A Breath of Fresh Air: High-Dose Flecainide Tackles Rare Muscle Disorder in Kids
Introduction: A Tough Nut to Crack
Hey everyone! So, I want to chat about something pretty remarkable we’ve been working on. You know, in medicine, sometimes you come across these incredibly tough cases, especially with rare genetic conditions. We’re talking about something called paramyotonia congenita, and when it’s really severe in newborns, it can cause these scary episodes of laryngospasm – that’s when the voice box clamps up, making it hard to breathe. This particular nasty version is often linked to a specific hiccup in a gene called SCN4A, the G1306E variant to be precise.
Now, treating this is a real challenge. The usual go-to meds for myotonia (that’s muscle stiffness) can have some pretty rough side effects, especially for little ones. But what if I told you we might have found a way to offer some real relief using an old drug in a new way? We’re talking about high-dose flecainide, and we’ve seen some pretty amazing results in two brave little sisters.
The Lowdown on These Muscle Channel Troubles
Alright, so what are these ‘non-dystrophic skeletal muscle voltage-gated ion channel myotonias’? Sounds like a mouthful, right? Basically, they’re inherited muscle diseases caused by tiny glitches in the channels that control ion flow in muscle cells. Think of them like faulty gates. These can pop up at any age. The main culprits are often genes like CLCN1 (which messes with chloride channels) and SCN4A (which deals with sodium channels). The SCN4A ones are usually dominant, meaning you only need one copy of the faulty gene.
Paramyotonia congenita with severe neonatal episodic laryngospasm (SNEL for short – much easier!) is one type. Kids with SNEL have these terrifying recurring laryngospasms, sometimes leading to severe apnea attacks where they stop breathing. There isn’t a ton of research on SNEL, but we’re seeing more cases linked to that G1306E variant in SCN4A. It’s a tough diagnosis for families, as you can imagine.
The Usual Suspects: Standard Treatments and Their Snags
So, when doctors are faced with SNEL, they usually turn to sodium channel blockers. You might have heard of some of them: mexiletine, lamotrigine, and carbamazepine. Acetazolamide, which works a bit differently as a carbonic anhydrase inhibitor, has also shown some promise. These drugs can definitely help, but here’s the kicker: for some patients, especially the little ones, the side effects can be a real deal-breaker. We’re talking about things that can make life miserable, and sometimes the drugs just don’t work well enough. It’s a constant balancing act, and when the scales tip towards too many side effects or not enough relief, we’re left searching for better options.
Enter Flecainide: A New Hope?
This is where flecainide comes into the picture. It’s a drug that blocks the fast inward sodium current in cells. By doing this, it slows down electrical conduction and can really help improve symptoms. Now, flecainide isn’t brand new for these conditions. Some studies, especially with that G1306E mutation, hinted that patients might respond better to flecainide than to mexiletine. There have been a few reports over the years:
- Rosenfeld and colleagues back in 1997 mentioned its use in a family with a different SCN4A mutation.
- Desaphy’s team in 2013 reported on a mother and son with the G1306E mutation who did better on flecainide after mexiletine didn’t cut it.
- Potaro et al. in 2016 described an 8-year-old girl with SNEL who improved significantly with flecainide.
- Another report from Desaphy’s group in 2016 showed an 11-year-old girl with myotonia getting much better on flecainide.
- Lehmann-Horn and his team in 2017 looked at ten patients with the G1306E mutation treated with various drugs, including flecainide.
- And Terracciano et al. in 2018 shared a story of an Italian family where symptoms vanished after 6 months on flecainide.
But here’s the thing: most of these reports used standard doses. What we were wondering was, could higher doses of flecainide be safe and even more effective for those really stubborn cases of laryngospasms? That’s what led us to our two little superstars.
Meet Patient A: A Rollercoaster Ride
Let me introduce you to Patient A. She’s a spirited young girl of Irish, Scandinavian, and German heritage. Her journey started right after birth. She was born via C-section after a full-term pregnancy, but almost immediately, there were concerns: stridor (that’s a high-pitched wheezing sound) and apneic spells. Initially, everyone thought it might be reflux, but things got worse. At 7 weeks old, she had a terrifying episode – her body went stiff, and she turned blue. Her parents had to do rescue breathing. Can you imagine?
She was quickly seen by her pediatrician, referred to neurology, and started on oxcarbazepine for what they suspected was myotonia congenita. Her myotonia (muscle stiffness) did get a bit better at first, but then a viral illness threw a wrench in the works, and her symptoms flared up.
