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Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab.

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Axonal Damage in Relapsing Multiple
Sclerosis is Markedly Reduced
by Natalizumab
Martin Gunnarsson, MD, PhD,1 Clas Malmeström, MD, PhD,2
Markus Axelsson, MD,2 Peter Sundström, MD, PhD,3 Charlotte Dahle, MD, PhD,4,5
Magnus Vrethem, MD, PhD,4 Tomas Olsson, MD, PhD,6 Fredrik Piehl, MD, PhD,6
Niklas Norgren, PhD,7 Lars Rosengren, MD, PhD,2 Anders Svenningsson, MD, PhD,3
and Jan Lycke, MD, PhD2
Objective: The impact of present disease-modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and
reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2
brain-specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.
Methods: CSF samples from 92 patients with relapsing forms of MS were collected in a prospective manner prior to
natalizumab treatment and after 6 or 12 months. In 86 cases, natalizumab was used as second-line DMT due to
breakthrough of disease activity. The levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were
determined using highly sensitive in-house developed enzyme-linked immunosorbent assays.
Results: Natalizumab treatment led to a 3-fold reduction of NFL levels, from a mean value of 1,300 (standard
deviation [SD], 2,200) to 400 (SD, 270) ng/l (p < 0.001). The later value was not significantly different from that
found in healthy control subjects (350ng/l; SD, 170; n ¼ 28). Subgroup analysis revealed a consistent effect on NFL
release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to
natalizumab treatment. No differences between pre- and post-treatment levels of GFAP were detected.
Interpretation: Our data demonstrate that natalizumab treatment reduces the accumulation of nerve injury in
relapsing forms of MS. It is anticipated that highly effective anti-inflammatory treatment can reduce axonal loss,
thereby preventing development of permanent neurological disability.
ANN NEUROL 2011;69:83–89
ultiple sclerosis (MS) is a chronic inflammatory
demyelinating disease of the central nervous system
(CNS). Axonal damage occurs both within MS lesions and
in the normal-appearing white matter already at early
stages of the disease, as demonstrated by neuropathological
studies,1 magnetic resonance imaging (MRI) techniques,2–4
and by use of biomarkers.5–9 Numerous findings suggest
that axonal loss followed by astrogliosis is ultimately responsible for the development of irreversible neurological
deficits.8–18 The role of immune system-mediated mechanisms in causing such processes, however, has not yet been
clarified. Disease-modifying treatments (DMTs) in MS
have so far been designed to modulate the immune system
and are almost exclusively effective in disease phases in
which the inflammatory component is prominent. Consequently, DMTs in current use reduce the number of relapses and appearance of T2 as well as gadolinium-enhanced
MRI lesions in relapsing-remitting MS (RRMS) patients.
Natalizumab, a monoclonal antibody preventing lymphocyte migration across the blood-brain barrier, is a highly
efficient agent in this respect.19–23 Whether early immunomodulatory intervention in fact retains axonal integrity and
View this article online at DOI: 10.1002/ana.22247
Received May 13, 2010, and in revised form Jul 26, 2010. Accepted for publication Aug 20, 2010.
Address correspondence to Dr Svenningsson, Department of Neurology, Norrlands University Hospital, S-901 85 Umeå, Sweden.
From the 1Department of Neurology, Örebro University Hospital, Örebro; 2Department of Neurology, Sahlgrenska University Hospital, Göteborg;
Department of Neurology, Norrlands University Hospital, Umeå; 4Department of Neurology and Neurophysiology, Linköping University Hospital,
Linköping; 5Clinical Immunology Unit, Department of Clinical and Experimental Medicine, Linköping University, Linköping; 6Neuroimmunology Unit, Center
for Molecular Medicine, Department of Clinical Neuroscience, Karolinska Institute, Stockholm; and 7UmanDiagnostics, Umeå, Sweden.
C 2011 American Neurological Association
of Neurology
TABLE 1: Demographics of Multiple Sclerosis
Patients and HCs
MS, n 5 92
n 5 28
n 5 30a
n 5 62b
Age, yr
36 (19–59),
p ¼ 0.020
vs HCc
38 (14–56), 43
p ¼ 0.034 (27–62)
vs HCc
9.0 (0.5–28) 10 (2–26)
Values for age and MS duration are given as mean (range).
