Expert Review of Neurotherapeutics

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Neurodegeneration in multiple sclerosis: novel treatment strategies Felix Luessi, Volker Siffrin & Frauke Zipp To cite this article: Felix Luessi, Volker Siffrin & Frauke Zipp (2012) Neurodegeneration in multiple sclerosis: novel treatment strategies, Expert Review of Neurotherapeutics, 12:9, 1061-1077, DOI: 10.1586/ern.12.59 To link to this article: http://dx.doi.org/10.1586/ern.12.59

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CME THEMED ARTICLE y Demyelinating Diseases For reprint orders, please contact [email protected]

Neurodegeneration in multiple sclerosis: novel treatment strategies Expert Rev. Neurother. 12(9), 1061–1077 (2012)

Felix Luessi, Volker Siffrin and Frauke Zipp* Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), 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 [email protected]

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. Keywords: multiple sclerosis • neurodegeneration • neuronal injury • neuroprotection • treatment

Medscape: Continuing Medical Education Online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and ­complete the evaluation at www.medscape.org/journal/expertneurothera; (4) view/print certificate.

Release date: 5 October 2012; Expiration date: 5 October 2013

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

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10.1586/ERN.12.59

© 2012 Expert Reviews Ltd

ISSN 1473-7175

1061

Review

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Luessi, Siffrin & Zipp

Financial & competing interests disclosure

Editor Elisa Manzotti Publisher, Future Science Group, London, UK. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. CME Author Laurie Barclay Freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Authors and Credentials 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.

Introduction

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disorder of the CNS, and the leading cause of nontraumatic 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 epidemiological and association studies make the interplay between environmental 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 inflammatory 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 t­ reatment 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 1062

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 histopathologic data clearly show that pathology in the neuronal compartment 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. Expert Rev. Neurother. 12(9), (2012)

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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 subclinical 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, evolution 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 disability 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 fraction determination [22] . The extent of brain atrophy seems to correlate 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 persistent ‘black holes’ [PBHs]) is a lesion-based MRI measure that reflects tissue rarefaction following axonal damage [16] and correlates 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 damage in patients with MS [28,29] . Here the neuronal metabolite N-acetyl-aspartate (NAA) – a highly specific marker of neuronal www.expert-reviews.com

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and axonal integrity – is quantified. Abnormally low NAA values were already observed in the early stages of disease, even before significant disability was clinically evident [15] . In longitudinal studies, the rate of decline of NAA concentration correlated 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 function and dysfunction, and can thus show pronounced and sometimes 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 neuroimmunology. 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 correlates 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 1063

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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 experimental neuroimmunology. The underlying disease pathophysiology 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 proinflammatory neurotoxic substances; direct damage processes, which involve cell contact-dependent mechanisms; and demyelination-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 neurodegeneration are associated with MS [40] . This lends weight to the idea that inflammation might be a relevant factor for neurodegeneration 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 correlation 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 surveillants 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 nonautoimmune pathogen-associated inf lammation, the microglia protects the neuronal compartment [46] . Contrarily, in MS, microglia and macrophages are shifted toward a strongly proinflammatory 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 amelioration of the clinical signs and in strong reduction of CNS inflammation, demonstrating their active involvement in damage processes [50] . However, it is doubtful whether monocyte-derived 1064

CME macrophages and microglia actually have the potential to influence 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 pathogenesis 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 significant 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 immunological constellations in cultured neurons and hippocampal 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 disease. 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 triggering 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 TNFrelated 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 Expert Rev. Neurother. 12(9), (2012)

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Table 1. Approved therapies in multiple sclerosis. Compound

Proposed mechanisms

Indication

Clinical outcome

MRI outcome

GA

Secretion of BDNF by GA-reactive T cells

CIS

Reduces disability rate

Reduces proportion of new lesions evolving to black holes

Modulation of T-cell activation and proliferation

RR-MS

Reduces relapse rate

Reduces gadoliniumenhancing lesions

Mitoxantrone

Inhibition of T-cell activation and costimulation

CIS

Delay to Poser MS in CIS patients

Reduces gadoliniumenhancing lesions

Modulation of antiinflammatory and proinflammatory cytokines

RR-MS

Reduces relapse rate

Reduces T2 lesions

Downregulation of T-cell migration

SP-MS (IFN-β1b)

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-β1b)

Stimulates the production of NGF in early stages of the disease

Slows progressive loss of brain tissue in CIS patients (IFN-β1a)

