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Seminar

Multiple sclerosis
Alastair Compston, Alasdair Coles

Lancet 2008; 372: 1502–17 Multiple sclerosis is primarily an inflammatory disorder of the brain and spinal cord in which focal lymphocytic
Department of Clinical infiltration leads to damage of myelin and axons. Initially, inflammation is transient and remyelination occurs but is
Neurosciences, University of not durable. Hence, the early course of disease is characterised by episodes of neurological dysfunction that usually
Cambridge Clinical School,
recover. However, over time the pathological changes become dominated by widespread microglial activation
Addenbrooke’s Hospital,
Cambridge, UK associated with extensive and chronic neurodegeneration, the clinical correlate of which is progressive accumulation
(A Compston FRCP, of disability. Paraclinical investigations show abnormalities that indicate the distribution of inflammatory lesions and
A Coles FRCP) axonal loss (MRI); interference of conduction in previously myelinated pathways (evoked electrophysiological
Correspondence to: potentials); and intrathecal synthesis of oligoclonal antibody (examination by lumbar puncture of the cerebrospinal
Dr Alasdair Coles, University of
fluid). Multiple sclerosis is triggered by environmental factors in individuals with complex genetic-risk profiles.
Cambridge Clinical School,
Addenbrooke’s Hospital, Hills Licensed disease modifying agents reduce the frequency of new episodes but do not reverse fixed deficits and have
Road, Cambridge CB2 2QQ, UK questionable effects on the long-term accumulation of disability and disease progression. We anticipate that future
[email protected] studies in multiple sclerosis will provide a new taxonomy on the basis of mechanisms rather than clinical empiricism,
and so inform strategies for improved treatment at all stages of the disease.

Introduction The principle of diagnosis is to establish from clinical


“…the chief curse of the illness...I must ask constant
evidence, supplemented by laboratory investigations, that
services of people I love most closely...it is an illness disease activity which is consistent with focal demyelination
accompanied by frustration...it is an illness that inflicts has affected more than one part of the CNS and on more
awareness of loss...sporadically it is, in its manifestations, than one occasion.
a disgusting disease”
Brigid Brophy, 1929–952 Diagnosis
In most patients, clinical manifestations indicate the
The depiction of “a remarkable lesion of the spinal cord involvement of motor, sensory, visual, and autonomic
accompanied with atrophy” by Robert Carswell in 18383 systems but many other symptoms and signs can occur
anticipated a more or less complete description of the (table). Few of the clinical features are disease-specific,
pathological anatomy and clinical features of multiple but particularly characteristic are Lhermitte’s symptom
sclerosis (named thus in 1955) by the last decades of the (an electrical sensation running down the spine or
19th century. Over the next 100 years, ideas developed for limbs on neck flexion) and the Uhthoff phenomenon
the cause and pathogenesis of this disease on the basis of (transient worsening of symptoms and signs when core
studies of the epidemiology, genetics, pathology, immun- body temperature increases, such as after exercise or a
ology, and neurobiology. The era of treatments that hot bath).
modify the disease gathered momentum in the 1990s. New criteria allow for safe and early diagnosis, which
Research has moved the study of multiple sclerosis from avoids incorrect attribution of symptoms and signs in
a system based on exploratory approaches into a young adults to multiple sclerosis, and allows timely
productive discipline grounded in first-class clinical discussion about management before tissue injury has
science. As a result, new questions relating to definition, compromised the ability to undertake activities of daily
nosology, cause, mechanisms, and management now living (figure 1).5,6 In many situations, clinical evidence is
challenge several existing concepts. Meanwhile, affected sufficient for establishment of the diagnosis and
people wait for a solution to this unpredictable and laboratory studies are superfluous; but, when the
frightening disease of the CNS; their hopes and fears are diagnosis is ambiguous, paraclinical features can decide
poignantly expressed, from time to time, in writing, the matter. MRI shows focal or confluent abnormalities
music, drama, and the visual arts.1 in white matter in more than 95% of patients. Their
presence alone, however, does not make the diagnosis of
Phenotype of multiple sclerosis multiple sclerosis; characteristic radiological lesions can
“April 30, 1913: went with M- to see a well known nerve
appear in people without clinical signs of disease and
specialist—Dr H-. He could find no symptoms of a
definite disease, tho’ he asked me suspiciously if I had
ever been with women. H- chased me around his Search strategy and selection criteria
consulting room with a drum stick, tapping my nerves
and cunningly working my reflexes. Then he tickled the
We reviewed McAlpine’s Multiple Sclerosis (4th edition)1 and
soles of my feet and pricked me with a pin—all of which I supplemented this summary of the published work with a
stood like a man.” PubMed search from October, 2005, to June, 2008, with the
search term “multiple sclerosis”, without restriction of language.
W N P Barbellion, 1889–19194

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Symptoms Signs Treatment


Established efficacy Equivocal efficacy Speculative
Cerebrum Cognitive impairment Deficits in attention, reasoning, and Cognitive training
executive function (early); dementia
(late)
Hemisensory and motor Upper motor neuron signs
Affective (mainly depression) Antidepressant drugs
Epilepsy (rare) Anticonvulsant drugs
Focal cortical deficits (rare)
Optic nerve Unilateral painful loss of vision Scotoma, reduced visual acuity, Low vision aids
colour vision, and relative afferent
pupillary defect
Cerebellum Tremor Postural and action tremor, Wrist weights, carbamazepine,
and cerebellar dysarthria isoniazid, β blockers, clonazepam,
pathways thalamotomy, and thalamic stimulation
Clumsiness and poor balance Limb incoordination and gait ataxia
Brainstem Diplopia, oscillopsia Nystagmus, internuclear and other Baclofen, gabapentin
complex ophthalmoplegias
Vertigo Prochlorperazine,
cinnarizine
Impaired swallowing Dysarthria Anticholinergic drugs Speech therapy
Impaired speech and emotional Pseudobulbar palsy Tricyclic antidepressant drugs Speech therapy
lability
Paroxysmal symptoms Carbamazepine, gabapentin
Spinal cord Weakness Upper motor neuron signs
Stiffness and painful spasms Spasticity Tizanidine, baclofen, dantrolene, Botulinum toxin, Cannaboids
benzodiazepines, intrathecal IV corticosteroids
baclofen
Bladder dysfunction Anticholinergic drugs and/or Desmopressin, Abdominal vibration, cranberry juice
intermittent self-catheterisation, intravesical botulinum
suprapubic catherisation toxin
Erectile impotence Sildenafil
Constipation Bulk laxatives, enemas
Other Pain Carbamazepine, gabapentin Tricyclic antidepressant
drugs, TENS
Fatigue Amantadine Modafanil Pemoline, fluoxetine
Temperature sensitivity and Cooling suit, 4-aminopyridine
exercise intolerance

TENS=transcutaneous electrical nerve stimulation.

