Primary Progressive Multiple Sclerosis (PPMS): mechanisms, diagnosis according to the 2024 McDonald criteria and treatment (DMTs, experimental approaches, symptomatic therapy)

PPMS is a form of multiple sclerosis in which neurological disability gradually increases, without the typical “bright” relapses. Important: today PPMS is not a “hopeless variant”, but a distinct clinical scenario where early diagnosis, an appropriate choice of DMTs (disease-modifying therapies), regular monitoring for activity, and high-quality symptomatic and rehabilitation support are especially important.

1) What PPMS is and how it differs

Primary progressive multiple sclerosis (PPMS) is an MS course in which, from the very beginning, there is a gradual increase in symptoms and limitations (for example, leg weakness/stiffness, worsening gait, fatigue), without clearly defined relapses—or with rare, minimal “activity flares.”

In some patients, PPMS may be accompanied by signs of active inflammation (for example, gadolinium-enhancing lesions on MRI), and this is typically where the probability of response to DMTs is higher.

2) Why PPMS progresses: key mechanisms

In progressive MS (including PPMS), not only “classic” immune attacks matter, but also processes that sustain slow, chronic damage to nervous tissue.

• Chronic inflammation within the CNS: immune activity may become “compartmentalized” within the brain/spinal cord and be less dependent on peripheral blood. This underlies interest in therapies acting on cells within the CNS (including microglia).
• Myelin injury and insufficient remyelination: over time, some lesions remyelinate less effectively, increasing the risk of persistent symptoms.
• Neurodegeneration and axonal loss: even with low “visible” MRI activity, gradual loss of nerve fibers may continue, leading to worsening gait, manual function, and balance.
• The role of B cells: the effectiveness of anti-CD20 therapy in PPMS (ocrelizumab) supports the importance of B-cell–driven mechanisms. This is one reason for interest in BTK inhibitors, which target B-cell pathways and components of innate immunity.

3) Diagnosing PPMS under the 2024 McDonald criteria

MS diagnosis (including a progressive onset) is based on a combination of clinical findings and evidence of dissemination in space and/or time, plus careful exclusion of alternative diagnoses. The 2024 McDonald criteria were substantially updated, adding new diagnostic opportunities while emphasizing specificity.

3.1. The clinical “framework” of PPMS

PPMS typically involves continuous (or near-continuous) progression of neurological impairment over time. In practice, the clinician clarifies onset and trajectory (gait, strength, coordination), whether any episodes resembled relapses, the impact of heat, and relevant comorbid explanations (spinal canal stenosis, nutritional deficiencies, vascular factors, etc.).

3.2. MRI and biomarkers: what the 2024 criteria added

• The optic nerve is now treated as a separate anatomical location (a fifth region) for assessing dissemination in space, which is important when supported by clinical and test findings.
• As supportive markers (where available), the following may be used: central vein sign (CVS), paramagnetic rim lesions (PRL), and CSF κ free light chains (as an alternative/add-on to oligoclonal bands in certain situations).
• The criteria also provide guidance for more complex scenarios: late onset (≥50 years), comorbidity, and cases requiring extra caution to avoid overdiagnosis.

3.3. A key principle: PPMS requires careful exclusion of mimics

In a progressive course, it is particularly important to rule out conditions that can mimic PPMS: compressive myelopathies, vitamin B12/copper deficiency, hereditary spastic paraplegias, inflammatory myelitis of other etiologies (including NMOSD/MOGAD), vascular and degenerative processes. This is why high-quality diagnostics are not “one scan,” but a systematic hypothesis check.

4) How we monitor PPMS: MRI, labs, and disability measures

• Brain and spinal cord MRI (with contrast when indicated): assessment of new lesions, inflammatory activity, and changes in atrophy/brain volume measures.
• Scales and tests: EDSS, T25FW (Timed 25-Foot Walk), 9HPT (9-Hole Peg Test), 6-minute walk, balance assessment, fatigue and cognitive screening.
• Therapy safety: blood tests and other assessments depending on the chosen DMTs and individual risk factors.

5) Treatment of PPMS: DMTs (disease-modifying therapy)

5.1. Ocrelizumab

Ocrelizumab is an anti-CD20 therapy that demonstrated efficacy in PPMS in the ORATORIO trial: reduced risk of confirmed disability progression versus placebo and a more favorable trajectory on several MRI outcomes. The greatest benefit is usually expected in younger patients and in the presence of active inflammation (for example, gadolinium-enhancing lesions).

