Progressive Multiple REVIEW ARTICLE

Sclerosis

CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Lilyana Amezcua, MD, MS, FAAN

ABSTRACT
PURPOSE OF REVIEW: This article provides an update on progressive forms of
multiple sclerosis (MS) commonly referred to as primary progressive MS and
secondary progressive MS. It discusses the importance of diagnosing and
detecting progression early, the similarities between progressive forms,
challenges in detecting progression, factors that could augment progression,
and the importance of disease-modifying therapies in patients with evidence
of active progressive MS. It also discusses the overall care of progressive MS.

RECENT FINDINGS: The pathogenesis of primary progressive MS and secondary

CITE AS:
progressive MS is overlapping, and in both presentations, patients with CONTINUUM (MINNEAP MINN)
relapses or focal MRI activity are classified as having active, progressive 2022;28(4, MULTIPLE SCLEROSIS
AND RELATED DISORDERS):
MS. All currently approved disease-modifying therapies are indicated for 1083–1103.
active secondary progressive MS. The therapeutic opportunity of
anti-inflammatory drugs for the treatment of progressive MS is enhanced Address correspondence to
Dr Lilyana Amezcua, 1520
in those who are younger and have a shorter disease duration. Vascular
San Pablo St, Ste 3000,
comorbidities may contribute to progression in MS. Los Angeles, CA 90033,
lamezcua@usc.edu.
SUMMARY: Several challenges remain in the diagnosis, follow-up, and treatment
RELATIONSHIP DISCLOSURE:
of progressive MS. Early identification of active progressive MS is needed Dr Amezcua has received
to maximize treatment benefit. The advantages of optimal comorbidity personal compensation in the
range of $5000 to $9999 for
management (eg, hypertension, hyperlipidemia) in delaying progression serving as a consultant for
are uncertain. Clinical care guidelines for advanced, severe MS are lacking. Biogen and Novartis AG and in
the range of $10,000 to $49,999
for serving as a consultant for
Genentech, Inc, and EMD
Serono. The institution of
INTRODUCTION Dr Amezcua has received

M
ultiple sclerosis (MS) is a chronic inflammatory condition of research support from
Bristol-Myers Squibb Company,
the central nervous system (CNS) that is characterized by Genentech, Inc, MedDay
demyelination and concomitant axonal and neuronal Pharmaceuticals, the National
degeneration. More than 2.5 million individuals are affected by Institutes of Health National
Institute of Neurological
MS worldwide, and MS is now considered the leading cause of Disorders and Stroke, and the
atraumatic neurologic disability in young adults.1 Approximately 85% of patients National Multiple Sclerosis
Society.
with MS present with a relapsing-remitting course of the disease (relapsing
remitting MS [RRMS]), and the majority of these patients, as shown in natural UNLABELED USE OF
history studies, advance to a progressive disease course after 15 to 20 years after PRODUCTS/INVESTIGATIONAL

disease onset (secondary progressive MS [SPMS]).2 The remaining USE DISCLOSURE:

Dr Amezcua reports no
approximately 10% to 15% of patients have a slow and gradual neurologic disclosure.
deterioration from the onset, termed primary progressive MS (PPMS). However,
progressive and relapsing forms of MS share many clinical, imaging, and © 2022 American Academy
pathologic features. Progression in MS can occur with or without disease activity of Neurology.

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PROGRESSIVE MULTIPLE SCLEROSIS

and with or without worsening deficits on neurologic examination. It is

important to clarify the application of the term progression in these cases; it is not
meant to be synonymous with increasing disability over time due to poor
recovery from individual relapses. Often, the terms disability progression and
disease progression are used interchangeably. However, disability progression
should be reserved for the accrual of physical disability, which may include that
due to poor relapse recovery. Disease progression, instead, refers to the
advancement of disease driven by underlying neurodegenerative processes that
can co-occur with inflammatory activity but also develop in its absence.
Delay in diagnosis of progressive MS is common because of the lack of defined
or reliable measures of disease progression in the clinic. Definitive clinical
biomarkers at the clinician’s disposal are lacking. Nevertheless, multiple possible
imaging and laboratory biomarkers are being assessed, and the use of
disease-modifying treatments (DMTs) in active SPMS offers a greater
opportunity to intervene earlier on. The classification of progressive MS by
Lublin and colleagues3 defines active as the presence of either a clinical relapse or
MRI activity over a specified period of time (FIGURE 5-1). MRI activity is defined as

FIGURE 5-1
2013 disease phenotype for both primary progressive (PP) multiple sclerosis (MS) and
secondary progressive (SP) MS according to Lublin and colleagues.3
PR = progressive relapsing.
a
Activity determined by clinical relapses and/or MRI activity (contrast-enhancing lesions, new or unequivocally
enlarging T2 lesions assessed at least annually); if assessments are not available, activity is “indeterminate.”
b
Clinically isolated syndrome, if subsequently clinically active and fulfilling current MS diagnostic criteria,
becomes relapsing-remitting MS.
Reprinted from Lublin FD, et al, Neurology.3 © 2014 American Academy of Neurology.