Table: Symptoms and signs of multiple sclerosis by site

many individuals older than 50 years have non-specific Clinical course


white matter cerebral lesions, which should not be 80% of patients present with an acute episode affecting
interpreted over-enthusiastically. Not only is MRI an one (or occasionally several) sites, which is known as the
indicator of the anatomical dissemination of lesions, clinically isolated syndrome. If accompanied by white-
when used serially it can also show new plaques appearing matter abnormalities detected by MRI at clinically
over time and so substitute, under new diagnostic criteria, unaffected sites, the chance of a second attack of
for a subsequent clinical episode (figure 1). At any age, demyelination subsequently occurring, and so fulfilling
lesions detected in the spinal cord are invariably abnormal. the diagnostic criteria for relapsing-remitting multiple
The unique contribution of evoked potentials to the sclerosis, increases from 50% at 2 years to 82% at 20 years.7
diagnosis of multiple sclerosis is that a prolonged latency New episodes occur erratically but the rate seldom exceeds
reflects the specific effect of demyelination on saltatory 1·5 per year. With time, recovery from each episode is
conduction. The presence of oligoclonal bands after incomplete and persistent symptoms accumulate.
protein electrophoresis of the cerebrospinal fluid, which Eventually, around 65% of patients enter the secondary
is seen in about 90% of patients, suggests intrathecal progressive phase; in 20%, the illness is progressive from
immunoglobulin synthesis. Inevitably, diagnostic criteria onset. In both these situations, progression starts at around
do not confer absolute protection against error, and 40 years of age.8 Primary and secondary progressive
confusion can arise (panel 1). multiple sclerosis often manifest as spinal disease, but

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syndromes that are attributable to dysfunction of optic


Clinical episodes? MRI CSF Diagnosis of nerves, cerebrum, or brain stem can also occur. Children
multiple sclerosis
with multiple sclerosis are usually girls and presentation is
commonly with encephalopathy. They take longer from
onset to reach the secondary progressive stage than adults,
Yes but nevertheless do so at a younger age.9 In all cases, the
clinical course usually evolves over several decades. Death
is attributable to multiple sclerosis in two-thirds of cases
and to the increased risk and complications of infections—
Delayed MRI
particularly of skin, chest, and bladder—in people with
advanced neurological disability. The median time to death
+ is around 30 years from disease onset, representing a
Yes
reduction in life expectancy of 5–10 years.10 People with
multiple sclerosis also have a greater risk of suicide,
reflecting an increased lifetime frequency of depression of
up to 50%, in some studies,11 which is either a manifestation
of cerebral inflammation or, more probably, a response to
the uncertainties and restrictions that are imposed by a
+ Yes progressive disabling illness.
The relapse rate decreases during each trimester of
CSF serum
+ pregnancy but with about a three-fold increase in the
+ Yes
puerperium, especially in women with disease activity in
the year before pregnancy and those who have new
episodes while pregnant.12 The clinical course is unaffected
by breast feeding or epidural anaesthesia. The risk of a
relapse is doubled after viral exposure (95% CI 1·4–3·0),13
especially upper respiratory (adenovirus) and gastro-
intestinal infections.14 Conversely, persistent parasitic
infection seems to protect from disease activity, perhaps by
Figure 1: Criteria for the diagnosis of multiple sclerosis promotion of T-regulatory-cell activity.15 Vaccinations do
Modified from the McDonald criteria.6 The principle is to establish dissemination in time and place of lesions—ie, not affect disease activity in multiple sclerosis.16
that episodes affecting separate sites within the CNS have occurred at least 30 days apart. MRI can substitute for
one of these clinical episodes. Dissemination in time of magnetic resonance lesions requires:
one gadolinium-enhancing lesion at least 3 months after the onset of the clinical event; or a new T2 lesion What causes multiple sclerosis?
compared with a reference scan done at least 30 days after onset of the clinical event. In the case of recurrent
stereotyped clinical episodes at the same neurological site, criteria for MRI definition of dissemination in space “As I sit and write, millions of bacteria are gnawing away
are three features from: (1) one gadolinium-enhancing lesion or nine T2 MRI lesions; (2) one or more my precious spinal cord, and if you put your ear to my
infratentorial lesions; (3) one or more juxtacortical lesions; or (4) three or more periventricular lesions; (a spinal back the sound of the gnawing I dare say could be heard”
cord lesion can replace some of these brain lesions). Primary progressive multiple sclerosis can be diagnosed after
W N P Barbellion, 1889–19194
1 year of a progressive deficit and two of: (1) a positive brain MRI; (2) a positive spinal cord MRI; and (3) positive
oligoclonal bands. Patients having an appropriate clinical presentation, but who do not meet all of the diagnostic
The cause of multiple sclerosis involves environmental
criteria can be classified as having possible multiple sclerosis. CSF=cerebrospinal fluid.
exposure and genetic susceptibility. Arguing the merits of
one faction versus the other is unproductive. Each is clearly
Panel 1: Differential diagnosis of multiple sclerosis implicated, together with the cultural condition of age at
• Systemic diseases complicated by CNS involvement that which the interplay between genes and the environment
follow a relapsing-remitting course (eg, systemic occurs.
vasculitis)
• Diseases of the brain and spinal cord confined to selected The environmental factor
physiological systems and usually following a progressive The global distribution of multiple sclerosis can be
course (eg, the hereditary cerebellar ataxias) generalised as increasing with distance north or south of
• Disorders affecting one anatomical site and with either a the equator, but that summary conceals many places with
relapsing-remitting or progressive course (especially, disproportionately high or low frequencies (figure 2).17,18
tumours and other structural lesions) Multiple sclerosis is common in regions populated by
• Monophasic disorders affecting many neuroantaomical northern Europeans but this distribution is modified by
sites (eg, acute disseminated encephalomyelitis) where individuals who are at risk of disease live early in
• Non-organic symptoms that, intentionally or otherwise, life. Several studies have also reported increasing
mimic the clinical features of multiple sclerosis (so-called incidence of multiple sclerosis over time, although these
functional or somatisation disorders) data can be confounded by heightened awareness of the
disease and new diagnostic techniques. Orton and

