Made on
Tilda
Modern multiple sclerosis therapy can substantially reduce the risk of new relapses and new lesions. The next obvious question for patients is whether it is possible not only to prevent new injury, but also to repair nervous tissue that has already been damaged.
The central nervous system can indeed partially restore the myelin sheath. This process is called remyelination. However, as of 2026, there is no approved treatment that has been convincingly shown to restore myelin in multiple sclerosis and, through this mechanism, produce clinically meaningful recovery of neurological function.
Improvement in neurological symptoms after a relapse does not mean that the affected area of the brain or spinal cord has completely returned to its previous state. Several mechanisms contribute to recovery at the same time.
As the acute inflammatory response resolves, tissue edema decreases and nerve fibers that were temporarily blocked by inflammation but not irreversibly damaged can regain function.
Even without full restoration of myelin, a demyelinated axon can partly reorganize the distribution of ion channels and resume impulse conduction.
A new myelin sheath can form around some surviving axons. It is usually thinner than the original sheath, but can improve impulse conduction and increase the metabolic resilience of the axon.
The nervous system can partly redistribute function among preserved neural networks and use alternative pathways. This mechanism is especially important in rehabilitation.
Clinical improvement alone therefore cannot show how much recovery is due to remyelination. In one patient, resolution of inflammation may dominate; in another, neuroplastic compensation may be more important; in a third, restoration of myelin may also make a measurable contribution.
Myelin is the specialized sheath surrounding nerve fibers. In the central nervous system it is produced by oligodendrocytes. Myelin enables rapid nerve conduction and also contributes to the metabolic support of the axon.
When an MS lesion forms, the myelin sheath is damaged. If the axon itself survives, new myelin can potentially form around it. This process is called remyelination.
The brain and spinal cord contain oligodendrocyte precursor cells (OPCs). After demyelination, these cells can migrate into the injured area, mature into oligodendrocytes and form a new myelin sheath.
A pathological hallmark of this process is the so-called shadow plaque — a lesion in which surviving axons have again become covered by a thinner layer of myelin.
A demyelinated axon requires more energy to maintain normal impulse conduction. At the same time, chronic inflammation and mitochondrial dysfunction limit its energy supply. Restoring the myelin sheath reduces this metabolic burden and probably improves the long-term resilience of the nerve fiber.
The presence of oligodendrocyte precursor cells in a lesion does not guarantee that they will form fully functional new myelin. In many chronic lesions the cells are present but fail to complete the necessary stages of maturation.
The efficiency of remyelination depends on several factors:
With age, oligodendrocyte precursor cells respond less effectively to signals that trigger maturation. Chronic lesions also accumulate molecular signals that inhibit oligodendrocyte differentiation.
Different lesions can therefore behave very differently even in the same person: one may undergo substantial remyelination while another shows very little.
If the axon has already been lost, remyelination is impossible because there is no surviving nerve fiber around which a new sheath can form. Preserving axons is therefore one of the major goals of modern MS treatment.
Neuroprotection means preventing irreversible damage to axons and neurons.
It is important to distinguish direct neuroprotective action from indirect protection of nervous tissue. Most current disease-modifying therapies primarily suppress pathological immune activity. By preventing new inflammatory lesions, they also prevent the axonal loss associated with those lesions.
The most effective strategy currently available for preserving nervous tissue is therefore to prevent new injury from occurring in the first place, rather than trying to repair it later.
There are still no separate drugs with convincingly proven direct neuroreparative efficacy in MS.
In some patients, neurological disability gradually worsens even when there are no new clinical relapses. This process is referred to as progression independent of relapse activity (PIRA).
PIRA can occur during relapsing MS and is not exclusively a feature of late secondary progressive multiple sclerosis.
Several processes are associated with gradual progression:
The absence of new gadolinium-enhancing lesions therefore does not always mean that the pathological process has completely stopped.
An acute MS lesion usually enhances with gadolinium only for a limited period. Once the blood–brain barrier has recovered, contrast enhancement disappears.
Some previously formed lesions, however, remain biologically active. Activated microglia and macrophages persist at the lesion edge, while tissue injury may slowly expand inward from the rim.
These lesions are called chronic active lesions (CAL).
One way to detect them in vivo is through paramagnetic rim lesions (PRL). On susceptibility-sensitive MRI sequences, a rim can be seen around the lesion, related mainly to iron accumulation in activated microglia and macrophages.
The presence of PRL is associated with greater tissue damage and a less favorable disease course. However, PRL count is not yet used as a stand-alone standard criterion for changing therapy.