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contrast-enhancing lesions, as well as new or enlarging T2 lesions. In this article, KEY POINTS
progressive MS, challenges in detecting it, potential modifiable factors, and its
● Disease progression
treatment are reviewed. refers to the advancement
of disease driven by
PATHOGENESIS OF PROGRESSIVE MULTIPLE SCLEROSIS underlying
Inflammation, which gradually subsides with age and longer disease duration, is neurodegenerative
processes that can co-occur
the predominant neuropathologic feature of RRMS, whereas neurodegeneration
with inflammatory activity
predominates in progressive MS.3,4 Importantly, evidence now supports that but also develop in its
both the neuroinflammatory and neurodegenerative processes can co-occur, and absence.
they often do, in an individual patient. The underlying mechanisms of primary
and secondary progressive forms of MS are not completely understood but are ● The term active in the
classification of multiple
thought to involve similar pathways, which could have therapeutic implications. sclerosis (MS) is defined as
The proposed mechanisms are the result of neurodegenerative processes driven presence of clinical relapse
by dysfunction of the innate immune system and B cells.5 In addition, oxidative or MRI activity.
stress, microglial activation, increased metabolic demand of demyelinating axons
● Inflammation that drives
due to injury,6,7 remyelination failure, iron accumulation, and mitochondrial tissue injury has become
damage with resultant virtual hypoxia are reported, among other processes, but compartmentalized behind
are beyond the scope of this article.8-10 an intact blood-brain barrier
Cortical involvement, with underlying gray matter pathology, likely in progressive MS.
contributes to disability progression in MS.11 Studies show cortical microglial
activation, neuritic transection, and apoptosis without the typical perivascular
lymphocytic inflammation that is characteristic of MS white matter pathology.12
The presence of subpial lesions with meningeal infiltrates containing B and T
lymphocytes, plasma cells, and macrophages is consistent with lymphoid follicles
and is thought to also drive progression in MS.13 Although meningeal
inflammation correlates with the severity of cortical demyelination and the
appearance of these lymphoid follicles is similar to B-cell follicles, it is unclear
whether these structures actively contribute to the pathology of progressive
MS.13 In addition, it is hypothesized in progressive MS that inflammation that
drives tissue injury has become compartmentalized behind an intact blood-brain
barrier. For more information on pathophysiology, refer to the review by
Faissner and colleagues13 and the article “Epidemiology and Pathophysiology of
Multiple Sclerosis” by Melanie Ward, MD, and Myla D. Goldman, MD, MSc,
FAAN,14 in this issue of Continuum.

CLINICAL FEATURES OF PROGRESSIVE MULTIPLE SCLEROSIS

Certain clinical differences exist between the onset of RRMS and PPMS. For
example, the female-to-male ratio is much closer to 1:1 in progressive-onset MS,
and the mean age at onset is older (about 10 years later; 40 years old and older).3,16
This is in contrast to RRMS, where a 3:1 female-to-male predominance of MS is
seen and the age of onset is between 20 and 40 years of age. In progressive MS, a
progressive myelopathy is common and characterized by an insidious and
worsening spastic paraparesis, usually without a discernable sensory level (80%
to 85% of cases). In some cases, PPMS may present with a progressive cerebellar
ataxia (10% to 15%) or other brainstem or visual symptoms (2% to 4%).17 Also,
approximately 5% of adults with PPMS have symptom onset at the age of
60 years or older.18 Older individuals with MS are reportedly more likely to
present with a progressive course (32% with PPMS and 23% with SPMS).18 This is
in contrast to the typical RRMS presentation of optic neuritis (approximately
25%), brainstem events, and partial spinal cord syndromes that can be

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PROGRESSIVE MULTIPLE SCLEROSIS

predominantly sensory, with or without sphincter dysfunction. Key clinical

differences between the relapsing and progressive phenotypes are presented
in TABLE 5-1.
Progression in MS can be variable throughout the disease course, with
superimposed relapses or MRI activity (ie, new or enhancing lesions) or both, as
well as periods of relative disease stability. Increasing clinical, imaging, and
genetic data suggest that PPMS is more similar than not to SPMS, and any
pathologic differences from SPMS are relative rather than absolute. For example,
a lower incidence in the global focal white matter lesion load and the presence of
gadolinium-enhancing lesions is said to be found in PPMS. Nevertheless, natural
history studies have shown that disability progresses at a similar rate in patients
with PPMS and SPMS with or without relapses.19-21

DIAGNOSING PROGRESSIVE MULTIPLE SCLEROSIS

The diagnosis of progressive MS, either SPMS or PPMS, is usually delayed. In
most RRMS cases, MS progression is identified retrospectively by using clinical
history that supports a gradual worsening of disability between 6 and
12 months.3,22,23 Observational studies, however, have reported a period of
uncertainty of 2 to 3 years before an SPMS diagnosis is made.24,25 In 2021, a
cross-sectional survey reported that neurologists who, through clinical history,
observed particular changes to ambulation were willing to consider making a

TABLE 5-1 Clinical Characteristics of Multiple Sclerosis Subtypes

Relapsing Secondary progressive Primary progressive

Mean age 20-40 years 10-15 years after initial ≥40 years
disease presentation

Female:male 3:1 3:1 1:1

Presenting event Optic neuritis, acute partial Progressive myelopathy, Progressive myelopathy, brainstem
transverse myelitis, brainstem brainstem or cerebellar or cerebellar syndrome
syndromes syndrome

Frequency of 85% Not applicable 10-15%

presentation at
start

Course Episodes of acute worsening of Gradual neurologic Steady functional decline from
neurologic functioning with total deterioration following a disease onset without relapses or
or partial recovery relapsing course with or remission
without relapses

Conventional Lesion load burden is more
brain MRI compared with primary
progressive MS; active lesions are
common, cortical lesions less
common
Rare active lesions; subpial
demyelination and cortical
atrophy are more common
Lesion load burden is less compared
with relapsing multiple sclerosis;
rare active lesions; subpial
demyelination and cortical atrophy
are more common

Conventional Lower lesion load Higher lesion load Higher lesion load
spinal cord MRI

MRI = magnetic resonance imaging.

