plik

CME

10.1586/ERN.12.59

1061

ISSN 1473-7175

www.expert-reviews.com

Review

Felix Luessi, Volker

Siffrin and Frauke Zipp*

Focus Program Translational
Neuroscience (FTN), Rhine Main
Neuroscience Network (rmn

Department of Neurology, University
Medical Center Mainz, Johannes
Gutenberg University Mainz,
Langenbeckstr 1, 55131 Mainz,
Germany
*Author for correspondence:
Tel.: +49 6131 17 7156
Fax: +49 6131 17 5697
frauke.zipp@unimedizin-mainz.de

In recent years it has become clear that the neuronal compartment already plays an important
role early in the pathology of multiple sclerosis (MS). Neuronal injury in the course of chronic
neuroinflammation is a key factor in determining long-term disability in patients. Viewing MS
as both inflammatory and neurodegenerative has major implications for therapy, with CNS
protection and repair needed in addition to controlling inflammation. Here, the authors’ review
recently elucidated molecular insights into inflammatory neuronal/axonal pathology in MS and
discuss the resulting options regarding neuroprotective and regenerative treatment strategies.

Neurodegeneration in multiple
sclerosis: novel treatment
strategies

Expert Rev. Neurother. 12(9), 1061–1077 (2012)

eywords

multiple sclerosis • neurodegeneration • neuronal injury • neuroprotection • treatment

Expert Review of Neurotherapeutics

2012

1061

1077

10.1586/ERN.12.59

1473-7175

1744-8360

Neurodegeneration in multiple sclerosis: novel treatment strategies

Luessi, Siffrin & Zipp

Expert Rev. Neurother.

Review

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Learning objectives
Upon completion of this activity, participants will be able to:

• Describe recent insights into inflammatory neuronal injury in multiple sclerosis, based on a review
• Describe methods of quantification of neuronal injury in patients with multiple sclerosis, based on

a review

• Describe applications of these findings to treatment for patients with multiple sclerosis, based on

a review

THeMed ArTICLe

y Demyelinating Diseases

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CME

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Introduction

Multiple sclerosis (MS) is the most common chronic inflammatory
demyelinating disorder of the CNS, and the leading cause of non-
traumatic neurological disability in young adults, affecting 0.1% of
the general population in Western countries

[1]

. Approximately 85%

of patients initially experience a relapsing-remitting disease (RR-MS)
course, which is characterized by recurrent episodes of neurological
deficits, such as limb weakness, optic neuritis, ataxia and sensory
disturbances, followed by periods of remission

[2]

. Remission is not

always complete, and after a variable number of years the majority
of these patients develop a secondary progressive disease course. In
15% of patients, MS is progressive from onset without superimposed
relapses, referred to as primary progressive MS

[3]

. The etiology of

this chronic disease has not been completely understood, but epide-
miological and association studies make the interplay between envi-
ronmental factors and susceptibility genes very likely. Consequently,
these factors trigger the infiltration of circulating myelin-specific
autoreactive lymphocytes into the CNS, leading to inflammation,
demyelination and neuronal injury. Relapses are considered to be
the clinical manifestation of acute inflammatory demyelination in
the CNS, and disability progression is thought to reflect chronic
demyelination, gliosis and axonal loss. Viewing MS as both inflam-
matory and neurodegenerative has major implications for therapy,
with CNS protection and repair needed in addition to controlling
inflammation

[4]

. Here, the authors review recently elucidated

molecular insights into inflammatory neuronal/axonal pathology
in MS and discuss the resulting options regarding neuroprotective
and regenerative treatment strategies.

Recent insights into inflammatory neuronal injury
in MS

Although MS was traditionally considered to be an inflammatory
demyelinating disease of the CNS, which leaves the axons

largely intact at least at onset of the disease

[5]

, recent studies

have shown that neurodegenerative processes also play an
important role early in the pathogenesis of MS. Interestingly,
axonal damage has already been in the focus of MS research
between 1880 and 1930

[6]

. State-of-the-art histopathological

analyses of brain tissue and neuroimaging studies demonstrated
significant damage to neuronal structures with axonal loss and
neurodegeneration, which ccurs in early disease stage and most
likely leads to irreversible neurological impairment

[3,7,8]

. Axonal

pathology is particularly pronounced in active and chronic active
MS lesions throughout the disease course and is closely associated
with the presence of immune cells

[8–10]

. In addition to axonal

damage, either immediate or subsequent to acute inflammatory
infiltration, neurodegeneration continues in the progressive
stage of the disease

[4]

. Quantitative morphological studies also

detected neuronal damage within the normal-appearing white
and gray matter, devoid of obvious demyelinating lesions

[11–13]

These observations have led to the hypothesis that the destruction
of myelin and neurons might, at least, partially represent an
independent processes.

Quantification of neuronal injury in patients

The clinically-measurable disability progression in MS patients
is very slow in the beginning of the disease, which makes it very
difficult to monitor pathology in the neuronal compartment in
the first years of the disease. However, imaging and histopatho-
logic data clearly show that pathology in the neuronal compart-
ment is widespread and dramatic from onset of the disease

[10,14]

This clinicoradiologic and clinicohistopathologic paradox might
be explained by strong compensatory processes of the rather
patchy affection of the CNS in the first years of the disease until
a crucial amount of neuronal tissue is lost and these processes
decompensate.

Financial & competing interests disclosure

ditor

Elisa Manzotti
Publisher, Future Science Group, London, UK.
Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.
CME A

uthor

Laurie Barclay
Freelance writer and reviewer, Medscape, LLC.
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
A

uthors

And

rEdEntiAls

Felix Luessi, MD
Department of Neurology, University Medical Center Mainz, Johannes Gutenberg University Mainz, Germany.
Disclosure: Felix Luessi, MD, has disclosed no relevant financial relationships.
Volker Siffrin
Department of Neurology, University Medical Center Mainz, Johannes Gutenberg University Mainz, Germany.

Disclosure: Volker Siffrin has disclosed no relevant financial relationships.

Frauke Zipp, MD
Department of Neurology, University Medical Center Mainz, Johannes Gutenberg University Mainz, Germany.
Disclosure: Frauke Zipp, MD, has received research grants from Teva, Novartis, Merck Serona and Bayer. She has received consultation funds from
Johnson & Johnson, Novartis, Ono and Octapharma. Her travel compensation has been provided by the aforementioned companies.

