High-dose flecainide for symptomatic relief in paramyotonia congenita/severe neonatal episodic laryngospasm due to SCN4A G1306E: a case report

Abstract

Background

Severe neonatal episodic laryngospasm has been previously reported in multiple patients with the heterozygous pathogenic variant G1306E in SCN4A. Treatment can be difficult due to side effects from therapies utilized conventionally for the management of myotonia and paramyotonia congenita.

Case presentation

We report on two female siblings of Irish, Scandinavian, and German ethnicity aged 7 and 3 years with severe neonatal episodic laryngospasm and paramyotonia congenita due to a paternally inherited heterozygous pathogenic variant of the SCN4A gene and the use of high-dose flecainide therapy for symptomatic management. Interestingly, one of the two siblings has a coexisting separate maternally inherited and pathogenic CLCN1 variant that may further impact phenotype. High-dose flecainide 220–250 mg/m²/day was not associated with any cardiac side effects.

Conclusion

This report supports the use of high-dose flecainide in combination with standard therapies in pediatric patients with SCN4A mutations to modulate acute symptoms and provides suggested dosing with an acute and long-term monitoring protocol.

Background

Non-dystrophic skeletal muscle voltage-gated ion channel myotonias are an inherited group of muscle disease channelopathies that may present at any stage of life. These conditions have been linked to pathogenic variants in the CLCN1 (dominantly or recessively inherited) and SCN4A (dominantly inherited) genes, which are responsible for expression of voltage-gated chloride and sodium ion channels, respectively [1]. Paramyotonia congenita with severe neonatal episodic laryngospasm (SNEL) is one type characterized by recurrent episodes of laryngospasm, followed by severe episodic apnea attacks. There is limited literature on SNEL, but there are increased incidences linked to variants in SCN4A, specifically G1306E [2, 3].

Sodium channel blocking therapies, including mexiletine, lamotrigine and carbamazepine, have become the standard treatment for SNEL [4,5,6]. Acetazolamide, a carbonic anhydrase inhibitor, has also been effective [7]. For certain patients, these medications have intolerable side effects. More recent studies have shown that patients with G1306E mutations appear to be more sensitive to flecainide than mexiletine [2, 8,9,10,11,12]. Flecainide functions by blocking the fast inward sodium current, which ultimately results in slowed conduction and improved symptoms.

Flecainide use was reported previously in limited series. Rosenfeld et al. (1997) described a family with a SCN4A V445M mutation and flecainide use in one subject [8]. Desaphy et al. (2013) reported the use of flecainide in a mother and son with the SCN4A G1306E mutation after little symptomatic improvement with mexiletine [9]. Potaro et al. (2016) described an 8-year-old female who presented with SNEL and was treated with flecainide at a dose up to 100 mg daily with significant symptomatic improvement [2]. Desaphy et al. (2016) reported an 11-year-old female with myotonia who was treated with flecainide at 35 mg twice a day with significant improvement in symptoms [10]. Lehmann-Horn et al. (2017) reported ten patients with SCN4A G1306E mutation treated with carbamazepine, mexiletine, and flecainide [11]. Terracciano et al. (2018) reported an Italian family treated with flecainide 100 mg twice daily and reported disappearance of symptoms after 6 months [12].

However, previous literature has not shown that higher doses of flecainide can be safe in patients with paramyotonia congenita and SNEL with persistent laryngospasms refractory to treatment. Here, we present two cases of patients who tolerated higher-than-standard doses of flecainide without cardiac side effects and demonstrated symptomatic improvement.