Denotes MS patients with relapses within 3 months prior
to natalizumab treatment onset.
Denotes MS patients in remission during this period.
t test.
MS ¼ multiple sclerosis; HC ¼ healthy control; N/A ¼
not applicable.
prevents astrogliosis deserves further investigation. Detection of axonal and astroglial cytoskeletal proteins, such as
neurofilament light (NFL) and glial fibrillary acidic protein
(GFAP), in the cerebrospinal fluid (CSF) reflects these
processes in vivo.8,9 To study the effects of intense immune
modulation within the CNS on axonal damage and astrogliosis, we quantified NFL and GFAP in the CSF from 92
MS patients undergoing 6 to 12 months of treatment with
Subjects and Methods
Patients and CSF Collection
Following acquisition of informed consent, 92 MS
patients (83 RRMS and 9 secondary progressive MS
with relapses [SPRMS]) were included consecutively
using a multicenter approach. Patients fulfilled the revised McDonald criteria24 and were scheduled to start
treatment with 300mg natalizumab intravenously once
monthly according to Swedish guidelines. All patients
presented either a highly active disease course de novo or
breakthrough disease activity in terms of relapses in the
presence of other DMTs. The mean annual relapse rate
was 1.2 (standard deviation [SD], 1.1) during the year
prior to natalizumab treatment. Among the 92 patients
included, 6 were treatment naive, whereas 86 had been
using other DMTs, of which 67 were treated with interferon-b, 4 with glatiramer acetate, 8 with mitoxantrone,
and 7 with other treatments. Thirty patients had experienced a relapse within 3 months prior to natalizumab
treatment, whereas 62 patients were in remission during
this period. Patient demographics are shown in Table 1.
Medical history and additional clinical data such as
relapse count during the study period were recorded prospectively in the medical record and in the Swedish MS
registry. CSF was collected consecutively by lumbar spinal taps prior to treatment with natalizumab and after 6
(n ¼ 8) or 12 (n ¼ 84) months. Clinical examination
using the Expanded Disability Status Scale (EDSS)25 was
performed by trained neurologists no more than 1 week
apart from the lumbar puncture. Ten milliliters of CSF
was centrifuged at 1,300 to 1,800g for 10 minutes. Aliquots of supernatant (0.5–1.0ml) were immediately snapfrozen to 80 C and not thawed until analysis. All
patients underwent routine CSF examinations including
cell counts, and protein electrophoresis and determination of immunoglobulin (Ig)G-index were performed in
59 patients. CSF samples from 28 healthy volunteers,
recruited among blood donors and university students,
were used as reference.
All NFL and GFAP analysis were performed simultaneously at the Section of Neurochemistry, Sahlgrenska
University Hospital, Mölndal. CSF samples were blinded
for laboratory personnel during all stages of analysis. The
study was approved by the local ethics committee at
Uppsala University, Sweden.
NFL Enzyme-Linked Immunoassay
The UmanDiagnostics NF-light enzyme-linked immunoassay (ELISA), developed by Norgren and coworkers,
detects 1 of the low molecular weight chains of neuronal
intracellular intermediate filaments.9 The assay is based
on 2 highly specific monoclonal antibodies and a biotinstreptavidin horseradish peroxidase (HRP) system. Analysis was performed at room temperature. Cerebrospinal
fluid samples were diluted 1:1 with sample dilution
buffer to a total volume of 100ll and incubated with
agitation (800rpm) for 1 hour in precoated anti-NFL
ELISA plates. Thereafter, a 100ll solution of tracer antibody (biotin anti-NFL) was added to each well and incubated for 45 minutes. Washing cycles were performed after all incubations. Detection was performed using 100ll
streptavidin-HRP incubated for 30 minutes, followed by
another incubation with 100ll 3,30 ,5,50 -tetramethylbenzidine for 15 minutes;. A volume of 50ll stop solution
(8% v/v sulphuric acid) was added to each well, and absorbance was read at k490nm. The sensitivity of the
NFL assay was 31ng/l.