Luessi, Siffrin & Zipp

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Neurodegeneration in multiple sclerosis: novel treatment strategies

To evaluate whether existing and emerging treatments for

MS have neuroprotective effects, it is essential to detect sub-
clinical disease activity. MRI techniques have been extensively
explored in this respect for use in clinical studies. Currently, it
is widely accepted to monitor contrast-enhancing lesions (CELs;
blood–brain barrier leakage) as a sign of acute inflammatory
lesions and numbers/volume of T2-hypointense lesions as a
marker of lesion accumulation over time. This approach has
been widely adopted in clinical trials

[15]

. However, advanced

MRI techniques are needed as the number of CEL is hardly and
the T2 lesion load is only weakly to moderately associated with
later disability progression

[16]

. The most promising alternative

outcome measures to quantitatively assess progressive axonal and
neuronal loss over time include change in brain volume, evo-
lution of persistent hypointense lesions on T1-weighted scans,
magnetic resonance spectroscopy, and retinal nerve fiber layer
(RNFL) thickness on optical coherence tomography (OCT) as
non-MRI technique

[17,18]

The assessment of whole-brain volume change with serial MRI is

one of the best-studied imaging outcome measures for MS-related
tissue destruction in the CNS

[19]

. Changes in brain volume are

relatively small, up to 0.5–1% of tissue loss per year, but appear
relatively constant over time and are highly correlated with dis-
ability progression

[20]

. Complex computational paradigms have

been established to quantify the small brain volume changes with
sufficient accuracy. These comprise structured image evaluation
using normalization of atrophy

[21]

and brain parenchymal frac-

tion determination

[22]

. The extent of brain atrophy seems to cor-

relate well with concurrent

[22]

and future disability

[23]

. However,

measurement of global brain atrophy is unspecific for location and
tissue-specific processes, such as increase in glial content and loss
of myelin or axons. Thus, interpretation of brain atrophy data
might be difficult because other factors such as aging, drug use
and comorbidities, as well as ‘pseudoatrophy’ due to absorption
of edema upon anti-inflammatory treatments, may also influence
atrophy rates

[24]

The evolution of persistent T1-hypointense lesions (or persis-

tent ‘black holes’ [PBHs]) is a lesion-based MRI measure that
reflects tissue rarefaction following axonal damage

[16]

and cor-

relates with disability

[17]

. A postmortem examination revealed a

strong correlation between the strength of hypointensity of the
PBH and the degree of axonal loss, with a reduction of up to 90%
in axonal density being observed in the most hypointense lesions

[25,26]

. However, similarly as with brain parenchymal fraction

determination, the assessment of PBH evolution depends on the
quality of and adherence to standardized imaging protocols. The
main problem of PBH evolution to measure treatment effects is
the generally low number of events available for analysis in the
usual time frame of clinical trials. Nonetheless, PBH evolution
is already being widely used to demonstrate neuroprotective and
reparative treatments effects

[27]

Magnetic resonance spectroscopic imaging is another method

that allows a noninvasive quantification of neuronal dam-
age in patients with MS

[28,29]

. Here the neuronal metabolite

N-acetyl-aspartate (NAA) – a highly specific marker of neuronal

and axonal integrity – is quantified. Abnormally low NAA val-
ues were already observed in the early stages of disease, even
before significant disability was clinically evident

[15]

. In longi-

tudinal studies, the rate of decline of NAA concentration cor-
related strongly with the rate of progression of disability assessed
by the Expanded Disability Status Scale (EDSS) over time

[30]

Interestingly, NAA concentration decreased more rapidly with
respect to EDSS at lower EDSS scores than at higher ones,
which is in line with findings of histopathologic studies of early
neuronal damage in MS

[10]

. Accordingly, NAA concentration

is inversely correlated with T1-hypointensity in PBHs

[31]

. These

findings highlight the value of magnetic resonance spectroscopy
for measuring the neuronal damage underlying development of
disability, which is a potential predictor for future disability

[28]

Furthermore, NAA is a very good marker for mitochondrial func-
tion and dysfunction, and can thus show pronounced and some-
times rapid improvement of pathological values during plaque
maturation as well as in the whole brain upon treatment with
anti-inflammatory drugs.

Magnetization transfer (MT) imaging is a technique that allows

detection of tissue loss in lesions by quantifying the capacity
of hydrated macromolecules to exchange magnetization with
surrounding free water molecules

[32]

. It is an indirect measure of

the structural integrity of brain tissue. The MT ratio correlates
well with residual axonal density

[26]

. The MT ratio seems to

predict the subsequent accumulation of disability. In a prospective
study in MS patients, the mean change in average lesion
MT ratio over the first 12 months of follow-up was the best
predictor of sustained disability after 8 years

[33]

. In addition,

a robust correlation of MT ratio with myelin content was
demonstrated, which suggests that the measurement of MT
ratios could be used to monitor potential remyelination
treatments

[34]

. All MRI-based techniques for measurement

of neurodegeneration seem to be very valuable for and widely
used under study conditions; however, they have not arrived in
everyday patient care due to the need for a very precise techniques,
and time-consuming extra data analysis.

OCT has gained a lot of interest in the field of neuroimmu-

nology. This technique uses the reflection patterns of infrared
light off the retinal layers to quantify RNFL thickness

[18]

. The

evaluation of RNFL thickness measures the unmyelinated axons
of retinal ganglion cells before their entry into the optic nerve.
In MS, and following optic neuritis, RNFL thickness corre-
lates with visual acuity, EDSS score and brain atrophy

[35–38]

Already 1 month after acute optic neuritis, loss of retinal nerve
fibers begins and goes on for half a year. Thus, OCT seems
to be a promising and easy to use tool for quantifying nerve
injury after clinical or subclinical acute optic neuritis. It has
been reported that the eyes of patients with MS who have no
clinical history of optic neuritis often have subclinical RNFL
thinning

[36]

, and longitudinal studies have shown that even in

the absence of an optic neuritis episode, a subset of patients will
have detectable thinning over a 2-year period

[16]

. However, one

study failed to detect significant RNFL changes over a period
of 22 months

[39]

, which might be because of the differences in

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Luessi, Siffrin & Zipp

machinery and precision of the technique. Hence, the value of
OCT for monitoring global CNS neurodegeneration in MS is
highly controversial and its role in everyday patient care has to
be evaluated.

