Diagnosis,management and outcomes of primary hypokalemic periodic paralysis during pregnancy

Abstract

Primary hypokalaemic periodic paralysis during pregnancy has been rarely reported. Four pregnant women with the acute onset of flaccid paralysis presented between January 2018 and December 2021. Focussed history and physical examination helped an appropriate radiological and laboratory investigation plan to be made. All women recovered within 4–7 days of potassium supplementation. Supplemental potassium continued until delivery. A pain management plan with continuous epidural infusion helped in avoiding stress-induced hypokalaemia. None of the women developed an episode of muscle weakness during the intervening period. In conclusion, a focussed history and targeted laboratory investigation are needed to diagnose primary hypokalaemic periodic paralysis. Early administration of oral or intravenous potassium is crucial in improving fetomaternal outcomes.

Keywords

Hypokalaemia periodic paralysis pregnancy potassium chloride distal renal tubular acidosis Sjogren syndrome fetomaternal outcomes

Introduction

Hypokalaemic periodic paralysis (HPP) is a neuromuscular disorder produced by calcium and sodium channel mutations.^1,2 A low extracellular potassium depolarises skeletal muscle sarcolemma and inactivates sodium channels to reduce action potential propagation.³ Other notable causes of periodic paralysis include hyperkalaemic periodic paralysis, normokalaemic periodic paralysis, Andersen-Tawil syndrome and renal tubular acidosis.^4,5 Hypokalaemia may be exacerbated during periods of increased nutritional requirements, increased excretion and drug-induced intracellular transfer of potassium.⁶ Periodic paralysis may occur during pregnancy, delivery and lactation due to increased requirements, stress or use of tocolytics.⁷ Due to its rarity, the diagnostic approach, management and fetomaternal outcomes have not been adequately described in the literature. In this case series, we described the medical and obstetric management and fetomaternal outcomes of four pregnant women who presented with the acute onset of muscle weakness due to primary HPP.

Case descriptions

Case 1

A 41-year-old woman in her second pregnancy, presented in the emergency department at 32 weeks of gestation, with difficulty in getting up from bed and poor neck control. She reported two similar episodes during the last 2 years. Her father also had episodes of generalised muscle weakness. Her GCS (Glasgow Coma Scale) was normal, with muscle power of 2/5 and 3/5 in the lower and upper limbs, respectively. The rest of the neurological and clinical examination was unremarkable. Laboratory examination showed serum potassium of 2 mmol/L (Table 1). Serological and immunological analysis was unrevealing. She received 40 mmol of potassium intravenously over the next 36 h. Her symptoms resolved entirely in the next 4 days. Subsequently, she was discharged from the hospital with oral potassium (10% potassium chloride oral solution USP; Brand name: Potklor; Manufacturer: Walter Bushnell, India; 15 mL = 20 mEq = 20 mmol;15 mL twice daily) prescription. She was admitted again for elective caesarean delivery at 38 weeks of gestation. She did not report symptoms during this period, and her potassium at admission with continued potassium supplementation was 3.5 mmol/L. She underwent elective caesarean delivery under combined spinal and epidural anaesthesia due to maternal indications (Cephalopelvic disproportion and previous caesarean delivery). Her baby was healthy and remained healthy at 1-year follow-up. She was advised to take an oral potassium supplement (15 mL twice daily), if symptoms recur. She was doing well at 1 year follow-up, and remained symptom-free during this period.

Table 1.

Laboratory investigations and fetal outcomes.