Case presentation

Patient A is a female of Irish, Scandinavian, and German ethnicity who was the firstborn to non-consanguineous parents delivered via elective Cesarean section after a 38-week pregnancy. There were concerns after birth owing to stridor (Video 1 in Additional file 1) and apneic spells, which worsened in the first few weeks of life but were thought to be related to reflux. At 7 weeks of age, she had an episode of body stiffening and cyanosis that resulted in her parents performing rescue breathing. She was seen by the pediatrician, referred for neurology evaluation, and started on oxcarbazepine for a presumed diagnosis of myotonia congenita. Her symptoms, including myotonia (Video 2 in Additional file 2), improved initially but soon worsened after a viral illness. Genetic workup revealed a heterozygous paternally inherited pathogenic variant in the SCN4A gene (c.3917G > A, p.G1306E) and a heterozygous maternally inherited pathogenic variant in the CLCN1 gene (c.2680C > T, p.R894). Due to worsening symptoms at 7 months of age, she was admitted to the cardiology service for mexiletine initiation and cardiac monitoring. However, mexiletine was discontinued due to related behavioral irritability, and acetazolamide was then started. Due to persistent symptoms of stiffness, stridor, and episodic laryngospasm, she was subsequently admitted to the cardiology service for flecainide initiation at 2 years of age. The echocardiogram performed on admission demonstrated normal structure and systolic function. A baseline electrocardiogram (ECG) demonstrated a corrected QT interval (QTc) of 450 ms and a QRS duration of 60 ms (Fig. 1). Flecainide was initiated at 100 mg/m²/day divided every 8 hours, and potential signs of toxicity were closely monitored with frequent ECGs and continuous telemetry. Once flecainide reached steady-state after five doses, a repeat ECG showed no changes from baseline. A flecainide trough level at discharge was < 0.1 μg/ml (normal range 0.2–1 μg/ml). A repeat outpatient flecainide trough level was 0.21 μg/ml. Due to recurrent laryngospasms over the next 10 months, the flecainide dose was steadily increased to 111, 133, 153, 171, 189, and 200 mg/m²/day divided three times a day. At 4 years of age, due to worsening symptoms, flecainide was again increased to 220 mg/m²/day. About 1 year later, she had worsening symptoms including musculoskeletal chest pains, and the dose was increased to 250 mg/m²/day (approximately 10 mg/kg/day). A repeat flecainide level at this dose was 0.53 μg/ml. A monitoring ECG showed a stable QTc of 453 ms and a QRS of 86 ms (Fig. 1). At the time of writing, the patient continues at this dose. There were surveillance Holter monitors performed at ages 3, 5, and 7 years, and results were normal. With minimal laryngospasm symptoms, muscle cramping and muscle pain became the predominant symptoms, and the patient started dantrolene at the age of 6 years. Increases in dantrolene dosing over the next 2 years only moderately improved muscle pains, and the patient was started on gabapentin with improvement. The patient remains on flecainide, oxcarbazepine, dantrolene, acetazolamide, and gabapentin. The patient is independently ambulant, with intermittent muscle stiffness and laryngospasms that can be worsened by temperature changes and humidity. The episodes can include muscle fatigue, weakness, and pain that last hours to days.

Fig. 1

Electrocardiogram tracings from flecainide monitoring show no significant differences from baseline to maximum dose. All measurements are within normal limits. A Patient A’s baseline electrocardiogram with QRS duration of 60 ms and QTc duration of 450 ms. B Patient A’s electrocardiogram performed at 250 mg/m²/day dosing, with a QRS duration of 86 ms and QTc duration of 453 ms. C Patient B’s baseline electrocardiogram with a QRS duration of 42 ms and QTc duration of 433 ms. D Patient B’s electrocardiogram performed at 220 mg/m²/day with a QRS duration of 64 ms and QTc duration of 443 ms

Patient B is a female of Irish, Scandinavian, and German ethnicity and is the younger sibling of Patient A. She was born to non-consanguineous parents via repeat Cesarean section due to maternal cholestasis at 32 weeks gestation with a birth weight of 2.36 kg and admitted to the neonatal intensive care unit. Genetic testing showed the same paternally inherited heterozygous pathogenic variant in the SCN4A gene (c.3917G > A, p.G1306E), but she was negative for the maternal CLCN1 mutation. Poor oral feeding and concerns for reflux triggering laryngospasms led to gastrostomy tube placement without Nissen fundoplication in the second month of life. She continued to have laryngospasms and stiffness mostly associated with oral feedings and was started on oxcarbazepine and acetazolamide. Due to minimal symptomatic improvement, at 1 month of age she was started on flecainide 50 mg/m²/day. She had a normal baseline echocardiogram and ECG with a QTc of 433 ms and a QRS duration of 42 ms. (Fig. 1) Her dose was titrated up to 90 mg/m²/day while inpatient, and then again as an outpatient to 110 mg/m²/day with a corresponding flecainide level of 0.23 μg/ml. She had increased symptoms associated with a viral illness, and the flecainide was increased to 150 mg/m²/day. At 8 months of age, her symptoms continued, prompting a dose increase to 175 mg/m²/day. At 1 year of age, she required two additional increases to 200 and 220 mg/m²/day (approximately 9 mg/kg/day). A flecainide level at this dose was normal at 0.22 μg/ml, and her ECG had stable measurements of a QTc of 443 ms and a QRS of 64 ms (Fig. 1). She has been maintained at this dose with a normal Holter monitor at 3 years of age. At the age of 3.5 years, she started on dantrolene to improve muscle cramping and muscle pain. At the time of writing, she remains on a stable dose with improvement in symptoms. The patient remains on flecainide, oxcarbazepine, dantrolene, and acetazolamide. The patient is independently ambulant with intermittent muscle stiffness and laryngospasm, though milder in severity and duration than her older sibling. The decrease in laryngospasms has allowed her to completely feed orally and plan for gastric feeding tube (G tube) removal.