5.2. If activity is low: why treatment and monitoring still matter

In PPMS there may be no obvious relapses and no “fresh” MRI lesions—yet symptoms may still slowly worsen. In such cases, key components are: optimization of rehabilitation, treatment of spasticity/pain/bladder dysfunction, fall prevention, sleep and fatigue management, and regular follow-up to detect emerging activity where DMTs may have a greater impact.

6) Experimental therapy in PPMS: what is realistically being studied

Below are actively investigated directions (some with available trial results). This is not standard of care, but understanding these approaches helps to interpret news and clinical trial discussions.

6.1. BTK inhibitors (Bruton tyrosine kinase inhibitors)

BTK inhibitors are of interest because they affect signaling pathways in B cells and innate immune cells, and some agents may cross the blood–brain barrier, which is theoretically relevant for progression.

• Fenebrutinib: in November 2025, Genentech reported that in its phase 3 program the drug slowed disability progression in PPMS (press-release data; detailed results are expected in publications/congress presentations).
• Tolebrutinib: in December 2025, it was reported that the PERSEUS PPMS study did not meet its primary endpoint for slowing progression (also based on press/news reports).

6.2. Neuroprotection and therapies targeting brain atrophy

Alpha-lipoic acid (ALA) is an example of a strategy primarily motivated by brain atrophy rates. In a recent randomized trial in progressive MS, ALA did not improve the primary clinical outcome (walking speed), while MRI showed differences in volumetric measures (stability/less negative change in some metrics). The safety profile required careful monitoring (for example, proteinuria was reported). This illustrates a common situation where a “nice” MRI signal does not necessarily translate into meaningful clinical benefit for a given patient.

Ibudilast (SPRINT-MS) was associated with slower brain atrophy progression in progressive MS. It did not become standard therapy, but remains an important evidence point supporting neuroprotection as a research direction.

6.3. Other immunomodulatory approaches

• Masitinib (a tyrosine kinase inhibitor): randomized trial data in progressive MS have been published, with a signal toward slowing disability worsening; the topic remains debated and requires confirmation.
• Vidofludimus calcium: phase 2 in progressive MS reported mixed results (including no effect on the primary atrophy endpoint with trends in disability outcomes in some subgroups). This remains investigational.

6.4. Cell-based therapies: AHSCT and mesenchymal cells

Autologous hematopoietic stem cell transplantation (AHSCT) is an intensive approach aiming to “reset” the immune system after high-dose immunosuppression followed by reinfusion of the patient’s own blood stem cells. The most robust AHSCT results are seen in highly active inflammatory MS (more often relapsing courses). In progressive MS without activity, effectiveness is substantially lower; large reviews emphasize appropriate patient selection, and in low-activity/high-disability settings the benefit may be limited.

Mesenchymal stromal cells (MSCs) and derivatives (for example, MSC-NP, MSC-derived neural progenitors) are explored for effects on inflammation, trophic support, and repair mechanisms. In a phase 2 randomized placebo-controlled trial of intrathecal MSC-NP, there was no difference in the primary composite endpoint in the overall group, but subgroup signals (for example, in patients with more pronounced gait limitation) suggested improvements in walking tests, and effects on selected measures were reported (including gray-matter volumetrics and bladder function outcomes). This remains experimental, and such approaches should be pursued within properly regulated clinical trials.

CAR-T technology is a promising direction for severe immune-mediated diseases. For MS, this is still a research area; as of now, specific PPMS-focused clinical outcome data have not been published.

7) Symptomatic therapy and device-based approaches: improving quality of life

In PPMS, quality of life often depends not only on DMTs, but also on systematic supportive care: spasticity, pain, fatigue, gait, balance, bladder function, sleep, anxiety. This typically involves a combination of medications, rehabilitation, and device-based strategies.

7.1. Spasticity, stiffness, cramps

• Medication management (individualized selection).
• Botulinum toxin therapy for focal spasticity — to improve gait and care, reduce pain, and lower the risk of contractures.
• Physiotherapy and stretching, with a structured home program.