In summary, quantification of neurodegeneration by imaging is

feasible in MS. Combining currently available methods seems to
be the optimal strategy to evaluate the neuroprotective capacity of
a novel treatment. New long-term studies are needed to validate
imaging markers in relation to clinical outcomes.

Mechanisms of neuronal injury

Improving the understanding of the mechanisms underlying
neurodegeneration in MS is a major challenge in experimen-
tal neuroimmunology. The underlying disease pathophysi-
ology is complex and involves the key features of the disease,
which include demyelination, inflammation, astrogliosis and
neurodegeneration. The potential causes of acute and chronic
neuronal and axonal injury are bystander damage by pro-
inflammatory neurotoxic substances; direct damage processes,
which involve cell contact-dependent mechanisms; and demy-
elination-dependent metabolic disturbances in the denuded
axons. A recently published genome-wide association study
showed that polymorphisms of immunologically relevant genes
rather than genes likely to be involved more directly in neuro-
degeneration are associated with MS

[40]

. This lends weight to

the idea that inflammation might be a relevant factor for neuro-
degeneration in MS and not a certain disposition of the neuronal
compartment itself.

Immune cell-mediated axonal injury

The inflammatory infiltrates of active and chronic active MS
lesions consist predominantly of CD4

T cells, CD8

T cells and

activated microglia/macrophages

[8,41]

. Because of the correla-

tion between the degree of inflammation and neurodegeneration

[42]

, exposure to the inflammatory milieu has been proposed as a

trigger of neurodegeneration

[43]

. However, direct cell-mediated

mechanisms have also been postulated as a cause of neuronal
pathology.

Endogenous microglia cells in the CNS are dynamic sur-

veillants of brain parenchyma integrity and rapidly react to
potential threats by encapsulation of dangerous foci, removal
of apoptotic cells and assistance with tissue regeneration in
toxin-induced demyelination

[44,45]

. In the context of nonauto-

immune pathogen-associated inflammation, the microglia
protects the neuronal compartment

[46]

. Contrarily, in MS,

microglia and macrophages are shifted toward a strongly pro-
inflammatory phenotype and may potentiate neuronal damage
by releasing proinflammatory cytokines (i.e., TNF-

α, IL-1β,

IL-6) and proinflammatory molecules such as nitric oxide,
proteolytic enzymes and free radicals

[47–49]

. In a MS animal

model of experimental autoimmune encephalomyelitis (EAE),
paralysis of microglia in vivo, resulted in substantial ameliora-
tion of the clinical signs and in strong reduction of CNS inflam-
mation, demonstrating their active involvement in damage pro-
cesses

[50]

. However, it is doubtful whether monocyte-derived

macrophages and microglia actually have the potential to influ-
ence their fate. The adaptive immune system is more likely to
direct the attack against CNS cells.

Clonally expanded CD8

T cells have been shown within MS

lesions as well as in the cerebrospinal fluid of MS patients

[51,52]

However, the significance of these CD8

T cells in MS patho-

genesis is controversial since there is evidence for a suppressor
function that inhibits pathogenic autoreactive CD4

T cells

[53–55]

and evidence for a tissue-damaging role because a signifi-

cant correlation between the extent of axonal damage and the
number of CD8

T cells has been reported

[10,42]

. In accordance

with the latter observation, MHC class I-restricted CD8

T cells

were found to induce neuronal cell death in certain immu-
nological constellations in cultured neurons and hippocam-
pal brain slices

[56,57]

. In addition, the transsection of MHC

class I-induced neurites by CD8

T cells has been described

[58]

a process that might also contribute to pathology in human dis-
ease. In contrast, a study in EAE has shown enhanced neuronal
damage in the absence of MHC class I molecules in vivo

[59]

supporting earlier reports on pronounced immunoregulatory
functions of CD8

T cells

[55,60,61]

. Up until now, direct CD8

T-cell-mediated neuronal damage has not been demonstrated
with sufficient evidence and a specific neuronal epitope trig-
gering CD8

T-cell-mediated neuronal damage in MS has not

yet been found.

Current evidence on the induction and, most likely, in the

perpetuation of MS still favors CNS-reactive CD4

T cells as

the single most important component in the induction of an
autoimmune response against the myelin sheath. Nevertheless,
the contribution of CD4

T cells to neurodegeneration is a matter

of debate. Doubts arise from the fact that CD4

T cells seem to

be quite rare in the lesions of MS patients – at least in later disease
stages – and that treatments with antibodies directed against
T cells and their differentiation – for example, ustekinumab
(IL-12/23 p40 neutral antibody) – did not show therapeutic
efficacy in MS patients

[62]

. However, the genetic risk of MS and

EAE is, to a substantial degree, conferred by MHC class II alleles
and to other genes involved in T-cell phenotype expression in
both the human disease and the murine disease model

[63,64]

. An

affinity between invading activated CD4

T cells and neurons

had not seriously been considered to date as neurons do not
express MHC class II molecules, which are required to make
target T cells accessible for this immune cell subset, and CD4

T cells invading the CNS in the course of neuroinflammatory
diseases are usually not specific for neuronal antigens. However,
due to recent advances in deep-tissue imaging using two-photon
microscopy, interactions between neurons and immune cells can
be investigated in vivo and in organotypic microenvironments.
These have revealed that encephalitogenic CD4

T cells possess

marked migratory capacities within the CNS parenchyma and
directly interact with the soma and processes of neurons, partially
leading to cell death

[65]

. Among others, the death ligand TNF-

related apoptosis-inducing ligand as a T-cell-associated effector
molecule contributes to the induction of neuronal apoptosis. It
has been shown that TNF-related apoptosis-inducing ligand

Luessi, Siffrin & Zipp

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Neurodegeneration in multiple sclerosis: novel treatment strategies

expressed by CD4

T cells induces collateral death of neurons

in the inflamed brain and promotes EAE

[66,67]

. Importantly, by

using in vivo live imaging in EAE, a direct contact between CD4

T cells, particularly T helper (Th17) cells, and neurons has been
confirmed that leads to neuronal dysfunction and subsequently
cell death

[68]

. This neuronal injury mediated by Th17 cells was

Table 1. Approved therapies in multiple sclerosis.