Measurements of GFAP were performed using the ELISA
procedure previously developed by Rosengren and coworkers.17 In brief, ELISA plates were coated with hen
Volume 69, No. 1
Gunnarsson et al: Relapsing MS and Natalizumab
TABLE 2: Clinical and Cerebrospinal Fluid Parameters following Natalizumab Treatment
Relapse, n 530a
Remission, n 5 62b
After 6–12
6–12 Months
2.0 (1.1)c
0.10 (0.31)c
0.84 (0.83)c
0.18 (0.39)c
p < 0.001c
p < 0.001c
3.5 (2.5–4.5)d
4.0 (2.25–6.0)d
p < 0.001d
p ¼ 0.023d
Cell count, 106 cells/l
5.8 (6.0)c
1.4 (1.2)c
5.2 (7.3)c
1.6 (1.4)c
p < 0.001c
p < 0.001c
IgG index
0.93 (0.32)c,e
0.83 (0.29)c,e
1.1 (0.68)c,f
1.0 (0.56)c,f
p ¼ 0.033c
p ¼ 0.001c
NFL, ng/l
2300 (3600)c
350 (170)c
860 (780)c
430 (310)c
p < 0.005c
p < 0.001c
Values are given as mean (standard deviation) except for EDSS, which is presented as median (25th–75th percentile).
Denotes MS patients with relapses within 3 months prior to natalizumab treatment.
Denotes MS patients in remission during this period.
Paried sample t test.
Mann-Whitney U test.
n¼ 17.
n ¼ 42.
EDSS ¼ Expanded Disability Status Scale; IgG ¼ immunoglobulin G; NFL ¼ neurofilament light; MS ¼ multiple sclerosis.
anti-GFAP IgG followed by incubation with CSF samples at room temperature for 2 hours. Rabbit anti-GFAP
IgG was added as secondary antibody and incubated for
1 hour at room temperature. Washing cycles were performed after each incubation step. Detection was performed with peroxidase-conjugated donkey antirabbit
IgG and 3,30 ,5,50 -tetramethylbenzidine substrate. Absorbance was read at k490 nm, and the sensitivity of the
GFAP assay was 16ng/l.
over, CSF inflammatory parameters were significantly
decreased in terms of cell count from a mean of 5.4
(SD, 6.9) to 1.6 (SD, 1.3) 106 cells/l (p < 0.001) and
IgG-index from a mean of 1.1 (SD, 0.60) to 0.94 (SD,
Statistical Analysis
Wilcoxon signed ranks test and Mann-Whitney U test
were used for analysis of nonparametric data. Analysis of
parametric data, paired and unpaired, was performed using
t test. Test for age influence on the NFL levels in MS
patients as compared to healthy controls was done via linear regression analysis. Statistical calculations were performed in SPSS 16.0 software (SPSS Inc., Chicago, IL).
Clinical Data and CSF Inflammatory Parameters
The annual relapse rate during the natalizumab treatment
period was reduced from a mean value of 1.2 (SD, 1.1;
year prior to treatment) to 0.15 (SD, 0.36; p < 0.001).
The median pretreatment EDSS score was 4.0 (2.5–5.5,
25th–75th percentile) as compared to 3.5 (2.0–5.0,
25th–75th percentile) post-treatment (p < 0.001). MoreJanuary 2011
FIGURE 1: Neurofilament light in cerebrospinal fluid (CSF)
following natalizumab treatment. Intravenous infusions of
300mg natalizumab were performed monthly in 92 multiple
sclerosis patients. Neurofilament light (NFL) levels in the
CSF were compared to levels obtained in 28 healthy
individuals. Pretreatment mean value was significantly
different from that obtained after treatment (p < 0.001) and
in healthy controls (p < 0.001). No significant difference was
found between mean values after treatment and in healthy
controls, respectively. SE 5 standard error.
of Neurology
0.50; p < 0.001). Stratification of the cohort into
patients with relapses within 3 months prior to natalizumab treatment and patients in remission during this period is shown in Table 2.