Current evidence suggests that existing DMTs are highly effective at preventing new inflammatory injury but are much less effective against chronic active lesions that have already formed. CAL and PRL are therefore regarded as important targets for future treatment of progressive MS.
Every new relapse and every new MRI lesion represents additional injury to nervous tissue. If the chosen treatment does not adequately control inflammatory activity, it is important to assess whether the MS treatment strategy should be changed. In that situation, remyelination inevitably becomes a secondary goal: first, new damage must be stopped.
During long-term follow-up, attention should be paid to gradual reduction in walking distance, slowing of gait, worsening hand function, impaired balance, or slowing of cognitive performance even when there are no obvious relapses.
When needed, quantitative measures are used, including walking tests, the 9-Hole Peg Test (9-HPT), cognitive testing and serial EDSS assessment.
Smoking, hypertension, diabetes, obesity and other vascular disorders reduce functional reserve in the nervous system and are associated with less favorable MS outcomes.
Correcting these factors is not remyelination, but it matters for preserving already vulnerable nervous tissue.
Rehabilitation does not directly create a new myelin sheath. Its role is to make the best possible use of preserved neural pathways, maintain strength, endurance and coordination, and develop more efficient motor strategies.
Tolebrutinib is a Bruton tyrosine kinase (BTK) inhibitor. An important feature of the drug is its ability to cross the blood–brain barrier.
BTK participates in intracellular signaling in B lymphocytes and in myeloid-lineage cells, including microglia. BTK inhibition is therefore being used as a way to target not only peripheral inflammation but also immune processes within the central nervous system.
The HERCULES trial included 1,131 patients with secondary progressive MS who had had no clinical relapses during the preceding two years and had documented disability progression.
Six-month confirmed disability progression occurred in 22.6% of patients receiving tolebrutinib and 30.7% of patients receiving placebo. The hazard ratio was 0.69.
In June 2026, Cenrifki (tolebrutinib) was approved in the European Union for adults with secondary progressive MS without relapses during the preceding two years.
Treatment requires liver-function monitoring because of the risk of drug-induced liver injury.
The trial demonstrated that the risk of disability progression can be reduced in a selected group of patients with nonrelapsing secondary progressive MS. It did not show that tolebrutinib restores myelin or damaged axons. Its relevance to this topic lies mainly in the attempt to target chronic inflammatory processes within the central nervous system.
Most current experimental strategies do not attempt to introduce new oligodendrocytes from outside. Instead, they aim to activate the patient’s own precursor cells already present within the central nervous system.
Several major directions are being investigated:
| Drug / approach | Proposed mechanism | Main clinical evidence | Status in 2026 |
|---|---|---|---|
| Clemastine | Blockade of M1 muscarinic receptors and stimulation of oligodendrocyte precursor-cell maturation. | The ReBUILD trial found a small reduction in visual evoked-potential latency. A later small study in progressive MS produced an unfavorable signal regarding disability worsening. | Not an MS therapy |
| PIPE-307 | Selective M1 muscarinic receptor blockade. | In preclinical models the drug stimulated oligodendrocyte maturation, but the phase II VISTA trial did not meet its predefined primary efficacy endpoints. | Clinical efficacy not demonstrated |
| Metformin | An attempt to restore the responsiveness of aging oligodendrocyte precursor cells to maturation signals. | The combination of metformin and clemastine was studied in CCMR Two. The study has been completed, but full efficacy results have not yet been published. | Experimental strategy |
| Ibudilast | Targeting neuroinflammation and mechanisms of chronic tissue injury. | In the phase II SPRINT-MS trial, brain-volume loss was slower; a subsequent analysis also showed an effect on slowly expanding lesions. | Not approved for MS |
| Opicinumab | Blockade of LINGO-1, a protein that inhibits oligodendrocyte maturation. | Despite a convincing biological rationale, clinical trials did not confirm a sustained functional benefit. | Development did not lead to an approved therapy |
| Bexarotene | Activation of retinoid X receptors and stimulation of oligodendrocyte differentiation. | Some electrophysiological signs suggested possible remyelination, but the primary trial endpoint was not met and tolerability was poor. | Not used to treat MS |
Clemastine is a first-generation antihistamine with marked anticholinergic activity. Interest in MS arose after experimental studies suggested that it could stimulate maturation of oligodendrocyte precursor cells.
In the small randomized ReBUILD trial in patients with chronic visual pathway injury, clemastine shortened visual evoked-potential latency by about 1.7 ms per eye.