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diagnosis of SPMS over a short patient history period (3 to 6 months).26 In KEY POINTS
contrast, the diagnosis of PPMS is much more standardized, and specific criteria
● The 2017 McDonald
exist to guide the neurologist in making the diagnosis (CASE 5-1). The 2017 diagnostic criteria for
McDonald criteria for PPMS require (1) 1 year of disability progression primary progressive MS are
(retrospectively or prospectively determined) independent of clinical relapse, the following: (1) 1 year of
plus two of the following criteria: (1) one or more T2-hyperintense lesions on disease progression
independent of clinical
brain MRI characteristic of MS in one or more of the following brain regions:
relapse and at least two of
periventricular, cortical, juxtacortical, or infratentorial; (2) at least two or more the following: one or more
T2-hyperintense lesions in the spinal cord; or (3) the presence of CSF-specific T2-hyperintense lesions
oligoclonal bands.23 The current updated criteria eliminated the distinction characteristic of MS in one
or more of the following
between symptomatic and asymptomatic lesions and emphasize the role of
regions: periventricular,
CSF-specific oligoclonal bands in fulfilling dissemination in time in the diagnosis juxtacortical, cortical, or
of PPMS.23 infratentorial; (2) two or
When considering a diagnosis of PPMS or SPMS, it is important to exclude more T2-hyperintense
other causes of chronic myelopathies that can present with gradual worsening lesions in the spinal cord;
or (3) the presence of
similar to progressive MS. This includes metabolic disorders such as subacute CSF-specific oligoclonal
combined degeneration associated with vitamin B12 or copper deficiency, as well bands.
as adrenoleukodystrophy and mitochondrial inherited disorders. Infectious
causes include neurosyphilis, progressive multifocal leukoencephalopathy ● Myelopathy is a common
feature of progressive MS.
(especially in patients on DMT for RRMS and who are progressing), and human
T-cell lymphotropic virus type 1 (HTLV-I)-associated myelitis. A particular ● To be considered
consideration of progressive multifocal leukoencephalopathy should be made in progressive MS, progression
individuals with MS who progress while on natalizumab and in patients receiving in disability should be
sustained and confirmed at
long-term immunosuppression.27 A slowly progressive spastic paraparesis
3 to 6 months.
associated with human immunodeficiency virus (HIV) may also mimic the
clinical course of PPMS. Inflammatory causes such as neurosarcoidosis and other
systemic inflammatory conditions should also be excluded.

DETECTING PROGRESSIVE MULTIPLE SCLEROSIS

Progression in PPMS and SPMS is not uniform over time and can include periods
of relative stability or slow insidious change that is difficult to measure by the
patient or physician. Currently, multiple efforts are being made to identify and
validate objective measures of progression, which are critically needed. At this
time, no specific guidelines or satisfactory measurements of MS progression are
available for use in the clinic.28,29 For years, the Expanded Disability Status Scale
(EDSS) score has been the main measure of clinical MS-related disability in
clinical trials.30
Originally implemented as a research tool, the EDSS is relatively insensitive
to common problems in MS outside of pyramidal dysfunction (ie, cognitive
progression). The addition of more quantitative measures such as adding
functional scores to the EDSS evaluation and the integration of Multiple
Sclerosis Functional Composite (MSFC),31 which is a three-part, standardized,
quantitative assessment instrument that originally integrated the timed
25-foot walk for leg function and ambulation, 9-hole peg test for arm and hand
function, and Paced Auditory Serial Addition Test (PASAT-3) for cognitive
function, increased the ability to detect a reliable change over time. The Paced
Auditory Serial Addition Test was replaced eventually by the Symbol Digit
Modalities Test, and low-contrast assessment of visual acuity was added.
In the setting of an acute relapse, disability may be reversible with resolution
of focal inflammation. As such, it is important in patients with “active”

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PROGRESSIVE MULTIPLE SCLEROSIS

progressive MS that any measured increase in disability is sustained and

confirmed at 3 to 6 months.22,25 Recently, the addition of a minimum worsening
of more than 20% on a timed 25-foot walk32 and 9-hole peg test33 (measure of
upper extremity function) and changed EDSS at 24 weeks further delineated the
separation between SPMS and nonprogression.34

Imaging
Several imaging biomarkers are under consideration to better detect and monitor
progression of MS in the clinic.35 It can be challenging to distinguish a clinical
relapse from clinical progression in the clinic; currently, conventional MRI with
corresponding new T2 and/or gadolinium-enhancing lesions is viewed as the best
surrogate marker of clinical relapse. However, a weak correlation exists between
MRI lesion load and clinical disability, which is likely related to the inability to
fully measure (ie, using EDSS) and capture heterogeneity of the underlying MS
pathology.36 Thus, the observation that primary progressive MS tends to have,
on average, fewer T2/fluid-attenuated inversion recovery (FLAIR) lesions does
not necessarily correlate to less disability. In part, this is likely because of the

CASE 5-1 A 46-year-old man with no significant past medical history reported
increasing neurologic symptoms of gait and balance difficulty for the past
3 years. Four years ago, while running, he noted numbness of his toes that
gradually spread to his knees. These symptoms worsened with fatigue
and running. He also reported that in the past year he has noted difficulty
in emptying his bladder and bladder urgency.
On neurologic examination, he was found to have intact cranial nerves
and 4/5 dorsiflexion on his right foot with increased tone bilaterally. His
coordination was intact, but his gait was consistent with a right foot drop.
Pinprick and vibration sensations were altered in both lower extremities,
and he had increased reflexes throughout with an upgoing toe on
the right.
Laboratory findings were unremarkable. MRI of the brain and cervical
spine showed several periventricular and juxtacortical brain lesions and
scattered lesions in the cervical spine (FIGURE 5-2). Lumbar puncture
results showed five oligoclonal bands specific to CSF.
The patient was diagnosed with a progressive myelopathy, and MRI
was suggestive of multiple sclerosis (MS). CSF was also consistent with
intrathecal antibody production, and no other etiology was found.
He met the 2017 McDonald criteria for primary progressive MS
diagnosis: 1 year of disease progression independent of clinical relapse
and at least two of the following characteristics: (1) one or more
T2-hyperintense lesions characteristic of MS in one or more of the
following regions: periventricular, juxtacortical, cortical, or
infratentorial; (2) two or more T2-hyperintense lesions in the spinal cord;
(3) or the presence of CSF-specific oligoclonal bands.

