Myasthenia Gravis: Understanding Fatigable Weakness and Modern Immunotherapy

Myasthenia gravis isn’t just muscle weakness-it’s weakness that gets worse the more you use your muscles. Imagine lifting your eyelids only to have them drop again after a few seconds. Or struggling to chew food, then feeling fine after a nap. This isn’t laziness or fatigue from overwork. It’s myasthenia gravis (MG), a rare autoimmune condition where the body attacks the connection between nerves and muscles. The result? fatigable weakness-a hallmark that sets MG apart from almost every other neurological disorder.

How Myasthenia Gravis Breaks the Muscle-Nerve Connection

At the heart of MG is a breakdown at the neuromuscular junction. Normally, nerves release acetylcholine, a chemical that tells muscles to contract. In MG, the immune system produces antibodies that block or destroy the receptors for acetylcholine. Without those receptors, muscles don’t get the signal to move. And when they do move, they tire quickly because the signal keeps getting interrupted.

About 80-90% of people with generalized MG have antibodies against the acetylcholine receptor (AChR). Another 5-8% have antibodies targeting muscle-specific kinase (MuSK), a different protein involved in nerve-muscle signaling. The rest are seronegative-no known antibodies found yet, but symptoms still match MG perfectly.

This isn’t random. The disease tends to hit in two waves: early-onset (under 50), often linked to thymus gland changes like hyperplasia, and late-onset (over 50), where about 10-15% develop thymoma, a tumor in the thymus. The thymus, once thought to be just a leftover organ, is now known to be a key player in triggering the autoimmune response in MG.

Fatigable Weakness: The Signature Symptom

You can’t diagnose MG by looking at someone at rest. You have to watch them move.

The classic signs? Drooping eyelids (ptosis) and double vision (diplopia) in 85% of cases. These aren’t constant-they come and go. A person might wake up with clear vision, but by lunchtime, they’re squinting. Chewing becomes exhausting. Speaking turns into slurred words. Arms feel heavy lifting a coffee cup. Legs buckle after walking a few blocks.

The key word is fatigable. Rest brings relief. A short nap can restore strength. That’s why many people go undiagnosed for years-they’re told they’re just tired, stressed, or anxious. But unlike regular fatigue, MG weakness follows a pattern: worse with activity, better with rest, predictable in its rhythm.

Doctors use the Quantitative Myasthenia Gravis Score (QMGS) to measure severity. A score above 11 usually means the disease has moved beyond mild symptoms and needs more than just symptom control-it needs immunotherapy.

First-Line Treatments: Symptom Control and Immunosuppression

Treatment starts with two goals: reduce symptoms fast and stop the immune system from attacking long-term.

Pyridostigmine, an acetylcholinesterase inhibitor, is the first drug most patients get. It works by slowing down the breakdown of acetylcholine, giving more of it time to bind to the remaining receptors. Doses range from 60 to 240 mg daily, split into 3-4 doses. It helps-but it doesn’t fix the root problem. It’s like turning up the volume on a broken speaker. The signal’s still weak, but you hear it better.

For real improvement, you need immunosuppression. Corticosteroids like prednisone are the go-to. Starting at 0.5-1.0 mg/kg per day, they suppress the immune system broadly. About 70-80% of patients see major improvement or even full remission. But side effects are real: weight gain, mood swings, bone loss, diabetes. Many patients gain 10-20 pounds within months. That’s why doctors don’t keep doses high forever.

That’s where steroid-sparing agents come in. Azathioprine and mycophenolate mofetil are added early-usually within a month or two. Azathioprine takes 6-18 months to kick in but works in 60-70% of cases. Mycophenolate is faster, helping 50-60% of patients. Both reduce the need for steroids over time. But they come with their own risks: liver damage, nausea, increased infection risk.

Immunotherapy for Acute Crises and Refractory Cases

When MG flares up badly-when swallowing or breathing becomes dangerous-speed matters. That’s when IVIG (intravenous immunoglobulin) or plasma exchange (PLEX) are used.

IVIG floods the bloodstream with healthy antibodies, which confuse the immune system and temporarily shut down the bad ones. It takes 5-7 days to work, and effects last 3-6 weeks. It’s safer, easier to give, and doesn’t require needles in large veins.