Discussion and conclusions

This case report highlights the potential severity and management of SNEL related to the SCN4A G1306E variant and demonstrates the role of high-dose flecainide up to 220–250 mg/m²/day in combination with additional therapies providing symptomatic relief for two siblings. There were no cardiac side effects, and flecainide levels remained within the therapeutic range. This case also highlights Patient A, who demonstrated more severe stiffness, laryngospasms, muscle fatigue, and episodic muscle pain compared with her younger sister, which can possibly be attributed to the coexisting maternally inherited pathogenic CLCN1 variant.

Flecainide is most commonly used for cardiac arrhythmias. A standard therapeutic dosing range for flecainide is 50–120 mg/m²/day (maximum of 200 mg/m²/day) or 3–6 mg/kg/day (maximum of 8 mg/kg/day), with a target serum level of 0.2–0.8 μg/ml [13]. Clinical signs of toxicity include bradycardia, dizziness, blurred vision, nausea, and headache, and ECG findings include prolonged PR and QRS intervals [14]. However, the reported patients did not have decreased laryngospasm symptoms until supratherapeutic flecainide dosing. Patient A received 250 mg/m²/day (approximately 10 mg/kg/day), and Patient B received 220 mg/m²/day (approximately 9 mg/kg/day). Both had normal/low serum levels (0.21–0.53 μg/ml) with no clinical or ECG signs of toxicity.

On the basis of these patients, a protocol for the initiation and titration of flecainide in patients with SCN4A mutations who are poorly responsive to other standard therapies was developed. Patients are admitted to the inpatient cardiology service with cardiac monitoring. A baseline ECG is performed to demonstrate normal intervals, and an echocardiogram is performed to assure normal structure and systolic function. If these baseline studies are normal, the patients are started at an initial dose of 50 mg/m²/day divided three times a day. Dosing is based on the DuBois method of calculating body surface area (BSA; 0.007184 × Height^0.725 × Weight^0.425) [15]. An ECG is repeated and a flecainide trough level obtained after completing five doses of flecainide. If there are no significant changes on ECG, specifically looking for QRS widening, atrioventricular block, QT prolongation, or arrhythmias, the dose can be increased to 100 mg/m²/day. After five doses at this level, an ECG is repeated and flecainide level checked. If the ECG is stable and the flecainide level is within the normal range (0.5 to 1 μg/ml), patients can be discharged home.

Further increases are based on symptomatic responses over a 2–3 month period. Our two patients did not see consistent significant symptomatic relief until 150–200 mg/m²/day. The dose can be increased by 50 mg/m²/day until 200 mg/m²/day. After a minimum of five doses after each increase but usually at least a week of therapy, an ECG and flecainide trough level are repeated. Holter monitors were performed yearly or at the time of any concerning symptoms as needed. After 200 mg/m²/day, dose increases were lowered to 10–20 mg/m²/day increments. Similar monitoring was used for these changes. Pediatric dosing used the 20 mg/ml solution divided three times a day. Additional therapies, including oxcarbazepine, acetazolamide and dantrolene, were still needed to manage symptoms in these siblings, highlighting the potential refractory nature of symptoms in individuals with SCN4A G1306E mutation. This case report demonstrates that high-dose flecainide, in addition to standard therapies, may be promising as an alternative treatment for recurrent laryngospasm and skeletal muscle symptoms in SCN4A G1306E-related disease.