Hypokalemic periodic paralysis associated with atypical CACNA1S in pregnancy: New challenge for a rare syndrome

We presented the case of a 21-year-old primigravid woman with hypokalemic periodic paralysis affected by heterozygous NM_000069.3:c3716G>A mutation of the CACNA1S gene. From the beginning of the pregnancy, the patient reported sporadic episodes of muscle weakness, primarily distal in the arms and legs, with an average of 2–3 weekly, which progressively resolved with rest and potassium supplementation. An exacerbation of recurring paralysis occurred in the 35 weeks of pregnancy due to the patient's improper use of potassium medication and failure to adhere to the nutritionist's low-carbohydrate diet. In addition, the patient reported hypothyroidism induced by pregnancy, corrected with levothyroxine supplementation (50 mcg/day). Her treatment included oral iron, folic acid, and cholecalciferol and potassium chloride (600 mg, two times/day). The last ultrasound examination at 35 weeks + 2 days of gestation revealed fetal biometry at the 50th percentile. At 35 weeks + 4 days, the patient presented at our emergency department for a premature rupture of membranes. She had a positive Group B streptococcus vaginal–rectal swab test result. Due to the gestational age and in accordance with neurologist evaluation, respiratory distress syndrome prophylaxis was administered (two intramuscular doses of betamethasone 12 mg). Monitoring of the patient's potassium level was recommended twice a day and 48 h after the end of prophylaxis. In consideration of the patient's medical history and clinical data, multidisciplinary evaluation was executed (including an anesthetist, pediatrician, gynecologist, and neurologist), and it was established that labor would be induced with misoprostol 25 mcg administered sublingually (off-label application) every 4 h (for a total of six doses), limiting the use of oxytocin. Potassium dosage was repeated every 2 h with the concomitant administration of potassium chloride 600 mg every 4 h when potassium levels were lower than 3.5 mmol/L, associated with ringer acetate at a velocity of 60 mL/h. Labor started after the third administration of misoprostol. The patient was monitored with continuous electrocardiogram (12-led ECG recording), pulse oximetry, periodic non-invasive blood pressure determinations, and periodic serum electrolytes determinations (K+ as reports in Figure 1, Na+, Cl−, Ca++, Mg++; mean K+ value during labor was 4.01). The delivery was completed with an alive newborn, an umbilical cord arterial pH of 7.24, and a base excess of −4.9. Finally, blood loss was 100 mL. The umbilical artery K+ level was 6 mmol/L, while the serum potassium level was 5 mmol/L at 2 h postpartum and 3.9 mmol/L after 12 h. Misoprostol 800 mcg (rectal administration) was applied in the immediate postpartum, followed by misoprostol 200 mcg intrarectally every 6 h for a total of four doses as maintenance therapy. The patient reported no adverse events during labor or delivery or postpartum. Epidural analgesia was not used because of precipitous labor. After delivery, maternal potassium levels were periodically determined for 72 h (the median value was 4.06 mmol/L). No ECG abnormalities were observed during labor or delivery or postpartum. The K+ supplementation was maintained in the postpartum period. Hypokalemic periodic paralysis (HPP) represents an uncommon disorder, caused by calcium and sodium channel mutations in muscle fibers, which leads to muscle weakness of various duration triggered by several factors.1 Approximately one in 100 000 people have the disorder, which is typically brought on by autosomal dominant mutations in voltage-gated calcium channel (CACNA1S) or sodium channel (SCN4A) genes with variable penetration.1-3 Low serum potassium levels (<3.5 mmol/L) are linked to weakening episodes.1, 2 The triggers have important characteristics that aid in the diagnosis of the condition; the triggers are emotional factors; environmental factors, such as cold; dietary factors, such as high-carbohydrate meals consumption; increased nutritional requirements; physical exercise; increased excretion; higher renal or gastrointestinal loss and drug-induced intracellular transfer of potassium, including anesthetics and glucocorticoids.1, 2 The attacks are episodic, lasting from hours to days and occurring from every day to once every few years. Ocular, bulbar, or respiratory muscles are hardly ever affected, and the weakening usually affects proximal limb muscles more than distal limb muscles. Examination during an episode reveals flaccid paralysis with loss of muscular stretch reflexes, but crucially, there is no myotonia, and consciousness is retained during the attack. Patients might experience significant, permanent, proximal lower limb weakness later, but the weakness completely have a regression between attacks. An attack may result in potentially fatal heart arrhythmias.4, 5 Potassium is administered orally or intravenously to stop paralysis attacks during acute episodes and as maintenance therapy. In addition, carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide may be used as first-line therapy. Clinical findings and serum potassium measurement during the episodes help in diagnosing; however, definitive diagnosis is achieved by genetic testing. Mutation in the calcium channel gene are involved in 60% of cases, while mutations in the sodium channel gene represent 15%–20% of cases.1 The pathogenic variant in CACNA1S carried out by our patient is known to be related to different phenotypes: asymptomatic carriers; periodic paralysis and hypokalemia with variable duration from hours to days; progressive proximal permanent muscle