Compound

Proposed mechanisms

Indication

Clinical outcome

MRI outcome

Ref.

Secretion of BDNF by
GA-reactive T cells

CIS

Reduces disability rate

Reduces proportion of
new lesions evolving to
black holes

[89,96,97,143]

Modulation of T-cell
activation and proliferation

RR-MS

Reduces relapse rate

Reduces gadolinium-
enhancing lesions

Augmentation of the ratio
of anti-inflammatory to
proinflammatory cytokines

Increases
N-acetyl-aspartate/creatine
ratio

IFN-

and -

Inhibition of T-cell
activation and
costimulation

CIS

Delay to Poser MS in
CIS patients

Reduces gadolinium-
enhancing lesions

[101,144–146]

Modulation of anti-
inflammatory and
proinflammatory cytokines

RR-MS

Reduces relapse rate

Reduces T2 lesions

Downregulation of T-cell
migration

SP-MS
(IFN-

)

Increased time to
confirmed progression
in SP-MS

Reduces the mean
T2 lesion volume

Suppression of Th17 cell
differentiation

Reduces development of
permanent black holes
(IFN-

)

Stimulates the production
of NGF in early stages of
the disease

Slows progressive loss of
brain tissue in CIS
patients (IFN-

)

Mitoxantrone

B- and T-cell suppression

Active
RR-MS

Reduces relapse rate

Reduces the T2 lesion
load

[147,148]

Eliminates and deactivates
monocytes and
macrophages

SP-MS

Reduces progression of
disability

Reduces gadolinium-
enhancing lesions

Inhibits T-cell migration

Natalizumab

Inhibits transendothelial
migration of leukocytes
across the blood–brain
barrier

Active
RR-MS

Reduces relapse rate

Reduces gadolinium-
enhancing lesions

[149]

Reduces progression of
disability

Reduces T2 lesions

Fingolimod
(FTY720)

Modulates activation of
S1P receptors 1, 3–5

Active
RR-MS

Reduces relapse rate

Reduces the rate of brain
atrophy

[104]

Prevents egress of
lymphcytes from second-
ary lymphoid tissue to sites
of inflammation

Reduces risk of disability
progression

Reduces gadolinium-
enhancing lesions

Differentially retains
effector memory cells and
Th17 cells

Reduces the number of
new or enlarging
T2-hyper-intense lesions

Might promote remyelina-
tion by acting on oligo-
dendrocyte S1P5 receptors

BDNF: Brain-derived neurotrophic factor; CIS: Clinically isolated syndrome; GA: Glatiramer acetate; MS: Multiple sclerosis; RR-MS: Relapsing-remitting MS;

S1P: Sphingosine-1-phosphate; SP-MS: Secondary progressive MS; Th: T helper.

Adapted with permission from

[150].

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found to be lymphocyte function-associated antigen 1-dependent
and potentially reversible. These results suggest that once they
reach the CNS, CD4

T cells are directly involved in local

neuronal damage processes in EAE. However, these findings
based on experiences in animal models need to be confirmed in
MS patients.

Axonal degeneration as a consequence of demyelination

Although irreversible neurological disability in MS patients
results from axonal degeneration

[30,69]

, knowledge of the

mechanisms by which demyelinated axons degenerate is far
from complete. The ‘virtual hypoxia hypothesis’ postulates that
demyelination increases the energy demand in denuded axons

[43]

. To safeguard nerve conduction, since the voltage-gated Na

channels are usually concentrated in axons that have incom-
plete myelination, larger numbers of Na

channels are needed

to compensate for loss of saltatory axon potential propagation

[70,71]

. However, higher numbers of Na

channels necessitate an

increased energy supply to restore transaxolemmal Na

and K

gradients. In addition, an impaired axoplasmatic ATP produc-
tion in chronically demyelinated axons due to mitochondrial
dysfunction has been described

[72]

. The function of mitochon-

drial respiratory chain complex I and III was reduced by 40–50%
in mitochondrial-enriched preparations from the motor cortex of
MS patients

[73]

. Furthermore, defects of mitochondrial respira-

tory chain complex IV have been reported

[74,75]

, and have been

associated with hypoxia-like tissue injury

[76]

and reduced brain

NAA concentration

[77]

. The combination of increased energy

requirements and compromised ATP production as a result of
demyelination leads to a vicious circle by the loss of Na

ATPase

[78]

, which contributes to an increased intracellular Na

Consequently, Ca

is released from intracellular stores

[79]

and

the direction of the Na

/Ca

exchanger is reversed, resulting

in additional extracellular Ca

influx

[80]

. That in turn leads

to Ca

-mediated degenerative responses such as cytoskeleton

disruption and cell death

[81,82]

Aside from the summarized dramatic ion and energy imbal-

ances following demyelination, the lack of structural as well as
trophic support to axons provided by myelin and oligodendro-
cytes also contributes to neurodegeneration

[83,84]

. In vitro evi-

dence suggests that oligodendrocytes produce trophic factors such
as IGF-1 and neuregulin that promote normal axon function and
survival

[85,86]

. Moreover, mice lacking structural components of

compact myelin such as proteolipid protein demonstrated a late
onset, slowly progressing axonopathy

[87]

. However, oligoden-

drocyte dysfunction independent of and prior to inflammation
in classic MS still lacks direct evidence.

Therapeutic approaches to neuronal degeneration
in MS

All currently approved MS therapeutics primarily target inflam-
mation. However, recent insights into inflammatory neurodegen-
eration in MS indicate that an optimized therapeutic approach
should specifically tackle the promotion of neuroprotection and
repair to prevent chronic disability. This is even more important

as serious side effects of the highly effective anti-inflammatory
therapy regimen in MS and the need for a life-long treatment for
the authors’ MS patients preclude the majority of patients from
high-efficiency therapeutics, as risk–benefit evaluations are in
favour of the basic therapeutics.

The potentially neuroprotective effects of approved and novel

treatment strategies and most importantly direct neuroprotec-
tives, which might be used as an add-on to established basic
anti-inflammatory therapeutics, will be discussed below.

Current therapeutic concepts

At present, five disease-modifying drugs have been approved for
MS therapy

ablE

. Glatiramer acetate (GA) and the IFN-

preparations have been established as first-line disease-modifying
immune-modulatory treatments that reduce the relapse rate and
ameliorate relapse severity

[88]

, but also slow the progression of

disability in patients with RR-MS

[89,90]

. Through binding to a

specific receptor, IFN-

β exerts a variety of immunological effects.