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demonstrated findings of a shift from active to inactive plaques along with
progressive atrophy of gray and white matter that is evident on MRI in primary
progressive MS.37 In addition, diffuse abnormal white and gray matter of the
brain and spinal cord has been reported to be more prominent in patients with
progressive MS and is thought to reflect ongoing neurodegeneration and
inflammation.38 Spinal cord lesions are also reported to be more common in
progressive MS and are strongly associated with disability in progressive MS.39 As
with brain MRI, the ability to detect clinically relevant microstructural changes
in the spinal cord with conventional MRI is needed and is being developed.39
Changes in T2-hyperintense lesion load within the first few years after disease
onset are predictive of long-term disability worsening.40 Evaluation of cortical
lesion burden (greater than or equal to 7) and its accumulation over time (4 years
after disease onset) has been reported to predict conversion to SPMS and have
clinical relevance.41 Cortical involvement, with underlying gray matter
pathology, appears to be a major contributing factor to the disability seen in
progressive MS.11 Nevertheless, many of these measures are still only accessible
through research or in clinical trials, with heterogeneity in study methodology,

FIGURE 5-2
MRI of the brain and cervical spine of the patient in CASE 5-1. Lesions characteristic of multiple
sclerosis are seen on both axial T2 (A) and fluid-attenuated inversion recovery (FLAIR) (B)
brain MRI with periventricular and juxtacortical white matter lesions. Also seen are enlarged
right and left lateral ventricles, which are consistent with brain atrophy and a cystlike right
occipital lesion. Cervical spine sagittal short tau inversion recovery (STIR) MRI (C) reveals
scattered lesions primarily seen at C3 and C4.

This case exemplifies progressive MS with a short disease duration and age COMMENT
of onset younger than 50 years. Regardless of the absence of
gadolinium-enhancing lesions, this patient would likely benefit from
disease-modifying therapy approved by the US Food and Drug
Administration (FDA) for PPMS.

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PROGRESSIVE MULTIPLE SCLEROSIS

which is not exclusive to differences in the strength of the MRI magnet. Hence,
more advanced MRI techniques are being analyzed with the intention to better
assess axonal loss by measuring gray matter atrophy, thalamic volume, spinal
cord atrophy, hippocampal volume, gray matter fraction, cortical lesion
quantification, and sodium imaging, among others.29,42 Thus, developing tools to
readily assess these changes have the potential to be clinically relevant and
feasible to predict progressive MS (TABLE 5-2).35
Optical coherence tomography (OCT) is a noninvasive tool that allows the
measurements of retinal nerve fiber layer thickness, ganglion cell/inner
plexiform layer thickness, and macular volume. Loss of retinal nerve fiber layer
thickness and ganglion cell/inner plexiform layer thickness correlates with
clinical and paraclinical parameters such as visual function, disability, and MRI in
MS.43 Some studies indicate that OCT parameters may be able to predict
disability progression in MS. OCT is also being considered as an outcome
measure of axonal loss in several phase 2 proof-of-concept clinical trials of
progressive MS.44
Other imaging and nonimaging techniques have been used in remyelination
trials as biomarkers of myelin repair and include magnetization transfer ratio,
diffusion-weighted imaging, myelin water imaging, and visual evoked potentials.45

Laboratory
The association between CSF oligoclonal bands and MS has been known for
decades, and the presence of intrathecal oligoclonal bands is a widely used

TABLE 5-2 Biomarkers That May Have Clinical Relevance in Identifying Progression in
Multiple Sclerosisa

Clinical Clinically
Biomarker Pathological substrates relevance feasible Clinically available

MRI

White matter lesions Demyelination, inflammation, ++ +++ Yes

neuroaxonal loss, gliosis

Grey matter lesions Demyelination, inflammation, +++ + No; accessibility to high magnet
neuroaxonal loss, gliosis strength needed

Brain atrophy Demyelination, neuroaxonal +++ ++ No; some commercial software

loss available but not standard

Spinal cord damage Demyelination, inflammation, ++++ ++ Yes

neuroaxonal loss, gliosis

Serum neurofilament Neuroaxonal damage +++ +++ No

light chain levels

Optical coherence Neuroaxonal damage, + ++ Yes

tomography demyelination

+ = less relevant or feasible; ++ = modest relevance or feasibility; +++ = medium relevance or feasibility; ++++ = high relevance or feasibility;
MRI = magnetic resonance imaging.
a
Modified from Filippi M, et al, Ann Neurol.35 © 2020 American Neurological Association.

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diagnostic biomarker for MS.46,47 Numerous studies have shown that, after KEY POINTS
controlling for demographic, clinical, and MRI variables, CSF oligoclonal
● Better imaging tools are
bands are an independent predictor of a second clinical attack in an adult being assessed to help
with clinically isolated syndrome.38-46 Patients with MS with oligoclonal bands identify progression in MS.
have also been reported to have a more aggressive disease course than patients
with MS without oligoclonal bands.48 However, evidence generally does not ● Advanced biomarkers
that include measures of
support the utility of CSF oligoclonal bands as a marker of progression from
brain atrophy and spinal
RRMS to SPMS, but oligoclonal bands are an important biomarker in the 2017 cord damage, including
McDonald diagnostic criteria23 for PPMS and help avoid a false-positive optical coherence
MS diagnosis. tomography and serum
Recently, serum neurofilament light chain has been highlighted as a plausible neurofilament hold promise
to be clinically relevant and
marker of neurodegeneration that can be measured accurately, sensitively, and feasible in the care of
reproducibly.49-51 Findings from relapsing and progressive cohorts concur and progressive MS.
indicate that serum neurofilament light chain concentrations correlate with CSF
neurofilament light chain levels44 and imaging and disability measures predict ● In a person who has a
steady progression of
the future course of the disease and can predict response to treatment. However, disease since onset for 1 year
prior to its utility in progressive MS, standardization for sample processing and or more, dissemination in
analysis needs to be established and the possibility that serum neurofilament space can be satisfied by
light chain measurements are affected by aging and other comorbidities must be the presence of oligoclonal
bands in the CSF (2017
better understood.51
McDonald criteria) in
addition to two or more T2
Other Clinical Measures spinal cord lesions or one or
Clinical predictors and determinants of progressive MS have been primarily more MS-typical T2 brain
lesions.
quantitative, based on single-center or large-scale observational cohort studies.52,53
Nevertheless, patient-reported outcomes and real-world experience are starting to
be incorporated into algorithms for evaluating the transition to progressive MS,
which may enrich the physician-patient interaction in evaluating current disease
state and level of progression.54 Patient age, mobility, and self-care were identified
as the strongest patient-reported predictors of progression to SPMS.54 Recently,
other measures of performance, such as wearable digital devices (eg, a health
tracker than can be worn on the wrist) are being incorporated as additional
determinations of worsening in contemporary studies.55 Limitations to detection
include its retrospective nature and what definition is used to define progressive
MS. MSBase, an international registry of patients with multiple sclerosis, evaluated
various definitions of SPMS. The best performance definition included a three-
strata progression magnitude in the absence of a relapse, confirmed after 3 months
within the leading Functional System and required an EDSS step 4 or greater and
pyramidal score of 2 or greater.25 A current unmet need for patients and clinicians
is the accurate identification of patients who have transitioned to SPMS and a
validated tool to measure progression among those who are determined to have
progressive MS, either PPMS or SPMS.

