Progressive Multiple Sclerosis
Progressive MS encompasses both primary progressive MS (PPMS) and secondary progressive MS (SPMS), accounting for the phase of the disease in which neurodegeneration predominates over acute inflammation. Approximately 10–15% of patients present with PPMS from onset, while the majority of untreated RRMS patients transition to SPMS after 15–20 years. The 2024 McDonald criteria have adopted a unified diagnostic framework recognizing the biological overlap between these phenotypes. Despite advances, progressive MS remains one of the most challenging aspects of MS care, with limited therapeutic options and a pressing need for neuroprotective and reparative strategies.
Bottom Line
- PPMS: Gradual neurologic decline from onset without preceding relapses; mean onset age ~40; 1:1 female-to-male ratio; typically presents as progressive myelopathy
- SPMS: Gradual progression following an initial relapsing course; diagnosed retrospectively after 6–12 months of sustained worsening; 2–3 year diagnostic delay is common
- Shared pathogenesis: Both forms are driven by neurodegeneration, microglial activation, compartmentalized inflammation behind an intact blood-brain barrier, and cortical/gray matter pathology
- Ocrelizumab: The only FDA-approved DMT for PPMS; greatest benefit in younger patients (<55 years) with shorter disease duration and active MRI
- Active SPMS: All currently approved DMTs carry the active SPMS indication; siponimod has the strongest evidence from a dedicated SPMS trial (EXPAND)
- Emerging therapies: BTK inhibitors (fenebrutinib, tolebrutinib) are in phase 3 trials for progressive MS, targeting compartmentalized CNS inflammation
Pathogenesis of Progressive MS
While inflammation predominates in RRMS, neurodegeneration is the hallmark of progressive MS. Importantly, both processes co-occur throughout the disease, with the balance shifting over time:
Key Pathogenic Mechanisms
- Compartmentalized inflammation: In progressive MS, inflammation becomes trapped behind an intact blood-brain barrier, making it less accessible to peripheral anti-inflammatory therapies
- Meningeal inflammation: Lymphoid follicle-like structures containing B cells, T cells, and plasma cells form in the meninges and correlate with cortical demyelination severity
- Cortical/gray matter pathology: Subpial demyelination, cortical microglial activation, and neuritic transection without typical perivascular lymphocytic inflammation — a major contributor to disability
- Oxidative stress and mitochondrial dysfunction: Increased metabolic demand of demyelinated axons leads to "virtual hypoxia," energy failure, and progressive axonal degeneration
- Remyelination failure: Impaired oligodendrocyte precursor cell differentiation limits repair capacity
- Iron accumulation: Contributes to oxidative injury in the progressive phase
- Innate immune and B-cell dysfunction: Drives ongoing neurodegeneration independent of peripheral adaptive immunity
Clinical Features
| Feature | RRMS | SPMS | PPMS |
|---|---|---|---|
| Mean age at onset | 20–40 years | 10–15 years after RRMS onset | ≥40 years |
| Female:male ratio | 3:1 | 3:1 | 1:1 |
| Typical presentation | Optic neuritis, partial myelitis, brainstem syndromes | Progressive myelopathy, brainstem/cerebellar syndrome | Progressive spastic paraparesis (80–85%), cerebellar ataxia (10–15%) |
| Course | Discrete attacks with recovery | Gradual deterioration after relapsing phase ± superimposed relapses | Steady decline from onset without clear relapses |
| MRI features | Higher T2 lesion load, active enhancing lesions | Rare active lesions; subpial demyelination, cortical and brain atrophy prominent | Lower brain T2 lesion load; higher spinal cord lesion load; prominent atrophy |
| Frequency | ~85% at onset | Majority of RRMS patients eventually | 10–15% at onset |
Natural history data show that disability progresses at a similar rate in PPMS and SPMS, and the average age of onset of both progressive phenotypes overlaps around age 45 years. These observations support the concept that PPMS and SPMS represent the same underlying neurodegenerative process, with any pathologic differences being relative rather than absolute.
Diagnosing Progressive MS
PPMS Diagnostic Criteria
The 2017/2024 McDonald criteria for PPMS require:
PPMS Diagnostic Criteria
- Required: 1 year of disability progression (retrospectively or prospectively determined), independent of clinical relapse
- Plus two of the following three:
- One or more T2-hyperintense lesions characteristic of MS in ≥1 brain region (periventricular, cortical/juxtacortical, infratentorial)
- Two or more T2-hyperintense lesions in the spinal cord
- Presence of CSF-specific oligoclonal bands
The 2024 criteria additionally allow the optic nerve as a fifth DIS location and incorporate CVS and PRL as supportive biomarkers.