Presumed mechanisms of action include inhibition of T-cell
activation and co-stimulation, modulation of anti-inflammatory
and proinflammatory cytokines, and downregulation of T-cell
migration

[91,92]

. GA is a synthetic peptide composed of a random

mix of four amino acids resembling myelin basic protein that
leads to a shift in immune response from Th1 to a more anti-
inflammatory Th2-profile

[93]

. GA also takes effect by limiting

T cells through downregulating proliferation, activation
and induction of apoptosis

[88,94]

. There is evidence that in

addition to their immune-modulatory effects, GA and IFN-

also appear to have neuroprotective effects. GA-specific T cells
have demonstrated an increased production of brain-derived
neurotrophic factor (BDNF), which propagates neuronal survival

[95]

. Furthermore, GA treatment was associated with a reduction

of PBHs in patients

[96]

and increased the NAA concentration

in magnetic resonance spectroscopy

[97]

, which implies that this

treatment may reduce axonal injury in developing lesions and
maintain axonal metabolic function. It has been shown that
IFN-

β stimulates the production of NGF in early stages of disease

and inhibits microglia and gliosis

[98,99]

. In MRI-based studies,

treatment with IFN-

β was associated with a reduced development

of PBH as well as a decrease in brain atrophy rate

[22,100,101]

Whether these findings are mediated by direct neuroprotective
effects of GA and IFN-

β or result from their anti-inflammatory

properties remains to be established.

The newly approved immune-modulatory treatment with

Fingolimod (FTY720) is also supposed to have neuroprotective
properties. Following in vivo phosphorylation, it acts as a modula-
tor of the activity of sphingosine 1-phosphate receptors, thus pre-
venting lymphocyte egress from secondary lymphatic organs and
subsequent migration to sites of inflammation

[102]

. It might also

diminish astrogliosis and promote remyelination via sphingosine
1-phosphate receptors on astrocytes and oligodendrocytes

[103]

In a recent 2-year Phase III trial, fingolimod-treated patients had
a reduced rate of disability progression and brain volume loss as
well as a smaller increase in T1-hypointense lesion volume than
patients who were given placebo

[104]

Luessi, Siffrin & Zipp

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Neurodegeneration in multiple sclerosis: novel treatment strategies

Table 2. Novel therapies in multiple sclerosis currently undergoing clinical development.

Compound Proposed mechanisms

Phase

Indication n

Study design

Duration
(months)

Outcome

Ref.

Alemtuzumab • mAb to CD52, a surface

antigen of unknown function
on lymphocytes, monocytes
and dendritic cells
• Induces a sustained T-cell
depletion and a transient
B-cell depletion
• Increases levels of BAFF
and regulatory T cells
• Increases secretion of BDNF
by lymphocytes

RR-MS

334

12 mg  alemtuzumab/
day, eight times
a year
versus
24 mg  alemtuzumab/
day, eight times a
year
versus
44 μg IFN-

three

times a week

• Improves mean
disability score
• Reduces
relapse rate
• Reduces
gadolinium-
enhancing
lesions
• Reduces brain
atrophy rate

[115,116]

Daclizumab

• mAB to CD25, a
component of the high-
affinity IL-2 receptor on
T cells
• Inhibition of early IL-2
receptor signal transduction
events
• Blocks T-cell activation and
expansion
• Causes expansion of
regulatory CD56 bright
natural killer cells
• Decreases the number of
CD8

T cells

RR-MS

230

2 mg  daclizumab/kg
bodyweight every
2 weeks
versus
1 mg  daclizumab/kg
bodyweight every
4 weeks
versus
placebo as add-on to
IFN-

• Trend toward
reducing relapse
rate
• Reduces
number of new
or enlarging
T2-hyperintense
lesions
• Reduces
gadolinium-
enhancing
lesions

[119]

Fumarate
(BG00012)

• Activation of transcription
factor Nrf2
• Induction of Th2-like
cytokines
• Induction of apoptosis in
activated T cells
• Downregulation of
intracellular adhesion
molecules and vascular
adhesion molecules
• Upregulation of antioxidant
response elements

RR-MS

257

120 mg  fumarate/day
versus
360 mg  fumarate/day
versus
720 mg  fumarate/day
versus
placebo

• Trend toward
reducing relapse
rate
• Reduces
gadolinium-
enhancing
lesions
• Reduces
number of new
or enlarging
T2-hyperintense
lesions

[108]

Laquinimod

• Immunmodulator related to
linomide with unknown
molecular target
• Anti-inflammatory activity
via Th1–Th2 shift
• Modulation of BDNF
secretion

III

RR-MS

1106

0.6 mg laquinimod/
day
versus
placebo

• Reduces
relapse rate
• Lowers risk of
sustained
progression of
disability
• Reduces
gadolinium-
enhancing
lesions
• Reduces
number of new
or enlarging
T2-hyperintense
lesions

[110]

BAFF: B-cell-activating factor of the tumor necrosis factor family; BDNF: Brain-derived neurotrophic factor; mAb: Monoclonal antibody; Nef2: Nuclear factor

E2-related factor 2; RR-MS: Relapsing-remitting multiple sclerosis; SP-MS: Secondary progressive multiple sclerosis; Th: T helper.

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Novel therapies undergoing clinical development

Several new compounds are currently undergoing clinical devel-
opment for MS therapy, including immunomodulatory as well
as nonselective and selective immunosuppressive drugs

ablE

The mechanism of action of some of these therapies under
development is not well understood. Agents such as cladribine
and teriflunomide are antiproliferative agents that take effect
by interfering with DNA synthesis, nucleotide metabolism and
signaling pathways of activated immune cells

[105,106]

. In a 2-year

Phase III trial, treatment with cladribine tablets significantly
reduced relapse rates, the risk of disability progression and MRI
measures of disease activity

[107]

. Despite these promising results,

the European Medicines Agency did not approve cladribine for
the treatment of MS because of safety concerns in the context of
an increased number of patients with cancer observed in trials
with cladribine.

