–95. S., Kuhle, J., Stangel, M., Weber, F., Uhr, M., Linnebank, M., Wildemann, B., Jarius, S.,
A. Petzold / Journal of Neuroimmunology 262 (2013) 1–10 9
Guger, M., Ayzenberg, I., Chan, A., Zettl, U., Wiendl, H., Pilz, G., Hitzl, W., Weber, Jr, McMillan, S.A., McDonnell, G.V., Douglas, J.P., Hawkins, S.A., 2000. Evaluation of the
Kraus, J., 2012. Cerebrospinal fluid parameters of B cell-related activity in patients clinical utility of cerebrospinal fluid (CSF) indices of inflammatory markers in
with active disease during natalizumab therapy. Mult. Scler. (Epub ahead of print). multiple sclerosis. Acta Neurol. Scand. 101, 239–243.
Heard, R.N., Teutsch, S.M., Bennetts, B.H., Lee, S.D., Deane, E.M., Stewart, G.J., 1999. Monson, Nancy L., Brezinschek, Hans-Peter, Brezinschek, Ruth I., Mobley, Angela,
Lack of restriction of T cell receptor beta variable gene usage in cerebrospinal Vaughan, Gwen K., Frohman, Elliot M., Racke, Michael K., Lipsky, Peter E., 2005. Re-
fluid lymphocytes in acute optic neuritis. J. Neurol. Neurosurg. Psychiatry 67, ceptor revision and atypical mutational characteristics in clonally expanded B cells
585–590. from the cerebrospinal fluid of recently diagnosed multiple sclerosis patients.
Imrell, Kerstin, Landtblom, Anne-Marie, Hillert, Jan, Masterman, Thomas, 2006. Multi- J. Neuroimmunol. 158, 170–181.
ple sclerosis with and without CSF bands: clinically indistinguishable but immuno- Morrissey, S.P., Borruat, F.X., Miller, D.H., Moseley, I.F., Sweeney, M.G., Govan, G.G.,
genetically distinct. Neurology 67, 1062–1064. Kelly, M.A., Francis, D.A., Harding, A.E., McDonald, W.I., 1995. Bilateral simulta-
Jacobs, L.D., Kaba, S.E., Miller, C.M., Priore, R.L., Brownscheidle, C.M., 1997. Correlation neous optic neuropathy in adults: clinical, imaging, serological, and genetic
of clinical, magnetic resonance imaging, and cerebrospinal fluid findings in optic studies. J. Neurol. Neurosurg. Psychiatry 58, 70–74.
neuritis. Ann. Neurol. 41, 392–398. Mygland, A., Trydal, T., Vinje, B.U., Vedeler, C., 2007. Isoelectric focusing is superior to
Kabat, E.A., Moore, D.H., Landow, H., 1942. An electrophoretic study of the protein com- immunofixation electrophoresis in diagnosing CNS inflammation. Acta Neurol.
ponents in cerebrospinal fluid and their relationship to the serum proteins. J. Clin. Scand. 115, 122–125.
Invest. 21, 571–577. Obermeier, Birgit, Mentele, Reinhard, Malotka, Joachim, Kellermann, Josef, Kümpfel,
Kaiser, R., Obert, M., Kaufmann, R., Czygan, M., 1997. IgG-antibodies to CNS proteins in Tania, Wekerle, Hartmut, Lottspeich, Friedrich, Hohlfeld, Reinhard, Dornmair,
patients with multiple sclerosis. Eur. J. Med. Res. 2, 169–172. Klaus, 2008. Matching of oligoclonal immunoglobulin transcriptomes and
Keir, G., Luxton, R.W., Thompson, E.J., 1990. Isoelectric focusing of cerebrospinal fluid proteomes of cerebrospinal fluid in multiple sclerosis. Nat. Med. 14, 688–693.
immunoglobulin G: an annotated update. Ann. Clin. Biochem. 27, 436–443. Petersen, A.A., Sellebjerg, F., Frederiksen, J., Olesen, J., Vejlsgaard, G.L., 1998. Soluble
Keren, D.F., 2003. Optimizing detection of oligoclonal bands in cerebrospinal fluid by ICAM-1, demyelination, and inflammation in multiple sclerosis and acute optic
use of isoelectric focusing with IgG immunoblotting. Am. J. Clin. Pathol. 120, neuritis. J. Neuroimmunol. 88, 120–127.
649–651. Petzold, Axel, 2005. Neurofilament phosphoforms: surrogate markers for axonal injury,
Khademi, Mohsen, Kockum, Ingrid, Andersson, Magnus L., Iacobaeus, Ellen, Brundin, degeneration and loss. J. Neurol. Sci. 233, 183–198.