NONGENETIC FACTORS THAT INCREASE VULNERABILITY TO

PROGRESSION IN MULTIPLE SCLEROSIS
Studies on the clinical presentation and course of MS have indicated that certain
initial demographics and clinical factors are predictive of disease progression.

Race/Ethnicity
An increasing number of studies have identified African ancestry as a risk factor,
not only for susceptibility to MS but also for disease progression. A greater

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PROGRESSIVE MULTIPLE SCLEROSIS

proportion of progressive forms and poorer disease outcomes is consistently

reported with African ancestry in the United States and elsewhere.56-62 Black
patients with MS have been reported to have a faster transition from RRMS to
SPMS.63 In Latin America, a worse prognosis for those with an African
background who have primary progressive MS is also reported.59 A recent
analysis of a northern California managed care network found Black patients,
compared with other groups, more often had primary progressive MS (10.0%
versus 0.0% to 4.0%) or progressive relapsing MS (6.0% versus 0.0% to 2.0%).61
In addition, greater structural changes in distinct anatomical regions of the brain,
the visual system as noted by retinal nerve fiber layer measurements, and spinal
cord (measurements of the medulla and upper cervical regions) are suggestive of
greater neurodegeneration in Black individuals compared with White
individuals.62,64,65 Whether these observations reflect greater encounters with
health disparities and inequities or genetic predispositions is not clear.

Age
Aging is the most important risk factor for the development of
neurodegenerative disease, and age-dependent degenerative processes likely
contribute to MS progression in aging patients with MS.66,67 Chronologic age has
been consistently associated with increased rates of MS disability accumulation
and the risk of progressive MS.67 These processes are superimposed on natural
brain aging processes, which makes it difficult to disentangle age-related changes
from those due to the pathophysiology of progressive MS. Nevertheless, efforts
are ongoing to determine how much normal aging contributes to brain atrophy,
which may increase with age, and to the rate of MS-specific brain atrophy areas
(ie, the thalamus), which may also increase with age.68 Whether older age at
disease onset is associated with a shorter time to disease progression has been
inconclusive.69,70 Interestingly, the average age of onset of both PPMS and SPMS
overlaps (around the age of 45 years), and subsequent disability progresses at a
similar rate independent of age of onset and previous clinical course. A recent
biomarker of aging, telomere length (using leukocyte telomere length), was
found to be associated with higher levels of disability and brain atrophy in people
living with MS.71

Smoking
Smoking is a modifiable risk factor in MS, and its association with disease
outcomes has mostly been researched in RRMS.72 Within the progressive MS
populations, the relationship between smoking and disease progression has
been less clear. Some studies report that smoking is associated with a more
severe disease course and faster disability progression, whereas others have
not found such an association.73-75 Importantly, modification of disability
following smoking cessation has been reported, supporting that it is never
“too late” for a patient with MS to quit smoking.74 In 2021, the risk of conversion
into secondary progressive disease was shown to increase among people who
smoke when self-reported smoking history was used to define those who
smoke.76 Collectively, the data support that, for an individual patient with MS,
smoking may contribute to inflammatory disease activity and disease
progression, as well as provide an opportunity to improve disability with
cessation. All patients with MS should be encouraged and provided resources
to stop smoking.

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Comorbidities KEY POINTS
The recognition is growing that comorbidities may influence disease progression
● Smoking is a modifiable
in MS.77 Vascular comorbidity, whether present at symptom onset, diagnosis, or risk factor in the progression
later in the disease course, has been associated with a substantially increased risk of MS and patients should
of disability progression in MS.77-82 be encouraged to quit
It is possible that vascular comorbidity augments neurodegeneration by smoking.
adding greater accumulation of white matter lesions and/or a diffuse
● Vascular comorbidities
hypoperfusion with consequent chronic hypoxia.82 Having type 2 diabetes, can increase the risk of
hypertension, dyslipidemia, or peripheral vascular disease has been reported to progression of MS and likely
be associated with greater disability progression.78 Each cardiovascular complicate treatment of
comorbidity at disease onset increased the risk of walking disability by 50%, and progressive MS.

patients with at least one comorbidity at diagnosis required unilateral assistance

to walk a median of 6 years earlier than those without a comorbidity at
diagnosis.77 A more granular look into vascular comorbidities suggests that
arterial hypertension in patients with MS is associated with an increased risk of
reaching higher levels of disability.79 Recently, patients with MS with systolic
blood pressure variability and greater blood pressure severity (stage II as staged
by the American Heart Association) were found to have greater risk of
MS-related disability.80,81 More research is needed to determine the pathways in
which having MS and vascular comorbidity interact. Beyond the current work
focused on vascular comorbidities, additional studies around the impact of other
comorbidities (eg, psychiatric comorbidities) and their impact on MS
progression are needed.

PRACTICAL APPROACH TO PROGRESSIVE MULTIPLE SCLEROSIS CARE

AND TREATMENT
The treatment of both PPMS and SPMS is challenging because of the
heterogeneity of mechanisms involved in the pathophysiology of progression.
Currently available evidence supports that CNS immune activation occurs in the
early course of progressive MS with increased levels of biomarkers of
demyelination and neuronal and axonal damage in CSF.1 As of 2019, all DMTs
indicated for RRMS have active SPMS added to their label based on the
assumption that progressive disease, still to a lesser degree, has inflammatory
activity concurrent with the underlying neurodegeneration (ie, brain atrophy)
despite limited effects noted in the clinical trials. Active SPMS refers to the
presence of clinical relapses or MRI activity.3 No DMTs are FDA approved to
treat nonactive SPMS. For more detailed information on DMTs, refer to the
article “Treatment of Multiple Sclerosis” by Anne Cross, MD, FAAN, and Claire
Riley, MD,83 in this issue of Continuum.