The study was important because, for the first time, a pharmacological intervention in humans changed an electrophysiological measure of a chronically demyelinated pathway in a direction compatible with presumed remyelination.
However, ReBUILD did not demonstrate clinically meaningful visual recovery or a reduction in disability.
Later, in a small group of patients with progressive MS in the TRAP-MS research platform, an unfavorable signal emerged: disability accumulation accelerated in some participants, and that study arm was stopped.
The investigators linked this observation to possible enhancement of inflammatory cell death under conditions of chronic neuroinflammation. The sample was small and cannot quantify risk for all patients with MS, but the finding substantially changed the view of clemastine use outside research studies.
Clemastine is not an approved treatment for multiple sclerosis. Self-treatment with higher doses in an attempt to induce remyelination is not supported by adequate clinical evidence.
One drawback of clemastine is that it acts on several receptor systems. PIPE-307 was therefore developed as a selective M1 muscarinic receptor antagonist that can enter the central nervous system.
In cellular and animal models, the drug promoted oligodendrocyte precursor-cell differentiation and remyelination.
However, in the phase II VISTA trial in relapsing MS, PIPE-307 did not meet its predefined primary efficacy endpoints.
This illustrates one of the central difficulties in developing remyelinating therapies: successfully targeting the right cell pathway in an experimental model does not guarantee functional recovery in humans.
Interest in metformin in MS research is unrelated to its glucose-lowering effect.
Experimental work has shown that with aging, oligodendrocyte precursor cells respond less effectively to the signals needed for maturation. In experimental models, metformin partly restored this responsiveness.
This led to the phase IIa CCMR Two trial, in which metformin plus clemastine was compared with placebo in patients with relapsing MS receiving stable DMT and with chronic visual pathway injury.
The trial has been completed, but at the time this page was updated, full efficacy results had not yet been published.
Therefore, prescribing metformin to a person without diabetes or another metabolic indication solely for remyelination in MS is not currently justified.
Ibudilast differs from drugs aimed directly at oligodendrocyte maturation. It has been studied mainly as a way to influence neuroinflammation and chronic tissue injury in progressive MS.
In the phase II SPRINT-MS trial involving 255 patients with progressive MS, the rate of brain-volume loss was lower with ibudilast than with placebo.
A subsequent analysis also found a reduction in the volume of slowly expanding lesions (SEL), which are considered one MRI marker of chronic lesion activity.
These findings suggest a biological effect on chronic tissue-injury processes. However, no phase III trial has demonstrated a reduction in clinical progression, and ibudilast is not approved as an MS treatment.
Some studies of modern DMTs show changes in MRI or electrophysiological measures that could be compatible with improved myelin status.
However, it is difficult to separate direct remyelination reliably from reductions in inflammation, edema and secondary tissue injury.
It is therefore more accurate to say that highly effective therapy creates more favorable conditions for natural recovery by preventing new inflammatory injury, rather than directly “growing new myelin”.
After early small studies, high-dose biotin was considered a possible metabolic therapy for progressive MS.
The large phase III SPI2 trial did not confirm clinical efficacy. High-dose biotin can also substantially distort the results of some laboratory tests.
High-dose biotin is not recommended as a neuroreparative treatment in MS.
An early high-dose simvastatin study found an interesting result for the rate of brain atrophy.
However, the phase III MS-STAT2 trial did not confirm a reduction in disability progression.
Statins should therefore be used in people with MS according to standard cardiovascular indications, not as a specific neuroprotective or remyelinating therapy.
After early findings suggesting a possible effect on brain atrophy, a larger randomized trial was conducted in progressive MS.
In results published in 2026, alpha-lipoic acid did not slow clinical worsening of walking.
This illustrates why a change in a single MRI measure cannot by itself be regarded as proof of a neuroprotective effect.
Correction of confirmed vitamin D, vitamin B12 or other nutrient deficiencies has its own medical indications.
However, no vitamin, omega-3 fatty acid, coenzyme Q10, antioxidant complex or other dietary supplement has been proven to restore myelin in multiple sclerosis.
Improving function in MS is not limited to restoring myelin.
The nervous system can reorganize neural networks, recruit alternative pathways and improve motor strategies. Together, these processes are referred to as neuroplasticity.
Regular physical activity and specialized neurorehabilitation can improve strength, endurance, balance, walking and performance of daily activities.
This represents clinically meaningful functional recovery, but it should not be called proven remyelination.
Rehabilitation should match the mechanism of impairment. Weakness, spasticity, ataxia and foot drop require different approaches. In selected patients, orthoses, functional electrical stimulation and robotic gait training may be used.