Lou, Sellebjerg, Finn, Hillert, Jan, Piehl, Fredrik, Olsson, Tomas, 2011. Cerebrospinal Petzold, A., 2012. Biological markers. Mult. Scler. J. 18, 121 (oral presentation).
fluid CXCL13 in multiple sclerosis: a suggestive prognostic marker for the disease Petzold, A., 2013. Progressive multiple sclerosis. In: Wilkins, A. (Ed.), Chap. Biomarkers
course. Mult. Scler. 17, 335–343. of Disease Progression. Springer-Verlag, pp. 115–146.
Klawiter, Eric C., Piccio, Laura, Lyons, Jeri-Anne, Mikesell, Robert, O'Connor, Kevin C., Petzold, A., Eikelenboom, M.J., Gveric, D., Keir, G., Chapman, M., Lazeron, R.H., et al.,
Cross, Anne H., 2010. Elevated intrathecal myelin oligodendrocyte glycoprotein 2002. Markers for different glial cell responses in multiple sclerosis: clinical and
antibodies in multiple sclerosis. Arch. Neurol. 67, 1102–1108. pathological correlations. Brain 125, 1462–1473.
Koch, M., Heersema, D., Mostert, J., Teelken, A., De Keyser, J., 2007. Cerebrospinal fluid Petzold, A., Keir, G., Sharpe, L.T., 2004. Spectrophotometry for xanthochromia. N. Engl.
oligoclonal bands and progression of disability in multiple sclerosis. Eur. J. Neurol. J. Med. 351, 1695–1696.
14, 797–800. Piazza, F., DiFrancesco, J.C., Fusco, M.L., Corti, D., Pirovano, L., Frigeni, B., Mattavelli, L.,
Komori, M., Matsuyama, Y., Nirasawa, T., Thiele, H., Becker, M., Alexandrov, T., Saida, T., Andreoni, S., Frigo, M., Ferrarese, C., Tredici, G., Cavaletti, G., 2010. Cerebrospinal
Tanaka, M., Matsuo, H., Tomimoto, H., Takahashi, R., Tashiro, K., Ikegawa, M., fluid levels of BAFF and APRIL in untreated multiple sclerosis. J. Neuroimmunol.
Kondo, T., 2012. Proteomic pattern analysis discriminates among multiple sclero- 220, 104–107.
sis-related disorders. Ann Neurol. 71, 614–623. Polman, C.H., 2011. Reply. Ann. Neurol. 70, 521.
Krakauer, M., Schaldemose Nielsen, H., Jensen, J., Sellebjerg, F., 1998. Intrathecal Polman, C.H., Koetsier, J.C., Wolters, E.C., 1985. Multiple sclerosis: incorporation of re-
synthesis of free immunoglobulin light chains in multiple sclerosis. Acta Neurol. sults of laboratory techniques in the diagnosis. Clin. Neurol. Neurosurg. 87,
Scand. 98, 161–165. 187–192.
Kuhle, J., Leppert, D., Petzold, A., Regeniter, A., Schindler, C., Mehling, M., Anthony, D.C., Polman, C.H., Reingold, S.C., Edan, G., Filippi, M., Hartung, H.P., Kappos, L., Lublin, F.D.,
Kappos, L., Lindberg, R.L.P., 2011. Neurofilament heavy chain in CSF correlates with Metz, L.M., McFarland, H.F., O'Connor, P.W., Sandberg-Wollheim, M., Thompson,
relapses and disability in multiple sclerosis. Neurology 76, 1206–1213. A.J., Weinshenker, B.G., Wolinsky, J.S., 2005. Diagnostic criteria for multiple sclerosis:
Lambracht-Washington, Doris, O'Connor, Kevin C., Cameron, Elizabeth M., Andrea 2005 revisions to the “McDonald Criteria”. Ann. Neurol. 58, 840–846.