weakness; and attacks of paralysis in combination with progressive permanent muscle weakness. Specifically, our patient manifests the second phenotype.3 Pregnancy needs to be carefully monitored because fetal requirements may alter maternal balance. In addition, labor and delivery represent a stressful condition, so assuring good pain control is fundamental with the purpose of not worsening hypokalemic paralysis.1 Most of the information in the literature about managing pregnancy and delivery in cases of periodic hypokalemic paralysis comes from case reports or small case series, where clinical management seems to be mostly done on the fly without any established protocols. Treatment included enteral or parenteral potassium supplements depending on the severity of hypokalemia. Normal range is considered 3.5–5 mmol/L. Our patient was administered basically with three doses of potassium chloride 600 mg/daily. We chose to integrate with supplemental doses of oral potassium chloride if K+ levels were <3.5 mmol/L, while intravenous supplementation was reserved for cases of severe hypokalemia (K+ <3 mmol/L) and especially during the intrapartum period. During labor and delivery, it was administered 600 mg six times a day. Literature findings report that4 the lowest K+ level that did not result in paralysis was 3.3 mmol/L; however, in our case, the patient had symptoms of weakness when her potassium level was 3.48 mmol/L. In addition, it is suggested to supplement when at an even higher level of 4.0 mmol/L, considering the rapidity with the K+ levels fall in hypokalemic paralysis. In cases of intravenous administration of K+, infusion is stopped when the level 4.5–5.0 mmol/L is reached.4 The relative prematurity and the potential requirement for a caesarean section in the event that labor had not begun determined the choice to implement RDS prophylaxis. Betamethasone administration has proven to be a possible cause of a drop in K+ level with subsequent paralysis and ECG abnormalities.5 Increased renal potassium clearance or transcellular potassium shifts due to increasing activity of Na/K ATPase pumps and the hyperglycemia-induced insulin secretion might be the origin of betamethasone's hypokalemic paralysis-causing effects. In our case, the awareness of the maternal pathology ensured strict monitoring and adequate supplementation, safeguarding the well-being of the patient during and after the completion of the administration without any critical events. Our choice to use misoprostol instead of oxytocin in the labor induction and for primary postpartum hemorrhage (PPH) prevention was dictated by evidence in the literature indicating its favorable side effect profile. Oxytocin, due to their similar structure to vasopressin, can also cause hyponatremia. These adverse effects might cause emotional and physiological stress, which might lead to an episode of hypokalemia.6, 7 In contrast, misoprostol has the most favorable side effect profile of any of drugs available for PPH prevention. It also reduces the chance of precipitating hyponatremia, so eliminating any potential electrolyte imbalances that could start an episode both during and after delivery. For these reasons, misoprostol might be the best first-line uterotonic challenge for primary prevention of PPH in this clinical condition.6, 7 In our case, we did not use epidural analgesia because of precipitous labor. Results in the literature show that potassium depletion might be caused by certain regional anesthesia techniques and that muscle blockers should be avoided.2 However, spinal anesthesia is considered a safe option. In addition, early epidural analgesia should be considered to reduce stress, pain, and hyperventilation, which are possible causes of lower potassium levels.2 Our patient did not use acetazolamide. We emphasize that there is no standardized treatment regimen and no consensus about its administration; in addition, data in the literature show that it is beneficial in approximately 50% of individuals with hypokalemia, but in 30% of affected individuals it has not any effect. Moreover, carriers of some pathogenic variants such as SCN4A might experience negative effects such as exacerbation of hypokalemia.8 Finally, its use is discouraged in pregnancy because of the lack of data on its safety. Obstetric management and delivery modality must be personalized based on fetal indications and the patient's characteristics. Because childbirth is a stressful time, an increase in serum catecholamine levels can cause a paralytic episode. Therefore, multidisciplinary assessment, as in our case, is essential to reduce the risk of paralysis onset during labor and delivery.6, 7 Delivery and labor both significantly increase the risk of an attack in patients with HPP because of the associated pain and the ensuing sympathetic stimulation of the neurological system and the sporadic, high-intensity physical activity that occurs during the second stage of labor.6, 7 To avoid hypokalemic attacks, K+ levels must be kept within a normal range. Decreases in K+ can occur suddenly and rapidly. Therefore, having a clear goal in the range for replacement is crucial. Serum K+ levels should be regularly checked during the postpartum period, and as soon as the K+ starts to decline, it should be promptly and forcefully restored. MD and MRP wrote the manuscript. BG revised the manuscript. All authors contributed to the article and approved the submitted article. The authors have no funding to declare. The authors have no conflict of interest to declare. Not applicable. The patients in this manuscript have given written informed consent to the publication of their case details. The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.