A more specific immune-modulatory mode of action has been

proposed for two compounds currently in advanced clinical tri-
als, dimethylfumarate (BG00012) and laquinimod. A 24-week
Phase II trial demonstrated that dimethylfumarate treatment
led to a significant reduction of CEL and PBHs

[108]

, likely as

a result of the activation of the neuroprotective nuclear factor
E2-related factor 2 transcription pathway

[109]

. Laquinimod

showed a modest reduction of the annualized relapse rate and
a reduction in the risk of confirmed disability progression in a
24-month Phase III trail with RR-MS patients

[110]

. In this study,

treatment with laquinimod was also associated with reduced
MRI-measured disease activity. The effect by which laquinimod
exerts its anti-inflammatory activity may be due to its impact
on the dendritic cell compartment and a Th1–Th2 shift

[111,112]

Furthermore, laquinimod ameliorated EAE via BDNF-dependent
mechanisms, which may contribute to neuroprotection

[113]

Targeting mechanisms of the immune system with biologics

such as recombinant antibodies might provide additional selective
treatment strategies for MS. A possible candidate is alemtuzumab,
a humanized monoclonal antibody targeting the CD52 antigen,
which is a protein of unknown function expressed on the surface
of T and B cells, natural killer (NK) cells, a majority of monocytes
and macrophages and some dendritic cells

[114]

. The binding of

alemtuzumab results in rapid and prolonged depletion of targeted
cells by complement-dependent and antibody-dependent T cellu-
lar toxicity. In a recent 3-year Phase II trial, alemtuzumab signifi-
cantly reduced the risk of relapse, brain volume loss and accumu-
lation of disability in early RR-MS compared with IFN-

[115]

Patients treated with alemtuzumab experienced an improvement
in disability at 6 months that was sustained in the 5-year follow-
up study

[116]

. These findings for alemtuzumab treatment might

result, in part, from neuroprotection associated with increased
lymphocytic delivery of BDNF to the CNS

[117]

. Alemtuzumab

is now being investigated in Phase III trials, which will determine
the risk–benefit ratio of this potent agent, since alemtuzumab led
to significant side effects including autoimmune thyroid disorders
(>10%) and idiopathic thrombocytopenic purpura (2.8%).

This incidence of rare but severe side effects highlights the need

for further strategies preserving the high efficacy but minimiz-
ing the risk. Daclizumab – a humanized anti-CD25 monoclonal
antibody – appears to be an alternative with a favorable risk profile
thus far. It is directed against the IL-2 receptor (IL-2R), which is
upregulated on activated T cells. In EAE, IL-2R antibody therapy
has been shown to induce the expansion of an immunoregulatory
subset of NK cells, most likely by increasing free IL-2 levels, which
express high levels of CD56

[118]

. Data from a recent Phase II

trial showed that add-on treatment with daclizumab reduced the
number of new or enlarged CEL compared with IFN-

β alone

[119]

Table 2. Novel therapies in multiple sclerosis currently undergoing clinical development (cont.).

Compound Proposed mechanisms

Phase

Indication n

Study design

Duration
(months)

Outcome

Ref.

Rituximab

• mAB to CD20, a surface
antigen expressed on
B cells, but not on
plasma cells
• Causes rapid depletion of
B cells

RR-MS

104

1000 mg rituximab
on days 1 and 15
versus
placebo

• Reduces
relapse rate
• Reduces
gadolinium-
enhancing
lesions

[151]

Teriflunomide • Active metabolite of

leflunomide used for
rheumtoid arthritis
Impairs cellular nucleotide
metabolism by inhibiting
the dihydroorotate
dehydrogenase
• Suppresses tyrosine
kinases involved in signal
transduction pathways

RR-MS
SP-MS

179

7 mg teriflunomide/
day versus
14 mg teriflunomide/
day versus
placebo

• Trend toward
reducing relapse
rate
• Reduces
gadolinium-
enhancing
lesions
• Reduces
number of new
or enlarging
T2-hyperintense
lesions

[142]

BAFF: B-cell-activating factor of the tumor necrosis factor family; BDNF: Brain-derived neurotrophic factor; mAb: Monoclonal antibody; Nef2: Nuclear factor

E2-related factor 2; RR-MS: Relapsing-remitting multiple sclerosis; SP-MS: Secondary progressive multiple sclerosis; Th: T helper.

Luessi, Siffrin & Zipp

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Promising therapeutic concepts with putative
neuroprotective effects

New therapeutic strategies have evolved that specifically tar-
get the neurodegenerative aspect of MS

ablE

. Following up

on the findings that demyelination leads to an altered energy
demand and changes in intracellular ion homeostasis in neurons,
several ion channel blockers already in use for other medical
conditions are now being investigated in CNS autoimmun-
ity. Evidence from animal studies has shown beneficial effects
in rats with chronic EAE for up to 180 days after treatment
with phenytoin

[120]

, a Na

channel blocker commonly used

for epilepsy. Interestingly, when the study was repeated using
either phenytoin or carbamazepine, another antiepileptic with
Na

channel blocker capacities, the animals became acutely

worse after the withdrawal of either drug

[121]

, indicating that

more work needs to be done to understand the consequences
of the long-term effects of Na

channel blockers and of their

withdrawal in MS. Two other Na

-blocking agents, the anti-

arrhythmic agent flecainide and the antiepileptic lamotrigine,
have now been shown to improve axonal survival and decrease
disability in EAE-affected rats

[122,123]

. However, in a Phase II

study in patients with secondary progressive disease course,
lamotrigine showed an increase of cerebral volume loss which
was not clinically relevant, but could not be explained

[123]

This ‘pseudoatrophy’, seen in the early stages of this trial under
lamotrigine treatment, indicates that the choice of this trial end
point was not adequate. It highlights the importance of clini-
cal design and selection of paraclinical markers to develop trial
protocols that are adequate to detect neuroprotective effects.
Another clinical study of the antiepileptic drug topiramate,
which has partial Na

channel-blocking capabilities, in combi-

nation with IFN-

β in patients with RR-MS is currently under-

way. A direct neuroprotective effect of Na

channel blockers

remains to be demonstrated. In addition, anti-inflammatory
mechanisms on microglia and macrophages have been suggested

[124]

, which might lead to the rebound of disease after treatment

termination

[121]

In light of the ‘virtual hypoxia hypothesis’, promoting remy-

elination by blocking the transmembrane protein Lingo-1 is
another promising strategy to prevent neuronal damage

[43]

Treatment with an antibody of Lingo-1 has been demonstrated
to prevent and therapeutically improve EAE symptoms

[125]

This is reflected biologically through improved axonal integrity,
as confirmed by magnetic resonance diffusion tensor imaging
and by newly formed myelin sheaths, as determined by elec-
tron microscopy. The anti-Lingo-1 antibody BIIB033 is cur-
rently being i nvestigated in a Phase I study with MS patients
(ClinicalTrials.gov identifier: NCT01244139).