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colleagues19 report a significant increase in incidence of adults. Lang and colleagues27 describe a basis for molecular
multiple sclerosis in Canadian women, but not men, over mimicry between Epstein-Barr virus and a self protein, so
the past 30 years, causing a change in the female to male that an immune response to the virus inadvertently
ratio to more than 3:1. What environmental factor this cross-reacts with myelin and induces demyelination; four
finding shows, however, is not so clear. DRB1* restricted T-cell receptor peptide contacts are
Migrations involving large numbers of people affect identical for myelin basic protein and Epstein-Barr virus.
the distribution of multiple sclerosis. Studies from South Studies investigating pathological changes suggest that a
Africa,20 Israel,21 Hawaii,22 and of immigrants to the UK23 high proportion of B cells, accumulating in lesions of
correlate the risk of multiple sclerosis with place of chronic multiple sclerosis, are infected by Epstein-Barr
residence in childhood (figure 2). Migration from virus.28 Frustrated by the low dividend from systematic
high-risk to low-risk regions in childhood is associated searches for candidate infectious agents with sophisticated
with a reduced risk, and from low to high prevalence methods for virus detection, some commentators have
parts of the world with an increased risk of developing suggested other environmental triggers such as low
multiple sclerosis by comparison with the population of sunlight, vitamin D deficiency, diet, geomagnetism, air
origin. However, analysis based on a homogeneous pollutants, radioactive rocks, cigarettes, and toxins.29–31
Australian population shows no effect of age-at-migration,
with 15 years as the point of stratification, suggesting that The genetics
the risk of exposure spans a wider age range than was Multiple sclerosis has a familial recurrence rate of
originally suggested.24 about 20%. Overall, the reduction in risk changes from 3%
Patients with multiple sclerosis report being infected in first-degree relatives (siblings, 5%; parents, 2%; and
with measles, mumps, rubella, and Epstein-Barr virus at children, 2%), to 1% in second-degree and third-degree
later ages than do HLA-DR2 matched controls.25 In relatives (figure 3). These confer relative risks of 9·2, 3·4,
particular, on the basis of a population of 3 million, and 2·9, respectively, compared with a background
infection with Epstein-Barr virus as a young adult increases age-adjusted risk in white northern Europeans of 0·3%.32–35
the risk of subsequently developing multiple sclerosis Population-based series of multiple sclerosis in twins
(relative risk 3·0 [95% CI 1·3–6·5]).26 These data lend from Canada and the UK show higher clinical concordance
support to the so-called hygiene hypothesis whereby rates in monozygotic than in dizygotic pairs (25% vs 5%).36,37
individuals not exposed to infections early in life, because Conversely, studies from France and Italy provide
of a clean environment, make aberrant responses to equivalent rates irrespective of zygosity.38,39 Individuals
infections when encountering these challenges as young with multiple sclerosis who were adopted soon after birth

High prevalence
Medium prevalence
Low prevalence

Figure 2: Geography of multiple sclerosis and migrations


The five continents are depicted to show medium prevalence of multiple sclerosis (orange), areas of exceptionally high frequency (red), and those with low rates
(grey-blue). Some regions are fairly uncharted and these colours are only intended to provide an impression of the geographical trends. Major routes of migration
from the high-risk zone of northern Europe, especially including small but informative studies, are shown as dotted arrows. Studies involving migrants from low-risk
to high-risk zones are shown as solid arrows.

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Genetic sharing Relationship

100% Monozygotic twin

Sibling with two affected parents

Sibling with one affected parent

Dizygotic twin
50%
Sibling

Parent

Child

Half sibling

25% Aunt/uncle

Nephew/niece

12·5% Cousin

Adoptee
0%
General population
0 5 10 15 20 25 30 35
Lifetime risk (%)

Figure 3: Recurrence risks for multiple sclerosis in families


Age-adjusted recurrence risks for different relatives of probands with multiple sclerosis, and degree of genetic sharing between relative and proband. Pooled data
from population-based surveys. Error bars indicate the estimated 95% CIs.

and those having affected members of their adoptive screening for a link between a chromosomal region of
family, have the same risk as does the general population interest50 or association between markers and susceptibility
and, therefore, a substantially lower frequency than that genes resulting from linkage disequilibrium.51 Third, the
observed in the biological relatives of index cases.40 The use of genetic isolates and other informative populations
same is true for step-siblings of index cases.41 The having implications for understanding the disease more
age-adjusted risk for half-siblings is lower than that for generally.52,53
full siblings and with no difference in risk for half-siblings With adequately powered studies and the availability of
reared together or apart.40 The recurrence risk is higher for reagents that allow high-density screens of the genome or
the children of conjugal than single-affected parents.42,43 regions of interest, new additions to the list of susceptibility
Together, these studies implicate genetic factors in loci include a protective effect conferred by HLA-C554 and
determining familial clustering and individual suscepti- of HLA-DRB1*11,55,56 and increased susceptibility associated
bility to multiple sclerosis. with single nucleotide polymorphic markers for the
Published work on the association of multiple sclerosis interleukin-2 and interleukin-7 receptor α chains.57–60
with other autoimmune diseases is conflicting. The most
consistent findings are of increased autoimmune thyroid Disease mechanisms
disease in patients, or their first-degree relatives,44 but “Yesterday, the wind was taken out of my sails…my eye
these results have not been supported by a large caught the title of an enormous quarto memoir in the
population-based study.45 Trans Roy Soc, Edinburgh: The Histology of ------ --------- . I
The association between multiple sclerosis and alleles of almost ran away to my room”
the MHC was identified in the early 1970s.46,47 These W N P Barbellion, 1889–1919,4 referring to James Dawson’s
markers have been refined as DR15 and DQ6 and the monograph61
corresponding genotypes DRB1*1501, DRB5*0101,
DQA1*0102, and DQB2*0602.48 The association is strongest The hallmark of demyelinating disease is formation of the
in northern Europeans but is seen in all populations apart sclerotic plaque, which represents the end stage of a
from Sardinians and some other Mediterranean groups in process involving inflammation, demyelination and
whom multiple sclerosis is associated with DR4 remyelination, oligodendrocyte depletion and astrocytosis,
(DRB1*0405–DQA1*0301–DQB1*0302).49 Following this and neuronal and axon degeneration (figure 4). Despite no
early success, three approaches were used unproductively shortage of opinion, the order and relation of these separate
over the next 30 years to identify other genetic risk factors. components remain fully to be resolved.
First, linkage or association with candidate genes chosen Myelin is synthesised by mature oligodendrocytes, each
from a-priori knowledge of the pathogenesis or some other of which contacts short segments of 20–40 juxtaposed
selection process.1 Second, non-prejudicial whole genome axons in white-matter tracts of the CNS. Developmental

