Multiple Sclerosis: Understanding Neurological Deterioration and How Disease-Modifying Therapies Work

When you’re first diagnosed with multiple sclerosis, the focus is often on the relapses - the sudden numbness, the blurred vision, the loss of balance. But what happens between those flare-ups? Why do some people keep getting worse, even when the flares stop? The truth is, multiple sclerosis isn’t just about inflammation. The real damage - the kind that changes your life permanently - happens quietly, over years, as nerves in your brain and spine slowly die.

What’s Actually Going Wrong in Your Nervous System?

Multiple sclerosis attacks the myelin sheath - the fatty insulation around nerve fibers that lets electrical signals zoom through your body. Think of it like the plastic coating on an electrical wire. When that coating gets stripped away, the signal stutters or dies. That’s what causes the symptoms: weakness, tingling, trouble walking, even memory problems.

But here’s the catch: your body can sometimes fix the myelin. In the early stages, especially in relapsing-remitting MS, your nervous system can repair itself. That’s why you might feel fine for months after a flare. The problem isn’t just the myelin loss - it’s what happens after. When nerves are left without myelin for too long, they start to break down. Axons - the long, thread-like parts of nerve cells - begin to wither. And once an axon dies, it doesn’t grow back.

Studies show that by the time someone has had MS for 10 to 15 years, about 40% of them have moved from relapsing-remitting to secondary progressive MS. That means the flares are fading, but the decline isn’t. They’re not getting new lesions on their MRI, but they’re still losing function. Why? Because the damage is no longer just surface-level. It’s deep inside the nerve fibers themselves.

Why Inflammation Isn’t the Whole Story

For decades, doctors thought MS was mostly about immune attacks on the brain and spine. And yes - inflammation is a big part of the early disease. That’s why drugs like interferons and monoclonal antibodies help reduce relapses by 30 to 50%. They calm the immune system down.

But here’s the problem: those drugs don’t stop progression. In fact, once someone enters the progressive phase - whether it’s secondary or primary - those same medications often do almost nothing. Why? Because the fire isn’t outside anymore. It’s inside.

Research shows that in later stages, the immune cells that cause damage aren’t coming from the bloodstream. They’re living inside the brain, clustered in the meninges - the membranes covering the brain. These clusters act like tiny factories, pumping out chemicals that slowly poison the nerves. B cells, a type of immune cell, are now seen as major players in this process. And they’re not responding to the old anti-inflammatory drugs.

Meanwhile, the nerves themselves are failing. Without myelin, they have to work harder to send signals. That means they burn through energy faster. Mitochondria - the power plants inside nerve cells - start to fail. Sodium channels, which help carry electrical signals, get damaged or disappear. The nerve can’t keep up. It starts to degenerate. And once it’s gone, it’s gone for good.

The Silent Progression: Atrophy and Hidden Damage

You won’t see this on a regular MRI scan. But if you look closely - using special techniques like magnetization transfer ratio (MTR) - you’ll find that even areas of the brain that look normal are changing. The white matter, the gray matter, even the spinal cord are shrinking. This is called atrophy.

A 2023 study tracked MS patients over six years and found that brain atrophy - especially in the gray matter - was the strongest predictor of long-term disability. Not the number of lesions. Not the frequency of relapses. The amount of tissue loss.

Gray matter atrophy correlates with how well someone can do everyday tasks - walking, using their hands, thinking clearly. That’s why doctors now use tools like the Multiple Sclerosis Functional Composite (MSFC) to measure disability, not just the old EDSS scale. EDSS looks at walking speed. MSFC looks at arm movement, leg strength, and thinking speed. And it’s more accurate.

This is why someone can have a clean MRI but still be getting worse. The damage isn’t visible. It’s happening at the cellular level. Axons are dying. Neurons are shrinking. The brain is losing its ability to compensate.

What Do Current Treatments Actually Do?

There are 21 FDA-approved disease-modifying therapies for MS. All of them target inflammation. All of them reduce relapses. None of them stop the slow, steady loss of nerves.

Drugs like ocrelizumab and cladribine work by wiping out certain immune cells. They’re powerful. They can cut relapse rates in half. But in progressive MS, their benefit is small - maybe a 10 to 15% delay in disability progression over two years. That’s not nothing. But it’s not a cure.

Some newer drugs, like siponimod, are approved for secondary progressive MS. They work by trapping immune cells in lymph nodes so they can’t reach the brain. But again - they don’t repair nerves. They just slow the immune attack a little longer.

The big gap? We still don’t have a drug that protects axons. That’s the holy grail.

What’s on the Horizon? The Next Generation of MS Therapies

Scientists are now chasing three main strategies to stop neurological decline:

• Neuroprotection: Drugs that shield nerves from damage. Some are targeting sodium channels to prevent nerve overwork. Others are trying to boost mitochondria function so nerves have more energy.
• Remyelination: Can we get the body to rebuild myelin? A few drugs in trials, like opicinumab and clemastine, are showing early signs of encouraging repair. But results are mixed.
• Stopping the inner brain inflammation: New drugs are being designed to target B cells inside the brain, not just in the blood. Some are even trying to block the toxic chemicals produced by immune clusters in the meninges.

As of October 2023, there were 17 active clinical trials focused on progressive MS - most of them aimed at protecting nerves, not just calming the immune system.

One promising area is the role of astrocytes - star-shaped brain cells that support neurons. Researchers found that MS patients lose a specific receptor on these cells - the β2-adrenergic receptor. Without it, astrocytes can’t help nerves survive. Giving drugs that activate this receptor might be a way to slow degeneration. Early animal studies look good. Human trials are starting.

What Can You Do Right Now?

While we wait for better drugs, there are things you can do to protect your nervous system:

• Don’t smoke. Smoking doubles the risk of progression from relapsing to progressive MS.
• Get enough vitamin D. Low levels are linked to more lesions and faster decline. Aim for blood levels above 40 ng/mL.
• Exercise regularly. Aerobic activity, strength training, and balance work don’t just improve function - they may help protect nerves by increasing growth factors in the brain.
• Manage stress. Chronic stress raises inflammation. Mindfulness, yoga, and therapy can help.
• See your neurologist regularly. Track changes with MRI and functional tests. Early detection of atrophy means earlier action.

The Hard Truth

Multiple sclerosis isn’t one disease. It’s two. The first is the inflammatory phase - the one we can treat. The second is the neurodegenerative phase - the one we’re still learning to fight.

The good news? We’re getting closer. We now know that axon loss is the main reason people with MS lose function over time. We know where the damage happens. We know which cells are involved. We’re not just guessing anymore.

The bad news? We still don’t have a drug that stops it. But we’re not powerless. We can slow it. We can protect what’s left. And with new therapies on the horizon, the next decade might finally bring real hope for stopping the decline - not just the flares.

What Comes Next?

If you’re living with MS, the goal now isn’t just to avoid relapses. It’s to protect your nervous system for the long haul. That means staying on treatment, monitoring atrophy, staying active, and watching for new therapies. The science is moving fast. The next breakthrough won’t be another anti-inflammatory drug. It’ll be the first one that actually saves your nerves.