The blockade of voltage-gated Ca

channels (VGCC) is a

potentially promising target, as the elevated intracellular Ca

lev-

els lead to axonal damage through activation of different enzymes,
in particular proteases. In a study of EAE-affected rats, the effect
of bepridil, a broad-spectrum Ca

channel blocker, was com-

pared with nitrendipine, which is a blocker of

-type VGCCs.

Both drugs prevented axonal loss and disablity in treated animals

[126]

. However, clinical trials in MS patients are not available at

the moment.

Intracellular Ca

is also increased by the excitatory neuro-

transmitter glutamate via

α-amino-3-hydroxy-5-methyl-4-

isoxazolepropionic acid (AMPA)/kainate receptors. Antagonism
of AMPA/kainate receptors in EAE models resulted in improved
disability and decreased apoptosis of spinal cord neurons

[127,128]

With respect to MS and EAE, the detailed underlying mechanism
of action remains to be elucidated to further explain the treat-
ment effects. In addition, the unexpected rebound of disease after
withdrawal of AMPA/kainate receptor antagonists in EAE needs
further investigation

[128]

Among potential candidate compounds for neuroprotection,

erythropoietin – a hemapoietic growth factor commonly used to
treat anaemia – is another promising agent. Erythropoietin and
its receptor are widely expressed in the CNS and appear to have a
beneficial effect on several models of neurological injury including
ischemia, trauma and epilepsy

[129,130]

. EAE studies have indi-

cated benefits in inflammatory demyelination through inhibition
of proinflammatory cytokines

[131]

. An early trial in MS demon-

strated clinical and electrophysiological improvement upon high-
dose erythropoietin treatment for half a year

[132]

. However, MRI

volumetric analysis of total brain and ventricles did not uncover
changes compared with baseline upon treatment with erythro-
poietin. Results of a larger, randomized controlled study are now
awaited.

Cannabis is used by MS patients for relief from a variety of

symptoms

[133]

, despite the equivocal results of several clinical trials

[134]

. Improved knowledge about the major psychoactive ingredi-

ent of cannabis,

δ-9-tetrahydrocannabinol, and its CB1 and CB2

receptors has resulted in an increase of experimental data from
MS animal models. In vitro evidence suggests that cannabinoids
have an effect on several potential mechanisms of axonal injury,
including glutamate release

[135]

, oxidative free radicals as well as

damaging Ca

influx

[136]

. Furthermore, exogenous agonists of the

cannabinoid CB1 receptor have possible neuroprotective effects in
EAE animal models

[137]

, and strategies to increase the endogenous

cannabinoid anandamide also appear to attenuate the clinico-
pathological features of EAE

[138]

. Despite these promising results,

neuroprotective effects in MS by canna binoids and the modulation
of the endocannabinoid system must still be established.

Statins, primarily used as effective cholesterol-lowering agents,

are now recognized to have unexpected neuroprotective effects,
which have been shown in animal models of MS

[139]

. In an MRI-

based study in patients with RR-MS, treatment with atorva statin,
alone or in combination with IFN-

β, led to a substantial reduction

in the number and volume of CEL

[139]

. Moreover, a clinical study

in RR-MS suggested that adding statins to IFN-

β may reduce the

relapse rate compared with IFN-

β alone

[140]

. However, it has been

shown that statins impair remyelination in vitro and in vivo

[141]

The clinical implication of this finding for statin treatment in

MS patients remains to be elucidated.

Combining anti-inflammatory and neuroprotective effects

should result in more efficient therapy. In light of this, the authors
are currently conducting a clinical controlled treatment trial in

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Table 3. Promising therapeutic approaches with putative neuroprotective effects in multiple sclerosis.

Compound

Proposed mechanisms

Phase

Indication

Study
design

Duration
(months)

Outcome

Ref.

Amiloride

• Blocks ASIC1
• Inhibits influx of sodium
and calcium into axons
and oligodendrocytes
• Protects both neurons
and myelin from damage
in EAE

II
(planned)

RR-MS

[152,153]

Cannabinoids
(

Δ9-THC)

• Modulation of
cannabinoid receptor
activation
• Reduces leukocyte
rolling and adhesion to
cerebral microvessels via
CB(2) receptor
• Reduces immune cell
invasion into CNS

RR-MS
SP-MS
PP-MS

657

Body-
weight-
adjusted
dose of

Δ9-THC
(maximum
25 mg/day)
versus
placebo

[154,155]

Epigallocatechin-
3-gallate

• Limits brain
inflammation and
neuronal damage in EAE
• Abrogates proliferation
and TNF-

α production of

encephalitogenic T cells
Protects against neuronal
injury induced by
N-methyl-

-aspartate or

TRAIL
• Directly blocks the
formation of neurotoxic
reactive oxygen species
in neurons

II
(ongoing)

RR-MS

800 mg
EGCG/day
versus
placebo

[156,157]

Erythropoietin

• Ameliorates the clinical
course in EAE
Reduces proinflammatory
cytokines
• Stabilizes blood–brain
barrier integrity
• Increases BDNF-positive
cells
• Stimulating oligoden-
drogenesis

PP-MS
SP-MS

48,000 IU
rhEPO
bi-weekly
versus
8000 IU
rhEPO
bi-weekly

• Reduces
disability
score
• Improves
cognitive
performance
• Trend
toward
improving
maximum
walking
distance

[130–132]

Flupirtine

• Centrally acting
nonopioid analgesic drug
• Neuroprotective via
activation of inwardly
rectifying potassium
channels
• Inhibits TRAIL-mediated
death of neurons
• Increases neuronal
survival by Bcl-2
upregulation

II
(ongoing)

RR-MS

300 mg
flupirtine/day
versus
placebo

[158,159]

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ASIC1: Acid-sensing ion channel-1; BDNF: Brain-derived neurotrophic factor; EAE: Experimental

autoimmune encephalomyelitis; EGCG: Epigallocatechin gallate; PP-MS: Primary-progressive multiple sclerosis; rhEPO: Recombinant human erythropoietin;

RR-MS: Relapsing-remitting multiple sclerosis; SP-MS: Secondary progressive multiple sclerosis; THC: Tetrahydrocannabinol; TRAIL: TNF-related apoptosis-inducing ligand.