Jowdry, E., Ward, Sally, Frohman, Elliot, Racke, Michael K., Monson, Nancy L., 2007. Polman, Chris H., Reingold, Stephen C., Banwell, Brenda, Clanet, Michel, Cohen, Jeffrey
Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B A., Filippi, Massimo, Fujihara, Kazuo, Havrdova, Eva, Hutchinson, Michael, Kappos,
cells from patients with relapsing remitting MS. J. Neuroimmunol. 186, 164–176. Ludwig, Lublin, Fred D., Montalban, Xavier, O'Connor, Paul, Sandberg-Wollheim,
Lechner-Scott, J., Spencer, B., de Malmanche, T., Attia, J., Fitzgerald, M., Trojano, M., Magnhild, Thompson, Alan J., Waubant, Emmanuelle, Weinshenker, Brian,
Grand'maison, F., Antonio, J., Gomez, C., Izquierdo, G., Duquette, P., Girard, M., Wolinsky, Jerry S., 2011. Diagnostic criteria for multiple sclerosis: 2010 revisions
Grammond, P., Oreja-Guevara, C., Hupperts, R., Bergamaschi, R., Boz, C., Giuliani, G., to the McDonald criteria. Ann. Neurol. 69, 292–302.
van Pesch, V., Iuliano, G., Fiol, M., Cristiano, E., Verheul, F., Laura Saladino, M., Slee, M., Poser, C.M., Paty, D.W., Scheinberg, L., McDonald, W.I., Davis, F.A., Ebers, G.C., Johnson,
Barnett, M., Deri, N., Fletcher, S., Vella, N., Shaw, C., Herbert, J., Moore, F., Petkovska- K.P., Sibley, W.A., Silberberg, D.H., Tourtellotte, W.W., 1983. New diagnostic
Boskova, T., Jokubatis, V., Butzkueven, H., 2012. The frequency of CSF oligoclonal criteria for multiple sclerosis: guidelines for research protocols. Ann. Neurol. 13,
banding in multiple sclerosis increases with latitude. Mult. Scler. 18, 974–982. 227–231.
Li, B., Dong, H., Zhang, J., Song, X., Guo, L., 2007. Cerebrospinal fluid IgG profiles and Presslauer, Stefan, Milosavljevic, Dejan, Brücke, Thomas, Bayer, Peter, Hübl, Wolfgang,
oligoclonal bands in Chinese patients with multiple sclerosis. Acta Neurol. Scand. Hübl, Walter, 2008. Elevated levels of kappa free light chains in CSF support the
115, 319–324. diagnosis of multiple sclerosis. J. Neurol. 255, 1508–1514.
Link, H., Huang, Y.M., 2006. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: Racke, Michael K., 2008. The role of B cells in multiple sclerosis: rationale for B-cell-
an update on methodology and clinical usefulness. J. Neuroimmunol. 180, 17–28. targeted therapies. Curr. Opin. Neurol. 21 (Suppl. 1), S9–S18.
Link, J., Söderström, M., Olsson, T., Höjeberg, B., Ljungdahl, A., Link, H., 1994. Increased Reiber, H., 1995. External quality assessment in clinical neurochemistry: survey of
transforming growth factor-beta, interleukin-4, and interferongamma in multiple analysis for cerebrospinal fluid (CSF) proteins based on CSF/serum quotients.
sclerosis. Ann. Neurol. 36, 379–386. Clin. Chem. 41, 256–263.
Losy, J., Niezgoda, A., 2001. IL-18 in patients with multiple sclerosis. Acta Neurol. Scand. Rolak, L.A., Beck, R.W., Paty, D.W., Tourtellotte, W.W., Whitaker, J.N., Rudick, R.A., 1996.
104, 171–173. Cerebrospinal fluid in acute optic neuritis: experience of the optic neuritis treat-
Lovato, Laura, Willis, Simon N., Rodig, Scott J., Caron, Tyler, Almendinger, Stefany E., ment trial. Neurology 46, 368–372.
Howell, Owain W., Reynolds, Richard, O'Connor, Kevin C., Hafler, David A., 2011. Rutter, C.M., Gatsonis, C.A., 2001. A hierarchical regression approach to meta-analysis
Related B cell clones populate the meninges and parenchyma of patients with mul- of diagnostic test accuracy evaluations. Stat. Med. 20, 2865–2884.
tiple sclerosis. Brain 134, 534–541. Sá, Maria José, Sequeira, Lucinda, Rio, Maria Edite, Thompson, Edward J., 2005.