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processes are regulated by defined growth factors that surface bound tumour necrosis factor α (TNFα).74 Acute
orchestrate proliferation, migration, differentiation, and demyelinating lesions also show extensive axonal injury
survival of oligodendrocyte precursors into myelinating with transection62,75 (figure 4C) that correlates with T-cell
cells.65,66 The elongated oligodendrocyte processes make and microglial infiltration.76 With onset of the secondary
contact with nearby axons and form a cup at the point of progressive stage, areas of demyelination coexist with
contact that encircles the axon, thereafter extending along diffuse axonal and neuronal degeneration, associated with
the nerve fibre to form an internodal myelinated segment. the accumulation of hyperphosphorylated and insoluble
With maturation, Nav1.2 (sodium) channels are retained tau.77 Lesions seem to grow slowly by radial expansion as
along the myelinated axon but replaced by Nav1.6 channels focal brain inflammation fades into diffuse parenchymal
at the intervening nodes of Ranvier where electrical microglial activation resulting in extensive abnormalities
resistance is low, thereby facilitating depolarisation, of the normal appearing white matter,78 in which a delicate
generating electrical current and, in turn, triggering balance exists between anti-inflammatory genes
saltatory conduction.1 upregulated in oligodendrocytes and pro-inflammatory
pathways activated in microglia.79 B-lymphoid follicles
Pathogenesis accumulate in the meninges sustaining a compart-
We believe that the disease process starts with increased mentalised humoral immune response that can drive
migration of autoreactive lymphocytes across the intrathecal antibody production and damage nearby
blood–brain barrier. The transition from physiological cortex;80 these are the cells that harbour Epstein-Barr
surveillance to a pathological cascade arises from regulatory virus.28 Pathological changes of primary progressive
defects that allow these cells to set up an immune response multiple sclerosis are characterised by reduced plaque
within the brain. Regulatory lymphocytes from people with load, less evidence for inflammation, and the absence of
multiple sclerosis fail to suppress effector cells.67 These lymphoid follicles.
autoreactive cells do not effectively apoptose on stimulation, Remyelination (figure 4) accounts for the appearance
because of overexpression of β-arrestin 1, which is a key of shadow plaques. It is most active during the acute
promoter of naive and activated CD4+ T-cell survival.68 inflammatory process coinciding with phagocytic
Presumably, failure of local regulatory mechanisms within removal of myelin debris, but also occurs in the
the brain accounts for the particular sites of inflammation, progressive phase. The mature nervous system maintains
dominated by perivascular CD8+ cell infiltrates, causing a pool of oligodendrocyte precursors that can migrate in
so-called plaques that cluster around the lateral ventricles response to semaphorin 3A and 3F.81 Undifferentiated
and corpus callosum, in the cortex and subcortical white oligodendrocyte precursors surround the lesions of
matter, the optic nerves and brainstem, and throughout multiple sclerosis82,83 and presumably act as the source of
the spinal cord. Investigators have recently discovered that cells having the potential to remyelinate naked axons.84
the key role assigned historically to T-helper 1 (Th1) In 20% of people with multiple sclerosis, plaques are
(interferon-γ secreting) cells in experimental allergic eventually remyelinated.85 Clearly, remyelination is less
encephalomyelitis was misplaced. Rather, inflammation is successful in other instances, with cycles of demyelination
driven by a newly-designated T-lymphocyte subtype that and remyelination apparently exhausting the capacity for
secretes interleukin-17 under interleukin-23 control.69 tissue repair.
Interleukins 17 and 22 disrupt the human blood–brain To some extent, every pathological component can be
barrier, allowing efficient penetration of Th17 cells into the detected in life with MRI: to distinguish inflamma-
brain where they can kill human neurons.70,71 tion (Gadolinium-diethylenetriaminepenta-acetic acid
The antigen specificity of these immune responses is [Gd-DTPA] enhancement), axonal loss,86 demyelination
unresolved, not least because many autoreactive and remyelination (magnetisation transfer ratio), astro-
lymphocytes can be detected in healthy individuals. cytosis (T₂-weighted lesions), and alterations in normal
Originally, myelin proteins were favoured as candidates for appearing white matter.87 Provisional reports suggesting
initiation of the disease process in multiple sclerosis, but that the presence of serum antibodies against myelin
other specificities are now also implicated. For example, it proteins predict early conversion from clinically isolated
is suggested that an autoimmune response against αB syndromes to definite multiple sclerosis have not been
crystalline prevents physiological suppression of confirmed.88 However, antibodies to specifically cleaved
inflammation;72 and that antibodies against neurofascin products of myelin-basic protein do seem to be associated
might mediate axonal injury in multiple sclerosis.73 As with multiple sclerosis.89 Concentrations of neurofilament
T and B lymphocytes, plasma cells, and macrophages light chain and glial fibrillary acidic protein in cerebrospinal
accumulate, pro-inflammatory cytokines amplify the fluid indicate tissue damage and therefore correlate loosely
immune response through recruitment of naive microglia. with disability.90
Contact is established between activated microglia and
components of the oligodendrocyte-myelin unit that is Pathophysiology
opsonised with ligands for microglial Fc and complement Although compensation can arise from redundancy in
receptors. A lethal signal is then delivered through cell individual systems or tracts, pathways that are strategically

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Relapsing remitting Secondary progressive