Genetic testing was the key. It revealed she had a heterozygous pathogenic variant in the SCN4A gene (the G1306E one we’ve been talking about), which she inherited from her dad. But, plot twist! She also had another heterozygous pathogenic variant, this time in the CLCN1 gene (R894), inherited from her mom. This double whammy might explain why her case was particularly tough.
When she was 7 months old, her symptoms were still bad, so she was admitted to the cardiology service to start mexiletine, with close heart monitoring, of course. Unfortunately, mexiletine had to be stopped because it made her super irritable – a no-go for a baby. So, they switched to acetazolamide.
Despite this, she still had persistent stiffness, stridor, and those scary laryngospasms. So, at 2 years of age, it was back to the cardiology service, this time to try flecainide. Her heart looked good on an echocardiogram (normal structure and function), and her baseline ECG (electrocardiogram) was fine, with a QTc of 450 ms and a QRS duration of 60 ms.
We started her on flecainide at 100 mg/m²/day, split into three doses. We watched her like a hawk, with frequent ECGs and continuous telemetry. Once the flecainide reached a steady level in her system, her ECG showed no scary changes. Her initial flecainide trough level was a bit low, but an outpatient check showed it in the normal range.
Over the next 10 months, those laryngospasms kept coming back. So, we had to gradually increase her flecainide dose – step by step: 111, 133, 153, 171, 189, and finally 200 mg/m²/day. At 4 years old, things got worse again, so we bumped it up to 220 mg/m²/day. About a year later, she started having musculoskeletal chest pains, so we went even higher, to 250 mg/m²/day. That’s roughly 10 mg/kg/day, which is pretty high!
But guess what? Her flecainide level at this dose was still well within the normal range (0.53 μg/ml), and her ECG remained stable (QTc 453 ms, QRS 86 ms). We did Holter monitors (those 24-hour ECGs) at ages 3, 5, and 7, and they were all normal. Phew!
With the laryngospasms mostly under control, muscle cramping and pain became her main complaints. So, at 6 years old, we added dantrolene. We tweaked the dantrolene dose over the next couple of years, but it only helped a bit with the pain. Next up was gabapentin, which thankfully brought more improvement.
As I’m telling you this, she’s still on this combo: flecainide, oxcarbazepine, dantrolene, acetazolamide, and gabapentin. She’s walking around independently, but still gets intermittent muscle stiffness and laryngospasms, especially with temperature changes and humidity. These episodes can bring on muscle fatigue, weakness, and pain that can last for hours or even days. It’s a testament to her strength, and her family’s, that she’s doing as well as she is.
And Then Came Patient B: A Similar Path, A Slightly Different Story
Patient B is Patient A’s younger sister, sharing the same Irish, Scandinavian, and German roots. She was born a bit early, at 32 weeks, due to maternal cholestasis and spent some time in the NICU. Genetic testing confirmed she had the same paternally inherited SCN4A G1306E variant as her sister. Importantly, though, she did not have the maternal CLCN1 mutation. This difference is quite interesting, as you’ll see.
Right from the start, she had trouble with oral feeding, and there were concerns that reflux was triggering laryngospasms. This led to a gastrostomy tube (G-tube) being placed in her second month of life. She continued to have laryngospasms and stiffness, mostly when trying to feed by mouth, so she was started on oxcarbazepine and acetazolamide, just like her sister.
But these didn’t bring enough relief. So, at just 1 month old, we started her on flecainide, beginning with 50 mg/m²/day. Her baseline heart checks were all normal (QTc 433 ms, QRS 42 ms). We gradually increased her dose to 90 mg/m²/day while she was in the hospital, and then up to 110 mg/m²/day as an outpatient. Her flecainide level was good (0.23 μg/ml).
When a viral illness made her symptoms flare up, we increased the flecainide to 150 mg/m²/day. At 8 months old, her symptoms were still bugging her, so we went up to 175 mg/m²/day. By the time she was a year old, she needed two more increases, first to 200 and then to 220 mg/m²/day (that’s about 9 mg/kg/day). Even at this dose, her flecainide level was normal (0.22 μg/ml), and her ECG was stable (QTc 443 ms, QRS 64 ms). She had a normal Holter monitor at 3 years old.
She’s been maintained at this dose, and it’s made a huge difference. At 3.5 years old, she also started on dantrolene to help with muscle cramping and pain. Right now, she’s doing well on flecainide, oxcarbazepine, dantrolene, and acetazolamide. She’s also walking independently and has intermittent muscle stiffness and laryngospasms, but they’re generally milder and shorter than her older sister’s. The best part? The decrease in laryngospasms has allowed her to start eating completely by mouth, and they’re even planning to remove her G-tube! That’s a massive win.