Disease-Modifying Therapies Found Effective in Studies of Progressive

Multiple Sclerosis
Despite all current available DMTs having the designation to treat active SPMS,
only a few have been actively studied for progressive forms of MS and showed
efficacy. Interferon beta medications are indicated, for example, to treat RRMS
and SPMS if relapses are present. Although multiple studies, including one in the
United States, were conducted to evaluate interferons, it was only a European
study on SPMS that found a significant slowing in disease progression that was
attributed to differences in patient characteristics (ie, more active disease)
(TABLE 5-3).82,84-91 Thus, interferon beta-1b has the designation for relapsing

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PROGRESSIVE MULTIPLE SCLEROSIS

SPMS in Europe. Mitoxantrone is a cytotoxic DNA intercalating agent that has

been used as an effective DMT in MS and has been approved since the year
2000. The MIMS (Mitoxantrone in Progressive Multiple Sclerosis) trial
(a double-blind, multicenter, phase 3 trial) and other clinical studies have
shown a reduction in progression of disability and relapses in patients with
SPMS.88 Mitoxantrone’s adverse effects, which include cardiotoxicity, bone
marrow suppression, and other life-threatening hematologic malignancies, have

TABLE 5-3 Phase 3 Trials in Secondary Progressive Multiple Sclerosis and Primary
Progressive Multiple Sclerosis

Progressive Presence of
multiple oligoclonal Clinical characteristics
Sample sclerosis bands Disability end point as enhancing disability end
Treatment size definition needed outcome point

Interferon beta-1b85 718 Active No Confirmed progression Younger age, shorter

secondary of disability measured disease duration, higher
progressive by the Expanded relapse frequency in the
multiple Disability Status Scale 2 years prior to study
sclerosis (SPMS) (EDSS) entry, and active MRI

Cladribine86 1326a Active SPMS No Confirmed progression Not applicable (NA)

of disability measured
by the EDSS

Siponimod87 1651 Active SPMS No Confirmed progression Younger age, active MRI
of disability measured
by the EDSS

Mitoxantrone88 194 About half had No Change in EDSS score, Similar treatment effects
SPMS ambulation, relapses, in patients with and
time to first relapse, and without relapses
changes in neurologic
status at 24 months

Ocrelizumab89 732 Primary Yes Confirmed disability Younger age, shorter

progressive MS progression in EDSS disease duration, active
(PPMS) score at 12 weeks MRI

Fingolimod90 970 PPMS No Time to confirmed NA

disability progression

Natalizumab91 889 SPMS No Proportion of Upper limb measures

participants with improved (via 9-hole peg
worsening of ≥1 on EDSS, test)
timed 25-foot walk, and
9-hole peg test

MD1003 (high-dose 642 SPMS or PPMS No Proportion of patients None, instead the
biotin) + disease- with disability potential serious nature of
modifying therapy54 improvement, measured misinterpretation of
by EDSS or timed abnormal laboratory
25-foot walk at month 9 results was found
and confirmed at month 12

MRI = magnetic resonance imaging.

a
A combination of relapsing-remitting MS and active progressive MS.

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limited its use in recent years. In 2020, a study of 10-year outcomes indicated KEY POINT
a more favorable efficacy profile in those with RRMS compared with patients
● Ocrelizumab is the only
with a rapid progression.92 US Food and Drug
Siponimod is a selective modulator of sphingosine-1-phosphate receptor Administration (FDA)-
subtypes 1 and 5 that is approved for the treatment of active SPMS.87 It is thought approved disease-modifying
to readily cross the blood-brain barrier and have direct actions in the CNS that therapy (DMT) for the
treatment of primary
limit inflammation and promote remyelination. Patients treated with siponimod
progressive MS.
in the EXPAND (EXploring the efficacy and safety of siponimod in PAtients with
secoNDary progressive multiple sclerosis) study experienced a significant
reduction in confirmed disability progression at 3 and 6 months, especially in
those with active SPMS compared with those given placebo, and less brain
volume loss, which led to its approval.87 A recent post hoc analysis assessed
cognitive processing speed and found siponimod to have a clinically significant
benefit observed in Symbol Digits Modalities Test scores.93 In the United States,
all second-generation sphingosine-1-receptor blockers (siponimod, ozanimod,
ponesimod) are approved across the MS spectrum from clinically isolated
syndrome to SPMS. Cladribine is a purine analogue used in the treatment of hairy
cell leukemia and approved also for active SPMS.86 The CLARITY (Cladribine
Tablets Treating Multiple Sclerosis Orally) study determined that cladribine
significantly reduced relapse rates, risk of progression of disability, and
MRI-measured disease activity in patients with RRMS and relapsing SPMS.86
However, it was not exclusively studied in SPMS.
To date, ocrelizumab is the first and only FDA-approved DMT for patients
with PPMS.89 The characteristics of patients treated in ORATORIO (A Study of
Ocrelizumab in Participants With Primary Progressive Multiple Sclerosis)
indicate that ocrelizumab exerts an anti-inflammatory effect most pronounced in
those who were younger than 55 years of age and with evidence of higher disease
activity (27.5% of those treated with ocrelizumab had gadolinium-enhancing
lesions on MRI).89,94 This idea is supported in the rituximab clinical trial in PPMS
that also showed greater benefit in those younger than 50 years of age and with
gadolinium-enhancing lesions on MRI.95 Thus, a stronger consideration should
be given to treat those younger and in early stages of PPMS.
Results of studies that were designed to specifically assess efficacy of
glatiramer acetate, fingolimod, and natalizumab in either PPMS or nonactive
SPMS have been dissapointing.90,91,96,97 Part of their failure to show benefit has
been attributed to trial design, trial duration, inclusion criteria, and selection of
appropriate clinical and imaging outcome measures.29
Trials focusing on mechanistic aspects of neurodegeneration in progressive
MS could be more promising. Unfortunately, the recent results from a study of
MD1003 (high-dose biotin), thought to enhance neuronal and oligodendrocyte
energetics, resulting in improved cell function, repair, or survival, did not show
benefit.55 Adding MD1003 to existing DMT compared with placebo in patients
with nonactive progressive MS (PPMS or SPMS) provided no improvement of
MS-related disability or prevention of worsening disability measured by the
EDSS.55 Efforts to evaluate therapeutics that more specifically target
inflammation compartmentalized to the CNS or neurodegeneration are at
various stages of development. Of these, ibudilast, a small molecule able to cross
the blood-brain barrier, is a promising investigational therapeutic; compared
with placebo, it slowed the progression of brain atrophy in patients with
progressive MS (PPMS or SPMS) in a phase 2 study.98 Additional small molecules