PLEX, on the other hand, physically removes antibodies from the blood. It works faster-often within 2-3 days-and is preferred in severe cases like bulbar weakness or respiratory failure. But it needs a central line, carries infection risks, and requires hospital visits over several days.

Both are equally effective in trials. The choice comes down to speed, access, and patient tolerance. In New Zealand, IVIG is more commonly used due to simpler logistics and fewer complications.

Targeted Therapies: The New Era of MG Treatment

The last decade brought the biggest shift in MG treatment since corticosteroids.

Rituximab, a drug that wipes out B-cells (the antibody factories), works wonders for MuSK-positive MG. Up to 89% of these patients reach minimal symptom status-far better than the 40-50% seen in AChR-positive cases. That’s why experts now test for MuSK antibodies early. If positive, rituximab might be the first immunotherapy, not a last resort.

Then came efgartigimod, approved by the FDA in 2021. It’s not a broad immunosuppressant. It blocks the neonatal Fc receptor (nFcR), the body’s recycling system for IgG antibodies. By doing that, it causes a rapid drop-60-75%-in all IgG, including the bad ones. In the ADAPT trial, 68% of patients reached minimal manifestation status in just weeks. It’s given as a weekly IV for four weeks, then as needed. No hospitalization. No central line. Fewer side effects than steroids.

Ravulizumab, approved in late 2023, targets the complement system-a part of the immune response that helps destroy muscle receptors. It’s given monthly by IV and shows promise for AChR-positive patients who haven’t responded to other treatments.

These drugs aren’t cures, but they’re turning MG from a chronic, steroid-dependent disease into one that can be managed with precision.

Thymectomy: Removing the Trigger

For patients aged 18-65 with AChR-positive generalized MG, removing the thymus gland (thymectomy) is now standard. The MGTX trial showed it nearly doubled the chance of reaching minimal manifestation status within three years compared to medication alone. About 35-45% of early-onset patients go into full remission after thymectomy and don’t need drugs anymore.

The surgery isn’t risky-it’s usually done laparoscopically. Recovery takes a few weeks. But the payoff? Freedom from daily pills, fewer infections, no more steroid weight gain.

What Doesn’t Work-and What Can Make Things Worse

Not all treatments are equal. Some can actually harm.

Immune checkpoint inhibitors (ICIs), used to treat cancers like melanoma and lung cancer, can trigger severe MG-or make existing MG explode. In one study, 60% of patients who developed ICI-induced MG also had heart inflammation (myocarditis). Eighty-three percent needed ICU care. If someone with MG gets cancer, oncologists must be warned. The risk isn’t theoretical-it’s deadly.

Also, some antibiotics (like macrolides and fluoroquinolones), beta-blockers, and even magnesium can worsen MG symptoms. Always check with a neurologist before starting any new medication.

Living with MG: Long-Term Realities

Most people with MG need long-term treatment. About 85-90% require ongoing immunosuppression. But that doesn’t mean a life on the sidelines.

Many reach minimal manifestation status-meaning symptoms are so mild they barely affect daily life. A 2023 study showed that with proper treatment, 90% of patients can work, drive, and travel normally.

The biggest challenge? Tapering. Doctors want to reduce drugs to avoid side effects. But if you taper too fast-before 2 years of stable symptoms-there’s a 40-50% chance of relapse. Patience is part of the treatment.

And while MG can’t be cured yet, it can be controlled. With the right mix of targeted immunotherapy, careful monitoring, and lifestyle adjustments, most people live full, active lives.

What’s Next for MG Treatment?

The future is focused on stopping the disease before it starts. Researchers are testing drugs that target specific B-cell types, block cytokines like IL-6, or silence autoantibody production without broad immune suppression.

Rozanolixizumab, a subcutaneous nFcR blocker, is in phase 3 trials. It could be given at home like insulin. Inebilizumab, which targets a different B-cell marker, is also showing promise.

The Myasthenia Gravis Foundation’s 2023 roadmap says the top goal is disease modification without chronic immunosuppression. In other words: fix the immune system’s mistake, not just cover it up.

For now, the tools we have-pyridostigmine, steroids, rituximab, efgartigimod, thymectomy-are better than ever. The goal isn’t just survival. It’s living without weakness.