Lowenthal, A., Karcher, D., Van Sande, M., 1960. The differential diagnosis of neurolog- Oligoclonal IgG bands in the cerebrospinal fluid of Portuguese patients with multi-
ical diseases by fractionating electrophoretically the CSF gamma-globulins. ple sclerosis: negative results indicate benign disease. Arq. Neuropsiquiatr. 63,
J. Neurochem. 6, 51–56. 375–379.
Lunding, J., Midgard, R., Vedeler, C.A., 2000. Oligoclonal bands in cerebrospinal fluid: a Sarchielli, Paola, Di Filippo, Massimiliano, Ercolani, Maria Vittoria, Chiasserini, Davide,
comparative study of isoelectric focusing, agarose gel electrophoresis and IgG Mattioni, Alessia, Bonucci, Michele, Tenaglia, Serena, Eusebi, Paolo, Calabresi,
index. Acta Neurol. Scand. 102, 322–325. Paolo, 2008. Fibroblast growth factor-2 levels are elevated in the cerebrospinal
Malmeström, C., Haghighi, S., Rosengren, L., Andersen, O., Lycke, J., 2003. Neurofilament fluid of multiple sclerosis patients. Neurosci. Lett. 435, 223–228.
light protein and glial fibrillary acidic protein as biological markers in MS. Neurol- Schumacher, G.A., Beebe, G., Kebler, R.F., et al., 1965. Problems of experimental trials of
ogy 61, 1720–1725. therapy in multiple sclerosis. Ann. N.Y. Acad. Sci. 122, 552–568.
Mattson, D.H., Roos, R.P., Arnason, B.G., 1980. Isoelectric focusing of IgG eluted from mul- Sellebjerg, F., Christiansen, M., 1996. Qualitative assessment of intrathecal IgG synthe-
tiple sclerosis and subacute sclerosing panencephalitis brains. Nature 287, 335–337. sis by isoelectric focusing and immunodetection: interlaboratory reproducibility
McAlpine, D., 1972. Multiple Sckrosis. A Reappraisal, 2nd ed. Churchill Livingstone and interobserver agreement. Scand. J. Clin. Lab. Invest. 56, 135–143.
225–226. Sellebjerg, F., Madsen, H.O., Frederiksen, J.L., Ryder, L.P., Svejgaard, A., 1995. Acute optic
McCombe, P.A., Brown, N.N., Barr, A.E., Parkin, L., 1991. Monoclonal immunoglobulin neuritis: myelin basic protein and proteolipid protein antibodies, affinity, and the
bands in the cerebrospinal fluid. Aust. N. Z. J. Med. 21, 227–229. HLA system. Ann. Neurol. 38, 943–950.
McDonald, W.I., Compston, A., Edan, G., et al., 2001. Recommended diagnostic criteria Silber, E., Semra, Y.K., Gregson, N.A., Sharief, M.K., 2002. Patients with progressive mul-
for multiple sclerosis: guidelines from the International Panel on the diagnosis of tiple sclerosis have elevated antibodies to neurofilament subunit. Neurology 58,
multiple sclerosis. Ann. Neurol. 50, 121–127. 1372–1381.
10 A. Petzold / Journal of Neuroimmunology 262 (2013) 1–10
Skov, A.G., Skov, T., Frederiksen, J.L., 2011. Oligoclonal bands predict multiple sclerosis Villar, L.M., Masjuan, J., Gonzalez-Porque, P., Plaza, J., Sadaba, M.C., Roldan, E., Bootello,
after optic neuritis: a literature survey. Mult. Scler. 17, 404–410. A., Alvarez-Cermeno, J.C., 2003. Intrathecal IgM synthesis is a prognostic factor in
Stangel, Martin, Fredrikson, Sten, Meinl, Edgar, Petzold, Axel, Stüve, Olaf, Tumani, multiple sclerosis. Ann. Neurol. 53, 222–226.
Hayrettin, 2013. The utility of cerebrospinal fluid analysis in patients with multiple Villar, L.M., Sádaba, M.C., Roldán, E., Masjuan, J., et al., 2005a. Intrathecal synthesis of
sclerosis. Nat. Rev. Neurol. 9, 267–276. oligoclonal IgM against myelin lipids predicts an aggressive disease course in MS.
Stoevring, Birgitte, Vang, Ole, Christiansen, Michael, 2005. (alpha)Bcrystallin in J. Clin. Invest. 115, 187–194.
cerebrospinal fluid of patients with multiple sclerosis. Clin. Chim. Acta 356, Villar, Luisa M., Masjuan, Jaime, Sádaba, María C., González-Porqué, Pedro, Plaza, José,
95–101. Bootello, Alfredo, Alvarez-Cermeño, José C., 2005b. Early differential diagnosis of
Thompson, E.J., Kaufmann, P., Rudge, P., 1983. Sequential changes in oligoclonal multiple sclerosis using a new oligoclonal band test. Arch. Neurol. 62, 574–577.
patterns during the course of multiple sclerosis. J. Neurol. Neurosurg. Psychiatry Vogt, M.H.J., Teunissen, C.E., Iacobaeus, E., Heijnen, D.A.M., Breij, E.C.W., Olsson, T.,
46, 547–550. Brundin, L., Killestein, J., Dijkstra, Christine D., 2009. Cerebrospinal fluid anti-
Tintoré, M., Rovira, A., Río, J., Tur, C., Pelayo, R., Nos, C., Téllez, N., Perkal, H., Comabella, myelin antibodies are related to magnetic resonance measures of disease activity
M., Sastre-Garriga, J., Montalban, X., 2008. Do oligoclonal bands add information to in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 80, 1110–1115.