Clinical threshold

Axonal loss
Brain volum
e

Inflammation
Pathology

A D

B E

C F

A D

B E

C F

07TL7754_4 Urgent Keys Labels Measuring bars Graph marks Arrows Font reference and s
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HC Text typed Key 1 Key 1
Key 2 Key 2 A B
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placed eventually lose the safety factor for conduction, Experimentally, remyelinated axons can again conduct
altering in ways that are characteristic and account for the nerve impulse and restore function.94 We can assume
particular manifestations of multiple sclerosis. Partially that remyelination in multiple sclerosis also contributes
demyelinated axons cannot transmit fast trains of impulse, to recovery.
explaining symptoms resulting from physiological fatigue.
Depolarisation might traverse the lesion but at reduced Are the inflammatory and degenerative processes
velocity, accounting for the characteristic delay of evoked independent?
potentials (figure 4B). Partially demyelinated axons can Disease progression in multiple sclerosis depends on
discharge spontaneously, producing unpleasant distortions accumulated axon degeneration. Therefore, attitudes
of sensation. Increased mechanical sensitivity results in have shifted in the past decade from the focus on multiple
symptoms induced by movement including flashes of light sclerosis as a demyelinating disease to a broader
provoked by eye movement, and the electric sensation felt perspective in which the relative contributions of acute
in the spine or limbs on neck flexion (Lhermitte’s symptom). and chronic axonal loss, and their dependence on
Spontaneous discharge in facial nerve neurons in the brain inflammation, also have to be understood in reaching a
stem accounts for myokymia. The failure of conduction in coherent account of the pathogenesis. Four formulations
partially demyelinated pathways associated with a rise in can be proposed. First, inflammation is the exclusive
temperature is an indicator of reduced capacitance of the pathogenic event from which all else follows. Second,
thinning myelin sheath, accounting for the temporary neurodegeneration occurs first and inflammation is
increase in severity of pre-existing symptoms with exercise merely a secondary response. Third, inflammation and
and a hot bath (Uhthoff symptom). Ephaptic transmission neurodegeneration both contribute to the clinical course,
between neighbouring and partially demyelinated axons but are fully independent processes. Finally, inflammation
causes brief and usually unpleasant paroxysmal attacks that exposes an intrinsic neurodegenerative susceptibility that
are often triggered by touch or movement. renders axons vulnerable to cumulative injury.
Symptom recovery might suggest resolution of Aspects of the natural history can serve as a surrogate for
conduction block in structurally intact nerve fibres as the the axonal contribution to tissue injury. Hensiek and
episode of inflammation wanes.91 When structural colleagues95 assessed 1083 families with two or more
damage has occurred, sodium channels are redistributed first-degree relatives having multiple sclerosis and showed
across the demyelinated axonal membrane92 (figure 4E). concordance for age at onset and clinical course, but not
Electrical activity is restored, but alterations in sodium severity. These findings suggest a familial effect both on
and calcium exchange can prove hazardous until normal episodic and progressive phases of the disease. In turn,
nodal arrangements are re-established by remyelination.93 axon degeneration is thought to be affected by factors,
Figure 4: The course and pathogenesis of multiple sclerosis
over and above those that establish inflammation. With
This scheme illustrates how the pathological processes of inflammation, use of natural history data, Kremenchutzky and co-workers96
demyelination, and axon degeneration explain the clinical course of multiple conclude that the progressive phase of multiple sclerosis is
sclerosis. (Arrows indicate the progression of pathology). Course: CNS an age-dependent degenerative process, and that chronic
inflammatory activity might precede clinical symptoms by many years, and MRI
has shown that for every clinical episode there are roughly ten new plaques; this axonal loss specific to the corticospinal tract is the
tenet is illustrated as a notional clinical threshold, below which the effects of pathological substrate for progression, beginning early in
individual inflammatory lesions can be compensated for and above which they the disease course and before clinical symptoms manifest.
cause symptoms. Pathology: the first event is lymphocyte-driven inflammation Confavreux and Vukusic8 also consider that times to reach
(A: lymphocytes are seen around a blood vessel, haematoxylin and eosin stain).
This inflammation might impede the saltatory propagation of the action potential disability milestones, and the ages at which these
(arrowheads) in three ways: soluble inflammatory mediators might cause landmarks are reached, follow a predefined schedule that
conduction block in structurally intact axons (A), or there may be demyelination is not obviously affected by episodes or by the initial disease
(B: luxol fast blue myelin stain showing very early lesion with several macrophages
course. According to this analysis, relapsing-remitting
laden with myelin and some intact myelinated nerves)1 or axonal transection
(C: non-phosphorylated neurofilaments [SMI32 staining] marks terminal axon disease can be regarded as multiple sclerosis in which
spheroids).62 Microglia are activated, and contribute to inflammation and to repair insufficient time has elapsed for conversion to secondary
by removal of myelin debris and promotion of remyelination (F: oligodendrocyte progression; secondary progressive multiple sclerosis is
with proteolipid protein mRNA [black] connected to remyelinated axon with
relapsing-remitting disease that has grown older; and
proteolipid protein immunoreactivity [red]).1 If this fails, persistently demyelinated
axons adapt by redistributing ion channels (E: sodium-channel redistribution along primary progressive disease is multiple sclerosis that has
denuded axons, antipan Nav channel antibody [green], antineurofilament [red]),63 been amputated from its usual preceding relapsing-
which might prove maladaptive and promote chronic neurodegeneration remitting phase. Panel 2 outlines the three mechanisms of
(G: confocal of a shadow plaque, with a remyelinating oligodendrocyte
axonal injury.
[red-proteolipid protein antibodies], and degenerating unmyelinated axons
[green-neurofilament antibodies]).64 Microglia can become chronically activated, Our position is that progression in multiple sclerosis is
in the absence of lymphocytic inflammation, in areas of normal appearing white due to cumulative loss of axons, initiated and maintained
matter and also lead to neuronal loss in later stages of the disease (D: CD68+ by complex inflammatory responses acting in individuals
microglia).1 In response to chronic tissue injury, astrocytes cause gliosis, which can
who are inherently susceptible to neurodegeneration, and
act as a mechanical barrier for repair (H: haematoxylin and eosin stain). Not
depicted is primary progressive multiple sclerosis in which there is significant changing as tissue damage increases. At any one time, the
axonal degeneration with or without a preceding inflammatory phase. extent of that injury indicates the interplay of active

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that acute plaques show pattern 2 pathology in all indi-