SPMS Diagnosis
Unlike PPMS, SPMS lacks standardized diagnostic criteria and is usually identified retrospectively through clinical history documenting gradual worsening of disability over 6–12 months independent of relapses. Observational studies report a diagnostic uncertainty period of 2–3 years before SPMS is confirmed. The MSBase international registry found the best-performing definition included a three-strata progression magnitude confirmed at 3 months with EDSS ≥4 and pyramidal score ≥2.
Before Diagnosing SPMS
- Exclude alternative causes of progressive myelopathy: vitamin B12/copper deficiency, adrenoleukodystrophy, neurosyphilis, HTLV-I myelitis, PML (especially on natalizumab), HIV myelopathy
- Assess for deconditioning, musculoskeletal complications of disability (meniscal tears, spinal stenosis), and medication side effects that can mimic progression
- Consider vascular comorbidities that may augment apparent progression
- Evaluate for pseudoprogression from deconditioning or loss of rehabilitation services
Classification of Disease Activity
Progressive MS is further classified by the presence or absence of disease activity and progression:
| Category | Definition | Treatment Implications |
|---|---|---|
| Active with progression | Clinical relapses or new/enlarging MRI lesions PLUS sustained disability worsening | Strongest indication for DMT; treat aggressively |
| Active without progression | Inflammatory activity without confirmed disability worsening | DMT indicated to suppress activity |
| Not active with progression | No inflammatory activity but ongoing disability worsening | Limited DMT benefit; focus on rehabilitation and symptom management |
| Not active without progression | Stable disease | Consider DMT discontinuation in appropriate patients |
Detecting Progression
Clinical Measures
The Expanded Disability Status Scale (EDSS) has been the primary measure of MS disability, but it is relatively insensitive to domains beyond pyramidal dysfunction. A more comprehensive assessment includes:
- Timed 25-Foot Walk (T25FW): A >20% worsening is clinically meaningful for leg function
- 9-Hole Peg Test (9HPT): A >20% worsening captures upper extremity deterioration
- Symbol Digit Modalities Test (SDMT): Sensitive measure of cognitive processing speed; ≥4-point worsening is clinically meaningful
- EDSS-Plus: Composite of confirmed EDSS change + T25FW + 9HPT that better delineates SPMS from nonprogression
- Patient-reported outcomes: Self-assessment of mobility, self-care, and daily activities are among the strongest patient-reported predictors of SPMS transition
Progression should be sustained and confirmed at 3–6 months to distinguish true progression from relapse-related worsening.
Imaging Biomarkers
| Biomarker | Pathological Substrate | Clinical Relevance | Availability |
|---|---|---|---|
| White matter lesion load | Demyelination, inflammation, gliosis | Moderate | Widely available |
| Gray matter/cortical lesions | Demyelination, neuroaxonal loss | High (≥7 cortical lesions predicts SPMS conversion) | Limited (requires high-field MRI) |
| Brain atrophy | Demyelination, neuroaxonal loss | High | Emerging (some commercial software) |
| Spinal cord damage/atrophy | Demyelination, neuroaxonal loss | Very high (strongly associated with disability) | Available |
| OCT (retinal nerve fiber layer) | Neuroaxonal damage | Moderate (may predict disability progression) | Available |
Laboratory Biomarkers
- CSF oligoclonal bands: Independent predictor of second attack in CIS and required for PPMS diagnostic criteria; patients with OCBs have a more aggressive disease course, but OCBs do not specifically predict RRMS→SPMS transition
- Serum neurofilament light chain (sNfL): Correlates with neurodegeneration, predicts future disease course and treatment response; standardization for clinical use is still in progress; levels are affected by aging and comorbidities
Factors Influencing Progression
Race and Ethnicity
African ancestry is consistently associated with a greater proportion of progressive forms, faster RRMS-to-SPMS transition, and poorer disease outcomes. Greater structural brain and retinal changes are observed in Black compared with White patients. Whether these observations reflect health disparities or genetic predispositions remains unclear.
Age
Chronologic age is the most consistent factor associated with increased disability accumulation and progressive MS risk. Age-related degenerative processes are superimposed on MS-specific pathology, making disentanglement challenging. The average age of onset of both PPMS and SPMS overlaps around 45 years, and subsequent disability progresses at a similar rate independent of initial clinical course.
Smoking
Smoking is a modifiable risk factor associated with faster disability progression and increased risk of conversion to SPMS. Modification of disability following cessation has been documented. All patients with MS should be provided resources and encouraged to quit smoking.