Autologous hematopoietic stem cell transplantation (AHSCT) is used in carefully selected patients with highly active inflammatory MS.
Its main mechanism is profound immune-system reconstitution and suppression of inflammatory activity.
After transplantation, hematopoietic stem cells do not transform into neurons or oligodendrocytes and do not directly replace damaged nervous tissue.
Neurological improvement after successful AHSCT may reflect cessation of inflammation, restoration of conduction, natural remyelination and neuroplasticity.
Cell-based technologies continue to be studied as potential ways to alter the inflammatory microenvironment, provide trophic support to nervous tissue and stimulate endogenous repair mechanisms.
However, there is still no routine cell therapy proven to restore lost myelin or axons and thereby reduce disability in MS.
Commercial claims of “restoring myelin with stem cells” should not be confused with evidence-based AHSCT or with an approved neuroreparative therapy.
Conventional clinical MRI is very good at detecting inflammatory lesions but does not directly measure the amount of myelin.
A reduction in lesion size, disappearance of enhancement or change in signal intensity can result from reduced inflammation and edema, altered water content, gliosis or tissue loss. Standard MRI therefore cannot reliably determine how much a specific lesion has remyelinated.
Research studies use more specialized methods:
Neurofilament light chain (NfL) and GFAP are among the most widely studied fluid biomarkers in MS. NfL reflects neuroaxonal injury, while GFAP mainly reflects astroglial pathology and biological processes associated with progression.
Both biomarkers may complement clinical and MRI assessment, but neither measures remyelination directly. A fall in NfL indicates less ongoing axonal injury, but does not prove that previously lost myelin has been restored.
Current evidence increasingly suggests that effective neuroreparative treatment will probably need to target several processes at the same time.
Stimulating oligodendrocyte maturation alone is unlikely to be sufficient. The axon itself must also be preserved, new inflammation suppressed, and the unfavorable microenvironment of chronic lesions changed.
The most plausible future strategy would combine:
Negative results from individual trials do not mean that the concept of remyelination is invalid. They show that repairing nervous tissue in MS is biologically more complex than stimulating a single cellular target.
Yes. Natural remyelination occurs in many people with MS and can be substantial in some lesions. Its effectiveness depends on age, lesion age, axonal preservation and the local inflammatory microenvironment.
No. As of 2026, there is no approved therapy with a proven clinically meaningful remyelinating effect in multiple sclerosis.
Partial remyelination of a chronic lesion is possible if viable axons remain. The likelihood of repair depends on lesion age, patient age and the degree of axonal injury.
A direct, clinically proven remyelinating effect of ocrelizumab has not been established. The drug suppresses inflammatory activity effectively, prevents new injury and may thereby create more favorable conditions for natural repair mechanisms.
There is no basis for self-treatment with clemastine for this purpose. An early study showed a small electrophysiological effect, but later data in progressive MS produced an unfavorable safety signal. Clemastine is not an approved MS therapy.
Not at present. The clinical efficacy of metformin as a remyelinating treatment has not been demonstrated. The CCMR Two trial has been completed, but full efficacy results have not yet been published.
It is more accurate to classify tolebrutinib as a disease-modifying therapy that targets immune mechanisms both outside and within the central nervous system. In HERCULES, it reduced the risk of progression in nonrelapsing secondary progressive MS. Direct remyelination or axonal regeneration was not demonstrated.
Yes. Some patients develop PIRA — gradual disability accumulation that is not directly linked to clinical relapses. Follow-up therefore evaluates not only new MRI lesions but also change in neurological function over time.
Not reliably. Standard MRI cannot quantify the amount of restored myelin within an individual lesion. Research studies use specialized quantitative MRI techniques, evoked potentials and other methods.
A direct clinically proven remyelinating effect of exercise in humans has not been demonstrated. Regular physical activity and rehabilitation do, however, improve strength, endurance, balance and everyday function and support neuroplasticity.
If walking distance gradually decreases without clear relapses, weakness or spasticity increases, hand function worsens, routine activities become slower, or persistent cognitive changes appear, a separate assessment is needed.
It is important to determine whether the worsening is related to PIRA, the consequences of older lesions, spasticity, gait impairment, a comorbid condition or another cause, and whether the current disease-modifying therapy matches the actual disease course.
Consult Dr. Lidiia PrakhovaThis material reflects the state of clinical evidence as of September 2026. Experimental treatments and methods discussed here are not recommendations for self-treatment.