Panel 2: Three mechanisms of axonal injury viduals, and the other patterns are seen rarely.111
1 Brief exposure of the (rat) spinal cord to nitric-oxide These separate mechanisms can explain differences in
donors produces reversible conduction block in normal the extent of demyelination, oligodendrocyte injury,
axons97 (figure 4A) remyelination, and axonal damage that are seen across
2 A separate and destructive sequence follows more the spectrum of multiple sclerosis85 and related
prolonged exposure to inflammatory mediators:98 nitric disorders—ie, neuromyelitis optica112 and Balo’s con-
oxide acts directly and indirectly via NMDA receptors on centric sclerosis (pattern 3).113 But an alternative
more mature neurons,99 and soluble factors released by interpretation is that the core process of T-cell mediated
activated microglia impair mitochondrial (cytochrome brain inflammation is merely modified by different
oxidase) activity of neurons100 resulting in energy failure immunological effector mechanisms, thus creating a
and altered ion exchange mechanisms across the axonal state of mechanistic complexity rather than true disease
cell membrane.1 This effect is exacerbated by the spread of heterogeneity (figure 5).
sodium channels away from the node of Ranvier across the
exposed demyelinated axon membrane; extrusion of the Neuromyelitis optica
consequent increased sodium influx makes yet greater “In December 1822, I ... was obliged to have my letters
metabolic demands on the axon and neuron63,101 (figure 4E) read to me, and their answers written as my eyes were so
3 Loss of trophic support by oligodendrocytes and myelin attacked that when fixed upon minute objects
contributes to neuronal and axonal loss: in vitro, cells of indistinctness of vision was the consequence”
the oligodendrocyte lineage support neuronal survival by Augustus d’Este, 1794–1848114
release of insulin-like growth factor (IGF)-1,102 whereas
neurofilament phosphorylation and axonal length are Until recently, the typical form of demyelinating disease
increased by glial cell derived nerve growth factor seen in Africa, Asia, east Asia, and Aboriginal populations
(GDNF);103 IGF-1 and GDNF modulate the direct effects of was neuromyelitis optica or optic-spinal multiple
nitric oxide on survival of neurons and axonal injury sclerosis. The relapsing-remitting phenotype, affecting
mediated by exposure to nitric oxide in vitro104 (figure 4G) many sites within the brain and spinal cord, was
uncommon.1 With the identification of anti-aquaporin
(AQP) 4 antibodies as biomarkers of neuromyelitis
inflammation, existing neurodegeneration, and the optica,115,116 awareness of neuromyelitis optica in northern
dynamic vulnerability of intact axons. Although the European people has increased. Diagnostic criteria for
absolute amount of inflammation can reduce, its effect is neuromyelitis optica are optic neuritis and myelitis with
never altogether lost in view of the increasing susceptibility two or more of three supporting criteria; a contiguous
of injured axons to residual inflammatory insult. spinal-cord lesion of three or more segments in length;
brain MRI at onset that is not diagnostic for multiple
Complexity and heterogeneity in demyelinating disease sclerosis; and neuromyelitis optica-IgG seropositivity.117,118
Genetic analyses are predicated on the assumption that Neuromyelitis optica is characterised by demyelination
multiple sclerosis is one disease, but some evidence for and necrosis of white and grey matter of the spinal cord,
genetic heterogeneity exists. For example, although acute axonal injury, antibody deposition, and perivascular
mitochondrial genes do not contribute generally to complement activation.112 AQP4 is not detectable in the
susceptibility in multiple sclerosis,105 mutations of optic nerve and spinal cord lesions.119,120 Conversely, AQP4
mitochondrial DNA are responsible for a rare illness expression is increased in active and recently remyelinated
similar to multiple sclerosis that is characterised by lesions of multiple sclerosis but lost in the chronic plaques.
disproportionate involvement of the anterior visual The gratifying response to plasma exchange in some
pathway.106,107 patients with neuromyelitis optica (and those with the
Specifically different mechanisms are thought to be pattern 2 neuropathology of multiple sclerosis) suggests a
involved in the pathogenesis of tissue injury in multiple primary pathogenic role for antibody and complement.121
sclerosis:108,109 T-cell infiltrates and macrophage associated In Japan, not all patients who are positive for AQP4
tissue injury (pattern 1); antibody and complement- antibodies show the typical phenotype of optic-spinal
mediated immune reactions against cells of the oligo- multiple sclerosis. Up to a third of seropositive patients
dendrocyte lineage and myelin (pattern 2); hypoxia-like and some with relapsing-remitting multiple sclerosis also
injury, resulting either from inflammation-induced vascular show the long thoracic spinal lesions, and the same cord
damage or macrophage toxins that impair mitochondrial appearance can be seen in those who are AQP4 negative.122
function110 (pattern 3); and a genetic defect or polymorphism This overlap suggests that patients can be intermediate
resulting in primary susceptibility of the oligodendrocytes between seropositive neuromyelitis optica and seronegative
to immune injury (pattern 4). The original proposal was relapsing-remitting multiple sclerosis. Perhaps the most
that each individual with multiple sclerosis had only one telling link is the switch in clinical phenotype from
type of pathological lesion; however, a recent study suggests optic-spinal to conventional multiple sclerosis that has

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been observed over a short period in Japan123 to coincide


Focal lymphocyte infiltration
with changes in industrialisation, and in the French West
Indies with patterns of migration.124 One interpretation is
that cultural changes expose the intrinsic vulnerability of
individuals who are at risk of demyelinating disease
encountering infections later in childhood and at a crucially
altered phase of maturation in their immune repertoire.
Together, these observations suggest that neuromyelits
optica is a prototypic demyelinating disorder from which,
through genetic stratification and selection in response
to epidemic microbial challenge, changes occur in the
immunopathogenesis, histological complexity, and distri-
bution of lesions converting to the phenotype of
relapsing-remitting multiple sclerosis.125

Management and treatment of Pattern 1 Pattern 2 Pattern 3 Pattern 4


demyelinating disease
“A physician from London will gallop up hotspur, tether
his horse and dash in waiving a reprieve—the discovery of
a cure”
W N P Barbellion, 1889–19194