Luessi, Siffrin & Zipp

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Neurodegeneration in multiple sclerosis: novel treatment strategies

RR-MS to investigate the efficacy of epigallocatechin-3-gallate.
In experimental studies, this flavonoid exhibited antioxidant and
proteasome inhibitory capacities, and thus anti-inflammatory as
well as neuroprotective effects in chronic neuroinflammation

[142]

Expert commentary & five-year view

Over the last decades, the immunological aspects of MS have
been extensively investigated, focusing on the immune system’s

contribution in the pathogenesis of the myelin-targeted inflam-
matory attack. The rediscovery of the importance of neuronal
damage in MS has now drawn attention to the neurobiologi-
cal consequences of autoimmune demyelination. As outlined
here, deeper molecular insights into the mechanisms of inflam-
matory neurodegeneration in MS will be necessary to further
identify molecular targets for the development of more efficient
treatment strategies.

Table 3. Promising therapeutic approaches with putative neuroprotective effects in multiple sclerosis (cont.).

Compound

Proposed mechanisms

Phase

Indication

Study
design

Duration
(months)

Outcome

Ref.

Lamotrigine

• Blocks voltage-sensitive
Na

channels

• Prevents from intracel-
lular calcium accumulation
via Na

/Ca

exchanger

Neuroprotective in EAE

SP-MS

120

40 mg
lamotrigine/
day
versus
placebo

• Reduces the
deterioration
of the
timed 25-foot
walk
• No beneficial
effect on
cerebral
volume loss

[123]

Riluzole

• Modulates glutamate
receptors
• Inhibits the release of
glutamate from nerve
terminals
• Suppression of disease
activity and reduction of
axonal damage in EAE

PP-MS

100 mg
riluzole/day

• Reduces the
development
of T1-hypo-
intense
lesions
• Reduces
the rate of
cervical cord
atrophy
• Only slightly
decreases
the rate
of brain
atrophy

[160]

Statins

• Attenuates immune
response by modulation
of dendritic cell
function
• Inhibition of rho family
functions promotes myelin
repair in EAE
• Increases serum levels of
the regulatory cytokine
IL-10

RR-MS

40 mg
simvastatin/
day
versus
placebo as
add-on to
30 μg IFN-

once weekly

• Reduces
relapse rate
• Trend toward
reducing
disability
progression
• Trend toward
reducing
gadolinium-
enhancing
lesions

[140]

Topiramate

• Blocks voltage-sensitive
Na

channels

• Inhibits excitatory
neurotransmission
• Enhances GABA-
activated chloride
channels
• Modulates kainate and
AMPA receptors

II (ongoing) RR-MS

Topiramate
versus
placebo as
add-on to
30 μg IFN-

once weekly

[161]

AMPA:

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ASIC1: Acid-sensing ion channel-1; BDNF: Brain-derived neurotrophic factor; EAE: Experimental

autoimmune encephalomyelitis; EGCG: Epigallocatechin gallate; PP-MS: Primary-progressive multiple sclerosis; rhEPO: Recombinant human erythropoietin;

RR-MS: Relapsing-remitting multiple sclerosis; SP-MS: Secondary progressive multiple sclerosis; THC: Tetrahydrocannabinol; TRAIL: TNF-related apoptosis-inducing ligand.

CME

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Key issues

•  Damage to the neuronal compartment already plays an important role early in the pathology of multiple sclerosis.
•  The neuronal injury in the course of chronic neuroinflammation is a key factor determining long-term disability in patients.
•  Quantification of neurodegeneration by modern imaging techniques is necessary to evaluate the neuroprotective capacity of novel

treatments.

• Viewing multiple sclerosis as both inflammatory and neurodegenerative has major implications for therapy, with CNS protection and

repair being needed in addition to controlling inflammation.

• Deeper molecular insights into the mechanisms of inflammatory neurodegeneration in multiple sclerosis will be necessary to further

identify potential drug targets.

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Luessi, Siffrin & Zipp

CME

1077

www.expert-reviews.com

Review

Neurodegeneration in multiple sclerosis: novel treatment strategies

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Activity Evaluation

Where 1 is strongly disagree and 5 is strongly agree

1 2 3 4 5

1. The activity supported the learning objectives.

2. The material was organized clearly for

learning to occur.

3. The content learned from this activity will

impact my practice.

4. The activity was presented objectively and

free of commercial bias.

1. Your patient is a 34-year-old woman recently diagnosed with relapsing-remitting multiple sclerosis (MS). Based on

the review by Dr. Luessi and colleagues, which of the following statements about the role of inflammatory
neuronal injury in this patient’s disease is most likely correct?

At this stage, the pathophysiology is exclusively inflammatory demyelination

Neuronal damage does not occur in the absence of demyelination

Axonal pathology is particularly evident in active and chronic active MS lesions throughout the disease course and is
closely associated with inflammatory infiltration

CD8

T cells within multiple sclerosis lesions activate pathogenic autoreactive CD4

T cells

2. Based on the review by Dr. Luessi and colleagues, which of the following statements about methods of

quantification of neuronal injury for the patient described in question 1 is most likely correct?

Monitoring contrast-enhancing lesions (CEL) on routine MRI is sufficient

T2 lesion load on MRI is an excellent predictor of later disability progression

Change in brain volume on MRI is not helpful, but evolution of persistent hyperintense lesions on T2-weighted scans
may be helpful

Magnetic resonance spectroscopy and retinal nerve fiber layer thickness on optical coherence tomography are useful
techniques

3. Based on the review by Dr. Luessi and colleagues, which of the following statements about therapeutic

approaches to neuronal degeneration in multiple sclerosis would most likely be correct?

Many currently approved agents for multiple sclerosis do not primarily target inflammation

To prevent chronic disability, an optimized therapeutic approach should target inflammation alone

Glatiramer acetate (GA) and interferon-

β (IFN-β) are first-line disease-modifying immune-modulatory treatments that

reduce relapses and slow the progression of disability

Fingolimod (FTY720) has no neuroprotective properties