Understanding Progressive Multiple Sclerosis: From Pathogenesis to Treatment

Progressive multiple sclerosis (PMS) continues to challenge neurologists and researchers, not only due to its debilitating nature but because of the limited therapeutic options available compared to its relapsing counterpart. In their comprehensive review published in Brain, Correale and colleagues shine a much-needed light on the complex mechanisms behind PMS, while also exploring diagnostic hurdles and treatment strategies. Here’s a human-friendly dive into their findings.

What Is Progressive Multiple Sclerosis?
Multiple sclerosis (MS) is a disease in which the immune system mistakenly attacks the protective covering (myelin) around nerves in the brain and spinal cord. This disrupts communication between the brain and the body and eventually can cause permanent damage or deterioration of nerves.

MS comes in different forms:

Relapsing-remitting MS (RRMS): Characterized by flare-ups (relapses) followed by periods of recovery.

Primary progressive MS (PPMS): Symptoms worsen steadily from the start without early relapses or remissions.

Secondary progressive MS (SPMS): Begins as RRMS but then enters a phase of continuous progression.

RRMS is the most commonly diagnosed form and has several treatment options. PMS, however—especially PPMS—has historically had fewer therapeutic successes.

Why Is PMS So Hard to Treat?
One of the biggest challenges in treating PMS lies in understanding its underlying disease mechanisms. RRMS is driven primarily by inflammation, which is responsive to immune-modulating therapies. PMS, however, becomes more about neurodegeneration—the slow death of nerve cells—and inflammation trapped inside the central nervous system (CNS), where medications in the bloodstream struggle to reach.

This change from an “outside-in” inflammatory model to an “inside-out” degenerative model marks a significant hurdle for current therapies.

What’s Going on in the Brain?
PMS features complex and overlapping processes:

Chronic Inflammation: While visible inflammation decreases, smoldering inflammation behind an intact blood-brain barrier continues. Cells like B cells, T cells, and microglia stay active within the CNS, particularly in the meninges, leading to continuous damage.

B Cell Activity and Meningeal Follicles: In SPMS, immune cells sometimes cluster into follicle-like structures that may promote ongoing immune attacks. These are less common in PPMS, suggesting possible differences in the disease's behavior.

Microglia and Astrocyte Activation: These resident brain cells, when hyperactive, release toxic molecules that harm myelin and neurons.

Mitochondrial Dysfunction: Mitochondria—the cell’s energy factories—are damaged by oxidative stress, leading to energy failure and neuron death.

Ion Channel Malfunctions: After myelin is stripped away, neurons mismanage sodium and calcium ions, leading to toxic buildups that hasten their destruction.

Glutamate Toxicity: Elevated levels of this neurotransmitter damage cells, a process called excitotoxicity.

Diagnosis: A Moving Target
Diagnosing progressive MS isn't straightforward. Unlike RRMS, where clear relapses signal disease activity, PMS progresses subtly, often being recognized only in hindsight after months or years of worsening symptoms.

Current tools like MRI can help, but they fall short in capturing the full picture of neurodegeneration. Advanced imaging techniques and biomarkers are being explored, but none yet offer definitive diagnosis or progression tracking. Treatment Landscape: Cautious Optimism
Historically, most RRMS drugs failed to show clear benefits in PMS. However, this is starting to change.

Approved or Promising Therapies:
Ocrelizumab: The first drug to show meaningful results in PPMS, reducing disability progression.

Mitoxantrone and IFN-β (for SPMS): Showed modest benefits but are limited by side effects.

Rituximab (investigational for PMS): May help in younger patients with active disease.

Laquinimod: An oral drug that reduces astrocyte and microglial activation in early studies.

Future Targets:
Mitochondrial Protection: Drugs like MitoQ aim to reduce damage from oxidative stress.

Ion Channel Blockers: Agents like amiloride (ASIC1 blocker) and glibenclamide (TRPM4 blocker) show neuroprotective effects in early trials.

Neurotrophic Factors: Compounds that support neuron survival and myelin repair, such as IGF-1 and BDNF, are under investigation.

Remyelination Therapies: Still experimental, aiming to help nerve fibers regain their protective covering.

The Road Ahead
The authors underscore the importance of rethinking clinical trial design, focusing more on the biological underpinnings of PMS rather than copying strategies from RRMS research. Personalized medicine, better imaging tools, and combination therapies targeting both inflammation and neurodegeneration are essential to changing the prognosis for PMS patients.

Final Thoughts
Progressive MS is no longer a mystery in the dark. Researchers like Correale et al. are pulling back the curtain on its hidden complexity. While challenges remain, a future with more effective treatments is emerging—one rooted in a deeper understanding of the disease’s biology and a commitment to innovation.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Correale, J., Gaitán, M. I., Ysrraelit, M. C., & Fiol, M. P. (2017). Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain, 140(3), 527-546.