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PROGRESSIVE MULTIPLE SCLEROSIS

being investigated with the capacity to cross the blood-brain barrier include the
Bruton tyrosine kinase (BTK) inhibitors. Current clinical trials actively recruiting
patients with SPMS and PPMS are shown in TABLE 5-4.

Approach to Nonactive Stable Progressive Multiple Sclerosis

Challenges and uncertainty still exist in treating disease progression in patients
without evidence of clinical relapses or MRI activity. No formal guidelines have

TABLE 5-4 Active Clinical Trial Recruitment in Progressive Multiple Sclerosisa

Clinical trial
identifier Title Type of multiple sclerosis

NCT03283826 A Phase 1/2, Two-part, Open-label Dose-escalation and Double- Primary progressive multiple sclerosis
blind, Placebo-controlled Dose-expansion Study With an (MS) and secondary progressive MS
Open-label Extension to Evaluate the Safety and Efficacy of
ATA188 in Subjects With Progressive Multiple Sclerosis

NCT04943289 Phase IA Trial of Intrathecal Administration of Human Umbilical Primary progressive MS

Cord Blood-Derived Cell Therapy (DUOC-01) in Adults With
Primary Progressive Multiple Sclerosis (PPMS)

NCT04544449 A Phase III Multicenter, Randomized, Double-Blind, Double- Primary progressive MS

Dummy, Parallel-Group Study to Evaluate the Efficacy And Safety
Of Fenebrutinib Compared With Ocrelizumab In Adult Patients
With Primary Progressive Multiple Sclerosis

NCT04458051 A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Primary progressive MS
Comparing SAR442168 to Placebo in Participants with Primary
Progressive Multiple Sclerosis (PERSEUS)

NCT04548999 A Phase IIIB Multicenter, Randomized, Double-Blind, Controlled Primary progressive MS

Study to Evaluate the Efficacy, Safety and Pharmacokinetics of a
Higher Dose of Ocrelizumab in Adults With Primary Progressive
Multiple Sclerosis

NCT03896217 A Double-blind, Randomised, Placebo-controlled Single-site Secondary progressive MS

Study of High Dose Simvastatin Treatment for Secondary
Progressive Multiple Sclerosis: Impact on Vascular Perfusion and
Oxidative Damage

NCT04411641 A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Secondary progressive MS
Comparing SAR442168 to Placebo in Participants With
Nonrelapsing Secondary Progressive Multiple Sclerosis

NCT03362294 A Prospective, Multicenter, Two Arms, Open Label, Phase IIa Primary progressive MS
Study to Assess the Safety and Efficacy of Once-a-month
Long-acting Intramuscular Injection of 25 mg or 40 mg Glatiramer
Acetate (GA Depot) in Subjects With Primary Progressive Multiple
Sclerosis (PPMS)

NCT04047628 A Multicenter Randomized Controlled Trial of Best Available Relapsing-remitting MS and

Therapy Versus Autologous Hematopoietic Stem Cell Transplant secondary progressive MS
for Treatment-Resistant Relapsing Multiple Sclerosis (ITN077AI)

NCT05122559 Randomized Controlled Trial of N-acetyl Cysteine as a Primary progressive MS and

Neuroprotective Agent in Progressive Multiple Sclerosis secondary progressive MS

a
Clinicaltrials.gov accessed June 11, 2022.

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been established surrounding when and how to stop DMTs in a patient with KEY POINTS
stable nonactive progressive MS. However, data support that safely stopping the
● Stopping DMT use in
use of DMTs for people with nonactive progressive MS is possible. Most studies patients with MS who are 55
indicate that older age, longer periods of stable disease on DMT with absent and older, are stable, and
relapses or MRI activity, and an EDSS score less than 6 are associated with a low have no evidence of active
risk of disease recrudescence and worsening when stopping DMT use. In contrast, disease on DMT is possible.
younger age (younger than 45 years) and a higher number of inflammatory lesions
● Before a patient is given a
on MRI are predictive of resumption of disease activity.99,100 Discontinuation of diagnosis of secondary
Disease Modifying Therapies in Multiple Sclerosis (not recruiting) is a prospective progressive MS, alternative
interventional randomized study that includes patients with MS who are 55 years causes for their worsening
old or older, including both progressive forms of MS, and no evidence of symptoms should be sought.

activity.101 In this study, nonactive is defined as no evidence of recent new

inflammatory disease with no relapse for at least 5 years and no new MRI lesion for
at least 3 years. The primary outcome is the number of patients developing new
disease activity with discontinuation of DMT. The results are expected in the next
year and will provide important guidance to patients and clinicians who are now
caring for an aging population in the therapeutic era of MS.
The short- and long-term potential toxicity and cost of DMTs need to be
carefully considered in aging patients who have MS and in those with progressive
MS. Similarly, the risk of stopping DMTs in those with significant disability and
active disease would be a significant risk. If discontinuation of DMT is decided,
continued monitoring for breakthrough disease is highly recommended. It is also
important to recognize the risk of inflammatory activity with the stopping of
certain agents (eg, natalizumab and fingolimod), known as rebound, in those
who would otherwise be candidates for discontinuation.