Prior to natalizumab treatment, the mean NFL concentration in CSF from the 92 MS patients studied was
1,300ng/l (SD, 2200), whereas healthy controls displayed
a mean value of 350ng/l (SD, 170; p < 0.001; Fig 1).
After treatment, however, the mean NFL level was significantly reduced to 400 (SD, 270) ng/l (p < 0.001).
Notably, the post-treatment value did not differ significantly from that found in healthy control subjects.
We have previously shown that NFL levels are
increased in the 3-month period after a relapse.7–9 Therefore, we made a separate analysis of the groups of
patients having a relapse versus being in remission during
this time period before lumbar puncture. Thus, the
mean NFL concentration in CSF was determined as
2,300ng/l (SD, 3,600) in MS patients with relapses (n ¼
30), as compared to 860ng/l (SD, 780) in patients displaying clinical remission for at least 3 months (n ¼ 62)
(p < 0.038; equal variance not assumed). When exclusively analyzing MS patients in remission, NFL levels
were still significantly reduced following natalizumab
treatment (p < 0.001; see Table 2). Both patients with
and those without ongoing relapses during the 3-month
period prior to natalizumab treatment displayed posttreatment NFL levels not significantly different from
those obtained in healthy controls (mean, 350ng/l; SD,
170; see Table 2).
Pretreatment levels of NFL in treatment-naive MS
patients (n ¼ 6) were higher (3,300ng/l; SD, 6,600) but
not significantly different from those obtained in patients
subjected to DMTs prior to natalizumab (1,200ng/l; SD,
1,600; n ¼ 86). An adequate comparison regarding different types of immune modulation was not possible due
to different treatment regimes and uneven patient distribution. After being on natalizumab treatment for 6 to 12
months, both treatment-naive MS patients and those
who had previously undergone immune modulation presented NFL levels similar to values obtained in healthy
controls (data not shown).
Subgroup analysis was also performed regarding
NFL levels in patients with SPRMS (n ¼ 9). These
patients presented a significantly higher mean post-treatment NFL concentration (630ng/l; SD, 420) as compared to the 83 RRMS patients (380ng/l; SD, 240; p <
0.001) and healthy controls (350ng/l; SD, 170; p <
0.001; Fig 2). Pretreatment NFL levels, however, were
not higher in the SPMRS group as compared to RRMS
FIGURE 2: Neurofilament light (NFL) in cerebrospinal fluid
in different disease courses of multiple sclerosis (MS).
Before intravenous treatment with 300mg natalizumab
monthly, mean NFL concentrations in secondary progressive
MS with relapses (SPRMS) and relapsing-remitting MS
(RRMS) patients were not significantly different. In both
groups of patients, values obtained after treatment were
significantly decreased (p < 0.001). After treatment, the
mean NFL level in SPRMS was significantly higher than that
determined in RRMS patients (p < 0.001) and healthy
controls (p < 0.001). SE 5 standard error.
patients. The SPRMS patients still presented a highly significant decrease in mean NFL concentration following
natalizumab treatment (p < 0.001). In terms of neurological deficits, the SPRMS patients had a median EDSS
score of 6.5 (6.0–7.25, 25th–75th percentile), whereas
the corresponding value in RRMS patients was 3.5
(2.375–5.0, 25th–75th percentile; p < 0.001). Disease
duration and age distribution were similar (data not
Because data in the control group indicated an agedependent variance in NFL concentration (data not
shown), we tested for a significant contribution of this
parameter in comparisons between values from controls
and MS patients after natalizumab treatment. Using
covariate analysis, we found no significant age-dependent
influence on the results presented (data not shown).