7.2. Gait impairment and balance

• Gait assessment (tests, video analysis, selection of cane/walker/orthoses).
• Functional electrical stimulation (FES) for foot drop (peroneal stimulation): selecting indications and training.
• Balance training, fall prevention, and addressing fear of falling.

7.3. Fatigue and cognitive difficulties

• Looking for “MS-mimicking” contributors: anemia, iron/vitamin D deficiency, sleep disorders, depression/anxiety, medication side effects.
• Energy conservation strategies, pacing, and managing heat sensitivity.
• Cognitive rehabilitation: attention/processing-speed training, practical daily strategies, and digital supports.

7.4. Pain, neuropathic symptoms, sleep

Pain in MS can be neuropathic, musculoskeletal, related to spasticity, or driven by posture/load. Correct pain classification is the key to effective treatment. Sleep and anxiety often amplify pain and fatigue, so these factors should be assessed together.

7.5. Bladder and pelvic symptoms

Bladder dysfunction is common in PPMS and often responds well to targeted management when properly evaluated (urodynamic testing is needed in some cases). The goal is to reduce urgency/incontinence, lower infection risk, improve sleep, and support daily functioning.

8) A practical step-by-step plan for patients

1. Confirm the diagnosis under the 2024 McDonald criteria and exclude alternatives (especially in a progressive course).
2. Assess activity (MRI, clinical features, lab markers) and discuss DMTs if indicated.
3. Map your symptom priorities: spasticity, gait, fatigue, sleep, pain, bladder—then choose “1–2 goals for the next 8–12 weeks.”
4. Start rehabilitation and, if needed, device-based support (orthoses, FES, etc.).
5. Track change using scales and tests: it is important to measure not only “how it feels,” but objective trends.

9) Questions and answers (FAQ)

10) References and sources

Below is an expanded list of key publications and sources. DOIs are clickable.

1. Montalban X, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376:209–220. DOI: 10.1056/NEJMoa1606468
2. Montalban X, et al. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol. 2025;24(10):850–865. DOI: 10.1016/S1474-4422(25)00270-4
3. Spain RI, et al. Lipoic Acid for Treatment of Progressive Multiple Sclerosis: A Phase 2 Randomized Clinical Trial. Neurology. 2026;106(1):e214454 (Epub 2025-12-15). DOI: 10.1212/WNL.0000000000214454
4. Fox RJ, et al. Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. N Engl J Med. 2018;379(9):846–855. DOI: 10.1056/NEJMoa1803583
5. Harris VK, et al. Efficacy of intrathecal mesenchymal stem cell-neural progenitor therapy in progressive MS: phase II randomized placebo-controlled trial. Stem Cell Res Ther. 2024;15:151. DOI: 10.1186/s13287-024-03765-6
6. Nabizadeh F, et al. Autologous Hematopoietic Stem-Cell Transplantation in Multiple Sclerosis: A Systematic Review and Meta-Analysis. Neurol Ther. 2022;11(4):1553–1569. DOI: 10.1007/s40120-022-00389-x
7. Masitinib in progressive MS (trial report). Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1148. DOI: 10.1212/NXI.0000000000001148
8. Spain R, et al. Lipoic acid in secondary progressive MS: randomized controlled trial. Neurology. 2017. PMID page (with DOI link): PubMed
9. Ocrelizumab in PPMS: long-term follow-up (ORATORIO extension). Lancet Neurol. 2021. DOI: 10.1016/S1474-4422(20)30342-2
10. Briggs FBS, Amezcua L. Alpha Lipoic Acid in Multiple Sclerosis: It’s All in the Details (commentary). Neurology. 2026;106(1):e214578 (Epub 2025-12-15). DOI: 10.1212/WNL.0000000000214578
11. Vidofludimus calcium phase 2 CALLIPER (progressive MS) — official congress materials/presentations (if you cite them as a data source). (Often without a DOI; see the press/news links below.)
12. Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol. 1997;29(3):315–331. DOI: 10.1016/S0306-3623(96)00474-0

Press releases and phase 3 news (no DOI)

• Genentech (Nov 9, 2025): press release on fenebrutinib (RMS and PPMS). open
• Reuters (Dec 15, 2025): report that PERSEUS (tolebrutinib) in PPMS did not meet its primary endpoint. open
• OHSU (Dec 15, 2025): press release on alpha-lipoic acid results in progressive MS (ahead of Neurology publication). open