MULTIDISCIPLINARY CARE AND CONTEMPORARY CONSIDERATIONS

IN THE CARE OF PROGRESSIVE MULTIPLE SCLEROSIS
Patients with progressive MS have complex physical and psychosocial needs,
which can make general care challenging. If identification of active progressive
MS is present, switching to a higher-efficacy medication in those already on a
DMT is strongly recommended (CASE 5-2). Regular patient visits and familiarity
with rehabilitative strategies and symptom management are also needed.102
Cognitive decline; falls; bladder, bowel, and sexual impairments; fatigue; and
mood changes are common symptoms that worsen over time. This includes
worsening cognitive fatigue and depression, which are symptoms that have been
reported to negatively affect quality of life for patients with MS.1,3 Routine
evaluations should include screening for these symptoms and evaluating and
treating for new ones, such as pseudobulbar affect (pathologic laughing and
crying, approximately 10% of MS cases), which mainly occurs in progressive MS.
Other conditions that can mimic or augment progression include musculoskeletal
conditions that have developed as a consequence of MS ambulatory disability (eg,
meniscal tears, knee and hip injuries) or independent of MS (ie, spinal stenosis and
other medical comorbidities such as vascular disease). Before a patient is given a
diagnosis of SPMS, alternative causes for their worsening symptoms should be
sought. This includes deconditioning as a result of lockdown measures during the
COVID-19 pandemic and the related postponements and delays in care, including
DMT changes.103,104 Many patients with progressive disease have become more
restricted to home during the COVID-19 pandemic and lost the opportunity for
physical therapy and/or gym participation, which has led to generalized worsening

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PROGRESSIVE MULTIPLE SCLEROSIS

that can be misclassified as progression. It is important to consider these possibilities

because they can represent sources of “reversible” progression for patients.
A multidisciplinary approach to care is recommended. This includes disciplines
such as physical therapy, occupational therapy, urology, pain management,
primary care, social services, counseling, and neuro-ophthalmologic evaluations.
The high prevalence of motor disorders and gait disabilities, the negative
impact on personal activities and quality of life, and the limited effects of specific
medications make gait rehabilitation a crucial part of the management.
Encouragement to follow a healthy diet, exercise regularly and stretch, and
maintain sleep hygiene is also recommended. Rehabilitation support should also
include caregiver support services, tending to the emotional needs of both the
patient and caregiver, and supportive services to assist with the physical and
cognitive deficits being experienced by the patient with progressive MS.105 For
more information on symptom management, refer to the article “Approach to
Symptom Management of Multiple Sclerosis With a Focus on Wellness” by
Rebecca Spain, MD, MSPH, FAAN,106 in this issue of Continuum.
Treatment in severe cases of progressive MS with disability levels where the
patient is restricted to a bed (an EDSS score of 8 or more) entails considering
palliative care. Palliative care is an interdisciplinary approach that improves the

CASE 5-2 A 45-year-old woman presented for evaluation and treatment guidance.
Her past medical history consisted of an episode of bilateral leg
weakness at the age of 19 years that resolved on its own and for which she
did not seek evaluation. She was diagnosed with MS after she had optic
neuritis in her twenties, and she then started treatment with an injectable
DMT. In the past 2 years, she noticed worsening sensory symptoms
involving her left arm, partial torso, and leg, and her left leg felt weak.
About 6 months ago, she developed double vision and balance problems
that partially resolved.
Her examination was notable for left leg weakness with spasticity, and
a timed 25-foot walk test took 13 seconds with poor balance. In addition,
she had a bilateral internuclear ophthalmoplegia, asymmetric brisk
reflexes, and an upgoing toe on the left. MRI of the brain showed
generalized atrophy, with multiple subcortical, periventricular, and
infratentorial (cerebellar, middle cerebellar peduncle, and midbrain)
T2/fluid-attenuated inversion recovery (FLAIR) lesions. One faint
gadolinium-enhancing lesion was seen.
The patient was diagnosed with active secondary progressive MS with
evidence of recent demyelination and inflammation. A combination of
pharmacologic and nonpharmacologic treatment was indicated. She was
switched to siponimod and referred to physical therapy, counseling, and
neuro-ophthalmology.

COMMENT This case exemplifies the opportunity to treat with higher-efficacy

disease-modifying therapy given recent clinical events and MRI suggestive
of active inflammation and progression.

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quality of life of patients and their families facing the problems associated with KEY POINT
incurable diseases or life-threatening illnesses, through the prevention and relief
● Palliative care may be a
of symptoms by means of early identification and impeccable assessment and beneficial option for those
treatment of physical and psychosocial concerns.107 Those with severe who are hospitalized and
progressive MS could benefit from palliative care approaches when the accrual of have accrued significant
physical and cognitive disability has been significant. An exponential increase in physical and cognitive
disability due to
the use of palliative care for hospitalized patients with MS was reported over a
progressive MS.
10-year period (0.2% to 6.1% from 2005 to 2014), mostly in those at higher risk of
in-hospital death.108 Palliative care guidelines are being developed to help
respond to the complex and varying physical and psychosocial needs of patients
with severe progressive MS.109,110 It is important to begin conversations early
with patients and their family members about their wishes and plans for when
their disability reaches a threshold that requires full-time care and loss of
independent activities of daily living.

CONCLUSION
Several challenges remain in the diagnosis, detection, biomarkers,
implementation of treatments, and care guidelines for progressive MS.
Nevertheless, several relevant biomarkers look promising and could be used to
distinguish active from inactive progressive MS in the clinic. Studies of the
currently available DMTs for active SPMS and PPMS underscore that younger
age at onset and shorter disease duration are likely to have greater benefit.
Whether therapeutic control of comorbidities delays progression is unknown.
Beyond inflammation, additional treatments that target neuroprotection and
repair are needed. Multidisciplinary care is crucial in caring for patients with
progressive MS, including the need to better understand where palliative care fits
into the care algorithm for severe progressive MS.

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