So, What’s the Big Deal? High Doses, Happy Hearts!
This case report is really exciting because it shows just how severe SNEL linked to that SCN4A G1306E variant can be, but also that there’s hope. We’ve demonstrated that high-dose flecainide, up to 220–250 mg/m²/day, can be a game-changer when used alongside other therapies. And the most crucial part? We saw no cardiac side effects in these two sisters, and their flecainide levels stayed within the therapeutic range, even at these ‘supratherapeutic’ doses by standard guidelines.
It’s also super interesting to compare the two sisters. Patient A, who has that extra CLCN1 variant from her mom, seems to have more severe stiffness, laryngospasms, muscle fatigue, and pain than Patient B. This really suggests that the CLCN1 variant might be making things tougher for her.
Now, flecainide is usually used for heart arrhythmias. The standard dose is typically 50–120 mg/m²/day (maxing out at 200 mg/m²/day) or 3–6 mg/kg/day (max 8 mg/kg/day), aiming for a serum level of 0.2–0.8 μg/ml. If the dose is too high, you can see signs of toxicity like:
- Bradycardia (slow heart rate)
- Dizziness
- Blurred vision
- Nausea
- Headache
And on an ECG, you might see prolonged PR and QRS intervals. But our girls? Patient A was on 250 mg/m²/day (around 10 mg/kg/day) and Patient B on 220 mg/m²/day (around 9 mg/kg/day), and both had normal to low serum levels (0.21–0.53 μg/ml) with zero clinical or ECG signs of toxicity. It seems their bodies handle flecainide a bit differently, or perhaps the target for symptom relief in this condition requires these higher inputs without hitting toxic internal levels for the heart.
Our Playbook: A Protocol for Flecainide Initiation
Based on our experience with these amazing kids, we’ve actually developed a bit of a protocol for starting and adjusting flecainide in patients with SCN4A mutations who aren’t responding well to other standard treatments. Here’s the gist:
- Admission and Baseline Checks: Patients are admitted to the inpatient cardiology service for cardiac monitoring. We do a baseline ECG to make sure all intervals are normal and an echocardiogram to check for normal heart structure and function.
- Starting Dose: If everything looks good, we start flecainide at an initial dose of 50 mg/m²/day, divided three times a day. We calculate the body surface area (BSA) using the DuBois method.
- Monitoring – Round 1: After five doses (to let it reach a steady state), we repeat the ECG and check a flecainide trough level. We’re looking closely for any QRS widening, atrioventricular block, QT prolongation, or arrhythmias.
- First Increase: If the ECG is stable, we can increase the dose to 100 mg/m²/day.
- Monitoring – Round 2: After five doses at this new level, another ECG and flecainide level check. If the ECG is still stable and the flecainide level is within the normal range (we aim for 0.5 to 1 μg/ml here, though our patients were lower and still benefited), they can usually go home.
- Outpatient Adjustments: Further increases depend on how their symptoms are responding, usually over a 2–3 month period. Our two patients didn’t see consistent, significant relief until they hit 150–200 mg/m²/day.
- Stepping Up: We can increase the dose by 50 mg/m²/day until we reach 200 mg/m²/day. After each increase (minimum five doses, but usually at least a week), we repeat the ECG and flecainide trough level. We also do yearly Holter monitors, or sooner if there are any worrying symptoms.
- Fine-Tuning: After 200 mg/m²/day, we make smaller increases, around 10–20 mg/m²/day increments, with the same careful monitoring. For kids, we use the 20 mg/ml solution, divided three times a day.
It’s important to remember that even with high-dose flecainide, these sisters still needed other medications like oxcarbazepine, acetazolamide, and dantrolene to manage their symptoms. This really underscores how tricky the SCN4A G1306E mutation can be to treat.
The Takeaway: A Brighter Outlook
So, what’s the bottom line? This case report really shines a light on the potential of high-dose flecainide. When added to standard therapies, it looks like a very promising alternative for treating those recurrent laryngospasms and tough skeletal muscle symptoms in kids with SCN4A G1306E-related disease. The fact that we could use these higher doses safely, without cardiac issues, is a massive step forward. It gives us another powerful tool in our toolkit for these incredibly resilient children and their families. It’s not a cure, but it’s certainly a big step towards better breathing and better quality of life, and that’s something to be really excited about!
Source: Springer