Temporary improvement can be achieved at times of


symptomatic deterioration with high-dose methyl predni-
solone.126 Plasma exchange given up to 1 month after onset
can usefully reduce persistent deficits although not Diffuse microglial activation and neurodegeneration
subsequent disease activity.127,128 In many situations, the
priority is to improve the quality of everyday life by masking Figure 5: Pathological heterogeneity
individual symptoms. The most amenable are the unstable The four principal patterns of multiple sclerosis pathology108,109 arising from the common mechanism of
bladder, erectile dysfunction, spasticity (whereas the inflammation and leading to the common terminal path of neurodegeneration and microglial activation.
Histological panels are from reference 1.
treatment of other motor disabilities is less rewarding),
pain, and paroxysmal episodes (table). For patients who
develop serious disabilities and impairments, compre- reduce the environmental triggers of multiple sclerosis.
hensive care includes access to physical and occupational γ interferon promoted relapses of multiple sclerosis,134
therapists, neuropsychologists, social workers, and other whereas β interferon reduced their frequency, albeit to
health-care professionals providing expertise in the no greater extent than was noted with azathioprine135
management of chronic neurological illness. Increasingly, which had been largely dismissed as toxic and
the available services and management of disability are insufficiently effective. Yet, because the β interferons
coordinated by specialist nurse practitioners. have a fairly innocuous profile of adverse effects, they
The pivotal studies of present licensed therapies of began to be used at earlier stages of the disease once
multiple sclerosis were fairly small (involving only a few modest efficacy had been shown. At this stage, copaxone
hundred patients) and of short duration (2–3 years).129–133 (glatiramer acetate) emerged from the attempt of one
Therefore, long-term efficacy is not established to the laboratory to generate new agents promoting experimental
satisfaction of all analysts. The available treatments are allergic encephalomyelitis; nowadays, this drug is
expensive and do not always meet standards for believed to act by inducing tolerance or anergy of
cost-effectiveness. As a result, use remains uneven, and myelin-reactive lymphocytes.136 At present, least con-
treatment of multiple sclerosis is a topic much debated tentious is the use of the β interferons (eg, Rebif, Avonex,
and besieged by the issues of health economics. and Betaseron) and copaxone in relapsing-remitting
The efficacy of present treatments varies with the stage disease, for which the pivotal studies initially showed a
reached in the course of the disease. In retrospect, the reduction in frequency of new episodes by about 30% for
negative results from trials of conventional immuno- 2–3 years.129–133 Research from extension studies suggests
therapies—such as cyclophosphamide and ciclosporin— that this effect persists beyond 2 years of treatment.131,137
recorded in the 1980s and early 1990s, reflect selection of Common sense suggests that if early intervention
patient cohorts with progressive disease, which we now reduces disease activity, it will necessarily also increase the
understand is largely driven by non-inflammatory interval between episodes and delay conversion to multiple
mechanisms. The type I interferons were first used in sclerosis—defined either by a second clinical episode or
the 1970s on the grounds that their antiviral activity might the accumulation of new MRI lesions—in patients with

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Seminar

clinically isolated syndromes. And, since a proportion of vigorous responses. Nowadays, there is a suggestion that
episodes do not recover fully, the accumulation of fixed efficacy might be enhanced by prescribing a higher dose
disabilities in relapsing-remitting multiple sclerosis, and than that which is approved at present.156
after conversion from a clinically isolated syndrome, will Two other drugs are now licensed. Mitoxantrone (an
also be decreased. Crucially, whether such treatment anthracenedione antineoplastic drug which intercalates
delays entry into the secondary progressive phase of with DNA and inhibits both DNA and RNA synthesis) is
multiple sclerosis is uncertain. The interferons certainly probably more efficacious than the interferons or
reduce the conversion rate to multiple sclerosis from copaxone, but its use is confined to cases that are
45–50% with placebo to 28–35% over 2–3 years in the characterised by disease which is sufficiently aggressive to
CHAMPS, ETOMS, and BENEFIT trials; a trial of justify its toxic effects (eg, cumulative cardiotoxicity and
copaxone in unifocal clinically isolated syndrome, yet to acute leukaemia in 0·2% of patients).157 In particular, it
report in full, suggests a similar effect.138–141 In an extension slows the accumulation of disability in difficult cases of
of the CHAMPS study, of 5 years total treatment, no gain rapidly worsening multiple sclerosis with frequent
in terms of disability with interferon treatment was relapses, but has less or no effect on non-relapsing
recorded;142 however, the BENEFIT trial, perhaps the best progressive disease.158,159 It is now licensed in the USA for
of the three studies, showed a marginally significant effect patients with secondary progressive, progressive relapsing,
of interferon on the accumulation of disability over or worsening relapsing-remitting multiple sclerosis but
3 years.140 These therapies have no useful treatment effect not those with primary progressive multiple sclerosis.
on the secondary progressive phase of the disease,143–146 The demonstration that an antibody against the α4β1
except in those unusual cases of progressive multiple integrin on the surface of lymphocytes could reduce
sclerosis continuing to have high relapse rates.147,148 lymphocytic infiltration and clinical disease in animals
Likewise, no agent has been shown to affect primary with allergic encephalomyelitis160 led to clinical trials of a
progressive multiple sclerosis.149 The main adverse effects humanised anti-α4 integrin antibody, natalizumab
of interferon β are local injection-site reactions and flu-like (Tysabri). Given indefinitely by monthly infusion, this
symptoms with hyperthermia, perhaps due to cytokine antibody showed greater efficacy against placebo than is
release. 5–30% of treated patients develop persistent seen with the interferons, reducing the relapse rate at
neutralising antibodies, usually in the first year of 1 year by 68% and the chance of acquiring fixed disability
treatment and more commonly in those receiving over 2 years by 42%.161 An unpublished interim analysis of
interferon β-1b. Their presence is associated with reduction these data led to a US licence being issued for natalizumab
in the treatment effect on relapse activity.150 in relapsing multiple sclerosis, only for the drug to be
New trials have been designed further to inform withdrawn from the market months later when two case
prescribing. These aim to position the individual of progressive multifocal leucoencephalopathy were
therapies in an increasingly competitive market, with an identified in a trial combining Avonex (IFNβ-1a) with
emphasis on earlier and broader prescribing indications, natalizumab.162 As a result, natalizumab is licensed as
dose responsiveness favouring increased exposure, and monotherapy for severe relapsing-remitting multiple
the use of MRI surrogates to anticipate clinical activity. sclerosis, which is defined in the UK by the National
Two studies have compared the efficacy of the interferons. Institute for Health and Clinical Excellence as two or
The EVIDENCE trial,151 which reported greater efficacy more disabling relapses in 1 year, and one or more
with high-dose subcutaneous Rebif (interferon β-1a) gadolinium-enhancing lesions or a significant increase in
three times per week than with low-dose Avonex T2 lesion load on MRI. Since licensing, the FDA has
(interferon β-1a) given once per week, lasted only warned that two further cases of PML have been identified
24 weeks. The 2-year INCOMIN trial152 showed greater in the second year of natalizumab monotherapy, from
efficacy with Betaferon (interferon β-1b) given on roughly 12 000 patients exposed for over 12 months.163
alternate days than with Avonex given once per week.
The recent BEYOND trial showed no difference in clinical The future of treatment
efficacy between two doses of Betaferon and copaxone.153 “Some London neurologist has injected serum into a
Some dampening of enthusiasm occurred with the woman’s spine with beneficial results, and as her disease
systematic review of interferons in multiple sclerosis154 is the same as mine, they wish me to try it too. I may be
concluding that evidence exists only for a reduction in able to walk again, to write etc, my life prolonged”
relapse frequency during the first year of treatment with W N P Barbellion, 1889–1919164
no convincing efficacy thereafter and no effect on the
accumulation of disability. The failure to confirm In 1993, there were no licensed therapies for multiple
treatment effects in these reviews partly reflects the large sclerosis. Now several exist. For the future, debate will
confidence intervals generated by trials that end early or hinge around the complex interplay of efficacy, safety,
contain many drop-outs. A systematic review concluding and convenience in which individual patients and
that glatiramer acetate does not alter relapse rate or practitioners may set different priorities. Some will see
progression in multiple sclerosis155 inevitably elicited efficacy as the overwhelming issue: others will regard