In contrast to NFL, determination of GFAP levels in
CSF prior to natalizumab treatment of the 92 MS
patients did not yield any significant difference as compared to values obtained in healthy controls (data not
shown). Subgroup analysis of the 9 SPRMS patients with
relapses, however, revealed a mean pretreatment GFAP
concentration that was significantly higher than that
found in the control group (790 [SD, 430] vs 400 [SD,
162] ng/l; p < 0.001; Fig 3). On the other hand, GFAP
Volume 69, No. 1
Gunnarsson et al: Relapsing MS and Natalizumab
FIGURE 3: Glial fibrillary acidic protein (GFAP) in
cerebrospinal fluid in different disease courses of multiple
sclerosis (MS). The mean pre-treatment GFAP concentration
was significantly higher in secondary progressive MS with
relapses (SPRMS) but not relapsing-remitting MS (RRMS)
patients as compared to healthy controls (p < 0.001). No
significant differences were found after intravenous
treatment with 300 mg natalizumab monthly. SE 5 standard
levels were similar in healthy controls and RRMS
patients (mean, 510ng/l; SD, 460; n ¼ 83).
Natalizumab treatment for 6 to 12 months had no
significant influence on the GFAP levels in CSF, neither
in the entire 92 MS patient population nor in cases of
subgroup analysis (see Fig 3).
Irreversible neurological deficits in MS likely emerge as a
consequence of accumulating nerve injury starting already in early phases of the disease.8–18 Due to the long
lag phase before clinical disability can be detected and a
lack of reliable biomarkers, the effect of current immunomodulatory treatments on tissue damage has been difficult to assess. Previously, we have characterized NFL as a
marker of ongoing axonal damage.7–9 In this study, we
demonstrate that elevated NFL levels in CSF from 92
patients with relapsing forms of MS are markedly
decreased following natalizumab treatment for 6 to 12
months. Post-treatment NFL levels were not significantly
different from values obtained in healthy individuals.
Moreover, the effect was consistent regardless of whether
the patients were treated with first-line DMT at the time
of natalizumab treatment onset or not.
The natalizumab mechanism of action and its CNS
anti-inflammatory potential has been well characterized.
In the pivotal natalizumab trial, a highly significant
reduction in relapse rate and MRI lesion formation was
obtained.19 These results have been confirmed in open
January 2011
follow-up studies of patients with treatment failure on
first-line DMTs and in highly active MS.20,21 The antiinflammatory effect is likely to be achieved by interference with lymphocyte migration into the CNS, reflected
among others by a reduced expression of proinflammatory cytokines and chemokines in the CSF compartment.26–28 In the present investigation, both clinical parameters, that is, relapse rate and EDSS score, and CSF
inflammatory markers in terms of inflammatory cell
counts in CSF and IgG-index were decreased following
natalizumab treatment. These data are well in line with
the results presented in the pivotal natalizumab trial and
several other studies.19–23 Therefore, it is of certain interest that we concomitantly demonstrate a normalization
of NFL levels in CSF from this cohort of MS patients.
In contrast to the marked effect on NFL release, no
changes in astrogliosis, as determined by GFAP quantification, were seen following natalizumab treatment. This
may be due to the characteristics of the patient cohort,
because earlier data suggest that GFAP is elevated in secondary progressive but not RRMS.8,9,12,17 Such a notion
is supported by the fact that increased GFAP levels, as
compared to healthy controls, were found exclusively in
patients presenting an underlying progressive disease
course and more pronounced neurological deficits in
terms of EDSS score.
Accurate identification of MS patients with insufficient treatment effect and at high risk for development of
future neurological disability is becoming increasingly important. Immune modulation in MS partly prevents development of sustained disability if initiated during the relapsing phase of the disease, but the evidence for long-term
treatment efficacy has not yet been clarified. Furthermore,
the risk-benefit profiles of current DMTs differ considerably, and difficulties in accurate assessment of treatment efficacy at the individual level in a short time perspective
present a clinical dilemma. Except for MRI parameters
reflecting CNS inflammation, there are presently no surrogate markers of disease activity in practical use. The UmanDiagnostics NF-light ELISA is based on 2 monoclonal
antibodies highly specific and sensitive for detection of
NFL in body fluids.9 By use of this assay and other immunochemical setups, it has been shown that neurofilament
levels are increased in CSF during MS exacerbations.7–9,29
Moreover, high NFL levels determined at diagnostic lumbar punctures, especially in the presence of relapses, correlate with a worse prognosis as determined using EDSS and
multiple sclerosis severity score (MSSS) at clinical followups after 5 and 14 years, respectively.9,18 Notably, we have
earlier demonstrated significantly higher NFL levels also in
phases of clinical remission as compared to control subjects.8,9 This likely reflects an ongoing clinically silent
of Neurology
axonal damage that, according to data presented here, is
amendable to more intense immunomodulatory treatment.