Vascular Comorbidities
Vascular comorbidities (hypertension, diabetes, dyslipidemia, peripheral vascular disease) are associated with substantially increased risk of disability progression. Each cardiovascular comorbidity at diagnosis increased the risk of requiring a cane by 50%, and patients with at least one comorbidity required walking assistance a median of 6 years earlier. Aggressive management of vascular risk factors is recommended.
Treatment of Progressive MS
DMTs with Evidence in Progressive MS
| Drug | Progressive Type | Key Trial | Key Findings |
|---|---|---|---|
| Ocrelizumab | PPMS | ORATORIO | Only FDA-approved DMT for PPMS; reduced confirmed disability progression; greatest benefit in younger patients (<55) with active MRI |
| Siponimod | Active SPMS | EXPAND | Reduced confirmed disability progression at 3 and 6 months; cognitive benefit (SDMT); approved for active SPMS |
| Mitoxantrone | SPMS | MIMS | Reduced progression and relapses; limited by cardiotoxicity, bone marrow suppression, and risk of hematologic malignancy |
| Cladribine | Active SPMS | CLARITY | Reduced relapses, progression, MRI activity; not exclusively studied in SPMS |
| Interferon beta-1b | Relapsing SPMS | European SPMS trial | Slowed progression in patients with active disease; benefit attributed to younger age, shorter disease duration, higher relapse frequency |
Failed trials in progressive MS include fingolimod (INFORMS, PPMS), natalizumab (ASCEND, SPMS), glatiramer acetate (PPMS), and high-dose biotin (MD1003, PPMS/SPMS). Failure has been attributed to trial design, duration, inclusion criteria, and insensitive outcome measures.
Therapeutic Window in Progressive MS
The benefit of anti-inflammatory DMTs in progressive MS is greatest in those who are:
- Younger (under 50–55 years)
- Earlier in the disease course (shorter disease duration)
- Active (clinical relapses or gadolinium-enhancing lesions on MRI)
This underscores the importance of early identification of progressive MS to maximize the window for therapeutic intervention.
Emerging Therapies
- Bruton tyrosine kinase (BTK) inhibitors: Small molecules that cross the blood-brain barrier; target microglial activation and compartmentalized CNS inflammation; fenebrutinib and tolebrutinib are in phase 3 trials for PPMS and nonrelapsing SPMS
- Ibudilast: Small molecule that slowed brain atrophy progression in a phase 2 trial; targets microglial activation
- ATA188: Autologous EBV-specific T-cell therapy in phase 1/2 for progressive MS
- Remyelination strategies: Multiple approaches targeting oligodendrocyte precursor cell differentiation are under investigation
- N-acetyl cysteine: Neuroprotective agent in randomized controlled trial for progressive MS
DMT Discontinuation
No formal guidelines exist for when to stop DMTs in stable nonactive progressive MS. Data support that safely stopping DMTs is possible in patients who are:
- Age ≥55 years
- Stable on DMT with no relapses for ≥5 years
- No new MRI lesions for ≥3 years
- EDSS <6
Younger age (<45 years) and inflammatory MRI lesions predict disease recrudescence with DMT cessation. If discontinuation is decided, continued MRI monitoring is essential. Rebound risk with natalizumab and fingolimod must be considered.
Comprehensive Care
Progressive MS requires a multidisciplinary approach addressing complex physical and psychosocial needs:
- Rehabilitation: Physical therapy (gait, balance, stretching), occupational therapy, speech therapy, driving evaluations
- Symptom management: Cognitive decline, falls, bladder/bowel/sexual dysfunction, fatigue, mood changes, pseudobulbar affect (~10% of progressive MS), spasticity, pain
- Comorbidity management: Aggressive treatment of vascular risk factors, depression, sleep disorders
- Wellness: Healthy diet, regular exercise adapted to disability level, sleep hygiene, smoking cessation
- Caregiver support: Address emotional needs of both patient and caregiver; connect with support services
- Palliative care: For patients with EDSS ≥8 (bed-restricted); focuses on comfort, quality of life, and psychosocial support. Utilization of palliative care in hospitalized MS patients increased from 0.2% to 6.1% over a decade (2005–2014). Early conversations about goals of care are recommended.
References
- Amezcua L. Progressive multiple sclerosis. Continuum (Minneap Minn). 2022;28(4):1083-1103.
- Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286.
- Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220.
- Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND). Lancet. 2018;391(10127):1263-1273.
- Faissner S, Plemel JR, Gold R, Wee Yong V. Progressive multiple sclerosis: from pathophysiology to therapeutic strategies. Nat Rev Drug Discov. 2019;18(12):905-922.
- Filippi M, Preziosa P, Langdon D, et al. Identifying progression in multiple sclerosis: new perspectives. Ann Neurol. 2020;88(3):438-452.