MRI in first attacks of multiple sclerosis? Neurology 70, 1079–1083. Xiao, B.G., Zhang, G.X., Ma, C.G., Link, H., 1996. The cerebrospinal fluid from patients
Tourtellotte, W.W., 1985. In: Koetsier, J.C. (Ed.), The Cerebrospinal Fluid in Multiple with multiple sclerosis promotes neuronal and oligodendrocyte damage by
Sclerosis, vol. 3. North–Holland Publishing Company, Amsterdam, pp. 79–130 delayed production of nitric oxide in vitro. J. Neurol. Sci. 142, 114–120.
(Wiley Interscience Division — John Wiley & Sons, Inc., New York). Yao, S.Y., Stratton, C.W., Mitchell, W.M., Sriram, S., 2001. CSF oligoclonal bands in MS
Tumani, H., Tourtellotte, W.W., Peter, J.B., Felgenhauer, K., 1998. Acute optic neuritis: include antibodies against Chlamydophila antigens. Neurology 56, 1168–1176.
combined immunological markers and magnetic resonance imaging predict subse- Yu, Xiaoli, Burgoon, Mark, Green, Miyoko, Barmina, Olga, Dennison, Kathryn, Pointon,
quent development of multiple sclerosis. The Optic Neuritis Study Group. J. Neurol. Tiffany, Davis, Molly, Gilden, Don, 2011. Intrathecally synthesized IgG in multiple scle-
Sci. 155, 44–49. rosis cerebrospinal fluid recognizes identical epitopes over time. J. Neuroimmunol.
Tumani, Hayrettin, Deisenhammer, Florian, Giovannoni, Gavin, Gold, Ralf, Hartung, 240–241, 129–136.
Hans-Peter, Hemmer, Bernhard, Hohlfeld, Reinhard, Otto, Markus, Stangel, Zadro, Ivana, Brinar, Vesna, Horvat, Gordana, Brinar, Marko, 2007. Clinical relevance of
Martin, Wildemann, Brigitte, Zettl, Uwe K., 2011. Revised McDonald criteria: the antibodies against myelin oligodendrocyte glycoprotein in different clinical types
persisting importance of cerebrospinal fluid analysis. Ann. Neurol. 70, 520. of multiple sclerosis. Clin. Neurol. Neurosurg. 109, 23–26.
Verbeek, M.M., Notting, E.A., Faas, B., Claessens-Linskens, R., Jongen, P.J.H., 2010. In- Zeman, A.Z., Kidd, D., McLean, B.N., Kelly, M.A., Francis, D.A., Miller, D.H., Kendall, B.E.,
creased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis. Rudge, P., Thompson, E.J., McDonald, W.I., 1996. A study of oligoclonal band nega-
Acta Neurol. Scand. 121, 309–314. tive multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 60, 27–30.
Villar, L.M., Gonzalez-Porque, P., Masjuan, J., Alvarez-Cermeno, J.C., Bootello, A., Keir, G., Zhou, S.R., Maier, C.C., Mitchell, G.W., LaGanke, C.C., Blalock, J.E., Whitaker, J.N., 1998. A
2001. A sensitive and reproducible method for the detection of oligoclonal IgM cross-reactive anti-myelin basic protein idiotope in cerebrospinal fluid cells in
bands. J. Immunol. Methods 258, 151–155. multiple sclerosis. Neurology 50, 411–417.
Villar, L.M., Masjuan, J., Gonzalez-Porque, P., Plaza, J., Sadaba, M.C., Roldan, E., Bootello, Zipoli, V., Hakiki, B., Portaccio, E., Lolli, F., Siracusa, G., Giannini, M., Pantoni, L., Pescini,
A., Alvarez-Cermeno, J.C., 2002. Intrathecal IgM synthesis in neurologic diseases: F., Sorbi, S., Amato, M.P., 2009. The contribution of cerebrospinal fluid oligoclonal
relationship with disability in MS. Neurology 58, 824–826. bands to the early diagnosis of multiple sclerosis. Mult. Scler. 15, 472–478.