B- and T-cell suppression

Active RR-MS

Reduces relapse rate

Reduces the T2 lesion load

Eliminates and deactivates monocytes and macrophages

SP-MS

Reduces progression of disability

Reduces gadoliniumenhancing lesions

Active RR-MS

Reduces relapse rate

Reduces gadoliniumenhancing lesions

Reduces progression of disability

Reduces T2 lesions

Reduces relapse rate

Reduces the rate of brain atrophy

Reduces risk of disability progression

Reduces gadoliniumenhancing lesions

Inhibits T-cell migration Natalizumab

Fingolimod (FTY720)

Inhibits transendothelial migration of leukocytes across the blood–brain barrier

Modulates activation of S1P receptors 1, 3–5

[89,96,97,143]

Increases N-acetyl-aspartate/creatine ratio

Augmentation of the ratio of anti-inflammatory to proinflammatory cytokines IFN-β1a and -β1b

Ref.

[101,144–146]

[147,148]

 

Active RR-MS

Prevents egress of lymphcytes from secondary lymphoid tissue to sites of inflammation Differentially retains effector memory cells and Th17 cells

[149]

  [104]

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

Might promote remyelination by acting on oligodendrocyte 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].

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 + www.expert-reviews.com

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 1065

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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 incomplete 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 production in chronically demyelinated axons due to mitochondrial dysfunction has been described [72] . The function of mitochondrial 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 respiratory 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 + /K+ ATPase [78] , which contributes to an increased intracellular Na+. Consequently, Ca 2+ is released from intracellular stores [79] and the direction of the Na +/Ca 2+ exchanger is reversed, resulting in additional extracellular Ca 2+ influx [80] . That in turn leads to Ca 2+ -mediated degenerative responses such as cytoskeleton disruption and cell death [81,82] . Aside from the summarized dramatic ion and energy imbalances following demyelination, the lack of structural as well as trophic support to axons provided by myelin and oligodendrocytes also contributes to neurodegeneration [83,84] . In vitro evidence 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, oligodendrocyte 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 inflammation. However, recent insights into inflammatory neurodegeneration 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 1066

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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 neuroprotectives, 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 (Table 1) . Glatiramer acetate (GA) and the IFN-β 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 antiinflammatory 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-β 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 modulator of the activity of sphingosine 1-phosphate receptors, thus preventing 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] . Expert Rev. Neurother. 12(9), (2012)

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

Proposed mechanisms

Phase

Indication n

Study design

Duration Outcome (months)

II 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/ 36 day, eight times a year versus 24 mg alemtuzumab/ day, eight times a year versus 44 μg IFN-β1a three times a week

• Improves mean [115,116] disability score • Reduces relapse rate • Reduces gadoliniumenhancing lesions • Reduces brain atrophy rate

Daclizumab

II • mAB to CD25, a component of the highaffinity 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 18 bodyweight every 2 weeks versus 1 mg daclizumab/kg bodyweight every 4 weeks versus placebo as add-on to IFN-β

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

[119]

Fumarate (BG00012)

• Activation of transcription II 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 12 versus 360 mg fumarate/day versus 720 mg fumarate/day versus placebo

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

[108]

Laquinimod

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

RR-MS  

1106 0.6 mg laquinimod/   day versus placebo

24

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

[110]

Ref.

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

Proposed mechanisms

Phase

Indication n

Study design

Duration Outcome (months)

Rituximab

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

II  

RR-MS  

104  

1000 mg rituximab on days 1 and 15 versus placebo

12

• Reduces relapse rate • Reduces gadoliniumenhancing lesions

[151]

II  

RR-MS SP-MS  

179  

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

9

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

[142]

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

Ref.

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.

Novel therapies undergoing clinical development

Several new compounds are currently undergoing clinical development for MS therapy, including immunomodulatory as well as nonselective and selective immunosuppressive drugs (Table 2) . 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 trials, 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] . 1068

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 cellular toxicity. In a recent 3-year Phase II trial, alemtuzumab significantly reduced the risk of relapse, brain volume loss and accumulation of disability in early RR-MS compared with IFN-β1a [115]. Patients treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained in the 5-year followup 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 minimizing 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] . Expert Rev. Neurother. 12(9), (2012)

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Promising therapeutic concepts with putative neuroprotective effects