1512 www.thelancet.com Vol 372 October 25, 2008


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oral versus parenteral therapy as important; yet more will


be rightly cautious concerning safety; and some may Panel 3: Remyelination and repair in multiple sclerosis
regard a long interval between administrations as • Will cessation of the inflammatory process allow sufficient
practical and psychologically advantageous. Against that repair and reversal of deficits, and does suppression of the
background, as new therapies are identified offering inflammatory process inhibit remyelination?
improved efficacy, profiles of adverse effects have also • Is the potential for enhancing endogenous remyelination real
changed. Therefore, a new dilemma arises. Should a enough to make the notion of exogenous rescue unnecessary?
more liberal attitude to the clinical risk-benefit ratio be • Is there a critical period when the naked axon can be
adopted, perhaps leaving a few individuals compromised rescued by reclothing it in myelin?
through having received a novel but complicated • How many axons must be remyelinated to achieve useful
treatment early in the course, even though this approach conduction through a critical pathway, and can axon
stabilises the disease process for many recipients? outgrowth be promoted to increase the so-called arena of
Oral agents have emerged as possible treatments of remyelinaton?
multiple sclerosis. In a phase 2 trial of 281 patients over • Which intervention provides the best medicine and how
6 months, fingolimod reduced the relapse rate from 0·77, can it most effectively be delivered?
on placebo, to 0·35.165 Its adverse effect profile remains
unclear, and is the subject of current phase 3 trials. In a
trial of 306 patients over 36 weeks, high-dose oral 1995–2000 when busulphan-based regimens were
laquinimod reduced the number of enhancing MRI lesions mainly in use rather than BEAM (carmustine, etoposide,
by 40% compared with placebo;166 and in a similar study of cytarabine, melphalan) or antithymocyte globulin
oral fumarate in 257 patients over 24 weeks, MRI enhancing without graft manipulation. Improvement or
lesions were reduced by 69% compared with placebo.167 stabilisation of neurological conditions occurred in
Furthermore, strategies are appearing to abrogate highly 63% of patients at a median follow-up of 42 months.174
selective immune processes; in general these processes As with alemtuzumab, disease progression is not
are technically demanding and have shown only limited checked if the intervention is given later in the course.
efficacy, as emphasised by vaccination with attenuated This clinical analysis accords with pathological studies
autologous antimyelin T-cell lines.168 Alternatively, of cases studied at autopsy after bone-marrow
monoclonal antibodies can be used to block specific cell transplantation that show extensive axonal loss in the
surface targets (eg, CD25169) or delete particular lymphocyte absence of active inflammation.175
groups; in a phase 2 trial of rituximab in 104 patients over Taken together, the results of clinical trials allow the
48 weeks, the number of patients having a relapse was conclusion that inflammation is necessary for new lesion
halved compared with placebo (20% vs 40%).170 formation and also conditions axon degeneration.
The early experience with the pan-lymphocyte depleting Immunological therapies might prevent progression of
antiCD52 antibody, alemtuzumab, is promising. Initial disability if given before the cascade of events, leading to
studies focused on secondary progressive multiple an irretrievable loss of tissue integrity. This notion explains
sclerosis in which alemtuzumab effectively suppressed the present restrictions of immunotherapy in patients
clinical and radiological disease activity. Nonetheless, with secondary progressive multiple sclerosis. The goal of
patients continued to have progression of their disability, future therapies in multiple sclerosis should be to limit
correlating with continued brain atrophy that was the neurodegenerative contribution to disease progression.
attributable to axon degeneration. The degree of This aim might need: prevention of immunological
progression and tissue loss were related to the MRI chronicity by inhibition of diffuse microglial activation;
inflammatory load before treatment, suggesting that protection of intact axons from acute injury with
these are post-inflammatory events.171 The lesson is that anti-excitotoxic and membrane-stabilising agents;
effective immunosuppression is required early to stabilise provision of trophic support to persistently demyelinated
the cascade of events that culminates in irreversible axons with growth factors and strategies that enhance
disability. There followed open-label treatment of such remyelination; and promotion of plasticity and axon
cases172 and a phase 2 single-blind trial comparing regeneration by manipulation of extracellular matrix
alemtuzumab and Rebif (IFNβ-1a). This trial shows that molecules and inhibitory environments.
alemtuzumab reduces the relapse rate compared with Most patients expect stem-cell biology to deliver a
Rebif by up to 74%, and the chance of accumulating dividend for remyelination and repair in multiple sclerosis.
disability by up to 71%, over 3 years.173 Validation of the evidence already gathered in experimental
Comparable suppression of the immune system can studies will need several issues to be settled, which are
be achieved with bone-marrow transplantation, with outlined in panel 3.
similar results. A review of 183 cases from the European
Blood and Marrow Transplantation Group (EBMT) Multiple sclerosis: past, present, and future
database with severe multiple sclerosis showed that Multiple sclerosis made a fleeting appearance on the
mortality was 5·3%, but was restricted to the years stage of neurological description early in the 19th century;

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