NFL levels in this study were considerably increased, in both
the presence and absence of relapses. Furthermore, treatment-naive patients as well as patients previously subjected
to first-line DMTs displayed increased NFL levels in CSF.
These results further strengthen the rationale for NFL determination as a measure of subclinical disease activity related
to ongoing nerve injury. We believe that our data also support NFL quantification in CSF as a putative outcome parameter in clinical trials of new drugs in MS. GFAP on the
other hand, does not seem to be a useful biomarker in this
aspect, at least not in relapsing-remitting phases of the disease. Further studies focused on correlations between levels
of NFL in CSF and atrophy measurements by emerging
MRI techniques may provide valuable additional data.
In conclusion, our data support the notion that
inflammatory activity in RRMS is associated with axonal
damage. Effective immunomodulatory treatment is likely
to be of utmost importance in preventing axonal loss
and development of irreversible CNS injury. It is anticipated that highly active control of CNS inflammation in
MS may have profound effects on the long-term course
of the disease, although this remains to be shown in
future studies. In this context, analysis of NFL levels in
the CSF have the potential to provide vital information
regarding treatment efficacy in the short-term perspective
and to facilitate treatment decisions.
has received lecture honoraria from Biogen, and has had
travel expenses partially reimbursed by Biogen Idec. M.A. has
had travel expenses reimbursed by Biogen Idec and
MerckSerono. P.S. has served on an advisory board for
Novartis; has received lecture fees from Biogen Idec; and has
had travel expenses reimbursed by Biogen Idec. C.D. has
received personal compensation for activities with Biogen
Idec, Merck, BayerScheringPharma, and SanofiAventis as a
speaker and consultant. M.V. has a grant pending from
Biogen Idec and has received lecture honoraria from Biogen
Idec and Merck Serono. F.P. has a grant pending from Biogen
Idec; has received payment for development of educational
presentations from Biogen Idec, Novartis, and MerckSerono;
and has had travel expenses reimbursed by Biogen Idec and
Novartis. N.N. is employed by UmanDiagnostics AB.A.S.
has served on an advisory board for MerckSerono; has
received lecture honoraria from Biogen Idec and Baxter; and
has had travel expenses partially reimbursed by Biogen Idec,
MerckSerono, and Baxter. J.L. has served on advisory boards
for Biogen Idec and Merck Serono; has a grant pending from
Biogen Idec; has received speakers honoraria from Biogen
Idec and Merck Serono; and has had travel expenses
reimbursed by Biogen Idec. T.O. has received consultancy
fees from Biogen Idec, SanofiAventis, Merck, and Novartis;
and has grants pending from Biogen Idec, Merck,
SanofiAventis, and Bayer.
Research performed in this project was supported by
grants from Örebro Society of Medicine (M.G.), Swedish
Society of the Neurologically Disabled (J.L.), Gothenburg Multiple Sclerosis Society (J.L.), Edith Jacobsson
Foundation (J.L.), Swedish Reasearch Council (T.O.),
Bibbi and Niels Jensen Foundation (T.O.), Söderbergs
Foundation (T.O.), Montell Williams Foundation, EU
fp6 (T.O.), Neuropromise (LSHM-CT-2005-018637)
(T.O.), and Biogen Idec (J.L.).
We thank S. Fridlund for skillful technical assistance.
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Potential Conflicts of Interest
M.G. has served on educational boards for Biogen Idec,
BayerScheringPharma, and Merck; has received speakers
honoraria from Biogen Idec, Merck, BayerScheringPharma,
and SanofiAventis; has received payment for development of
educational presentations from Biogen Idec; and has had
travel expenses reimbursed by Biogen Idec and Merck. C.M.
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