New therapeutic strategies have evolved that specifically target the neurodegenerative aspect of MS (Table 3). 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 autoimmunity. 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 antiarrhythmic 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 clinical 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 combination with IFN-β in patients with RR-MS is currently underway. 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 remyelination 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 electron microscopy. The anti-Lingo-1 antibody BIIB033 is currently being i­nvestigated in a Phase I study with MS patients (ClinicalTrials.gov identifier: NCT01244139). The blockade of voltage-gated Ca 2+ channels (VGCC) is a potentially promising target, as the elevated intracellular Ca 2+ levels 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 2+ channel blocker, was compared with nitrendipine, which is a blocker of l-type VGCCs. Both drugs prevented axonal loss and disablity in treated animals www.expert-reviews.com

Review

[126] . However, clinical trials in MS patients are not available at the moment. Intracellular Ca2+ is also increased by the excitatory neurotransmitter glutamate via α-amino-3-hydroxy-5-methyl-4isoxazolepropionic 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 treatment 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 indicated benefits in inflammatory demyelination through inhibition of proinflammatory cytokines [131]. An early trial in MS demonstrated clinical and electrophysiological improvement upon highdose 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 erythropoietin. 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 ingredient 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 Ca2+ 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 clinicopathological features of EAE [138]. Despite these promising results, neuroprotective effects in MS by canna­binoids 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 MRIbased study in patients with RR-MS, treatment with atorva­statin, 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

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  

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

II

RR-MS SP-MS PP-MS

Epigallocatechin3-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- d-aspartate or TRAIL • Directly blocks the formation of neurotoxic reactive oxygen species in neurons

II (ongoing)

RR-MS

Erythropoietin

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

II

PP-MS SP-MS

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

n

Study design

Duration (months)

Outcome

Ref. [152,153]

657

10

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

4

[154,155]

800 mg EGCG/day versus placebo

18

[156,157]

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

12

 

12 300 mg flupirtine/day versus placebo

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

[130–132]

[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.

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

Proposed mechanisms

Phase

Indication

n

Study design

Duration (months)

Outcome

Ref.

Lamotrigine

• Blocks voltage-sensitive Na + channels • Prevents from intracellular calcium accumulation via Na + /Ca2+ exchanger Neuroprotective in EAE

II

SP-MS

120

40 mg lamotrigine/ day versus placebo

24

• 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

II

PP-MS

15

100 mg riluzole/day

24

• 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

II

RR-MS

85

40 mg simvastatin/ day versus placebo as add-on to 30 μg IFN-β1a once weekly

12

• Reduces relapse rate • Trend toward reducing disability progression • Trend toward reducing gadoliniumenhancing lesions

[140]

Topiramate

• Blocks voltage-sensitive Na + channels • Inhibits excitatory neurotransmission • Enhances GABA­activated  chloride channels  • Modulates kainate and AMPA receptors

II (ongoing) RR-MS

Topiramate versus placebo as add-on to 30 μg IFN-β1a 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.

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 n ­ euroinflammation [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

www.expert-reviews.com

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

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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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Neurodegeneration in multiple sclerosis: novel treatment strategies

Review

Neurodegeneration in multiple sclerosis: novel treatment strategies

To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 70% passing score) and earn continuing medical education (CME) credit, please go to www.medscape.org/ journal/expertneurothera. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.org. If you are not registered on Medscape.org, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited provider, [email protected]. For technical assistance, contact [email protected]. American Medical Association’s Physician’s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please refer to http://www.ama-assn. org/ama/pub/category/2922.html. The AMA has determined 1.

that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits™. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in CME activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA CME credit certificate and present it to your national medical association for review. 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.

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?

£ A At this stage, the pathophysiology is exclusively inflammatory demyelination £ B Neuronal damage does not occur in the absence of demyelination £ C Axonal pathology is particularly evident in active and chronic active MS lesions throughout the disease course and is closely associated with inflammatory infiltration

£ D 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?

£ A Monitoring contrast-enhancing lesions (CEL) on routine MRI is sufficient £ B T2 lesion load on MRI is an excellent predictor of later disability progression £ C Change in brain volume on MRI is not helpful, but evolution of persistent hyperintense lesions on T2-weighted scans may be helpful

£ D 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?

£ A Many currently approved agents for multiple sclerosis do not primarily target inflammation £ B To prevent chronic disability, an optimized therapeutic approach should target inflammation alone £ C 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

£ D Fingolimod (FTY720) has no neuroprotective properties

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