	Patient 1	Patient 2	Patient 3	Patient 4
Arterial blood gas
pH	7.40	7.39	7.41	7.43
Bicarbonate (mmol/L)	23.6	22.3	24.3	20.4
Anion gap (mmol/L)	15	8	15	11
Serum biochemistry
Potassium (mmol/L)	2.2	1.7	2.3	1.9
Sodium (mmol/L)	134	130	137	130
Chloride (mmol/L)	98	102	96	101
Magnesium (mmol/L)	0.7	0.86	0.74	0.78
Calcium (mmol/L)	2.22	2.15	2.2	2.2
Urea (mmol/L)	2.33	3.16	3.33	2.49
Creatinine (umol/L)	61.9	44.21	44.21	53.05
Hormones and vitamins
TSH (mIU/L)	1.5	4.3	2.1	0.9
Serum thiamine (mcg/dL)		5.1	4.5
Urine analysis
pH	4.4	4.2	4.3,	4.1
Glucose (mmol/L)	0.5	0.3	0.3	0.5
Anion gap (mmol/L)	−4	−10	−14	5
Osmolality (mosm/kg)				164
Protein:creatinine				1.7
Immunology
Antinuclear antibody	Negative	Negative	Negative	Negative
Anti Ro/SS-A and La/SS-B	Negative	Negative	Negative	Negative
Fetal outcome
Birth weight (g)	2850	2550	2600	2100
Apgar scores at 1 and 5 min	8,9	8,9	8,9	4,6

TSH: thyroid-stimulating hormone.

Case 2

A 24-year-old woman in her first pregnancy presented with sudden onset of weakness in both lower limbs, at 16 weeks of gestation. She reported episodes of vomiting a week before the onset of weakness. She had noticed similar episodes of weakness twice during the last year, which resolved spontaneously within a day without medical assistance. Neurological examination showed muscle power of 2/5 in the lower and 4/5 in the upper limbs. The rest of the examination was unremarkable. Laboratory investigation showed serum potassium of 1.7 mmol/L (Table 1). Thiamine level was within the normal range (5.1 µg/dl). She was advised to continue oral potassium (15 mL twice daily) for the rest of her pregnancy. She was admitted at 38 weeks of gestation after the onset of labour. She delivered vaginally using epidural analgesia. Her baby was healthy. She was advised to take oral potassium (15 mL twice daily), if symptoms recur. She remained asymptomatic nearly 1 year after discharge from the hospital.

Case 3

A 28-year-old woman in her first pregnancy, presented at 18 weeks of gestation with a 3-day history of lower limb weakness. She described episodes of vomiting before the development of limb weakness. She had had two similar episodes of weakness in the last 4 years which had resolved spontaneously within 2 days without any medical intervention. However, she denied similar symptoms in any of her family members. Her GCS was normal (15/15) and muscle power was 2/5 in the lower limb and 4/5 in the upper limb. Deep tendon reflexes were hypoactive and cutaneous sensation was preserved. The rest of the physical and clinical examination was unremarkable. Laboratory investigation revealed serum potassium of 2.3 mEq/L. However, her thiamine level was normal (4.5 mcg/dL; Table 1). The rest of the laboratory investigation was within normal range. Oral potassium supplementation (10% potassium chloride oral solution USP; Brand name: Potklor; Manufacturer: Walter Bushnell, India; 15 mL = 20 mEq;15 mL three times daily) was initiated immediately, and her symptoms resolved within 6 days. She did not develop a further episode of muscle weakness during pregnancy. She continued to receive oral potassium supplementation (15 mL twice daily) after discharge from the hospital. She returned to the hospital at 38 weeks of gestation with spontaneous labour. She had an uneventful vaginal delivery, with the use of epidural analgesia. She was asked to discontinue oral potassium supplement in the postpartum period and was advised to take it (15 mL twice daily) whenever weakness recurs. She did not report episodes of muscle weakness in the next one year.

Case 4

A 32-year-old in her sixth pregnancy presented at 25 weeks of gestation with a 1-day history of bilateral upper and lower limb weakness. She had one similar episode in her previous pregnancy at 36 weeks of gestation and her symptoms resolved spontaneously after potassium supplementation. She had no family history of similar episodes. Her GCS was 15/15, and muscle power in upper and lower limb was 4/5 and 3/5, respectively. Deep tendon reflex was hypoactive. Sensory and cranial nerve examinations were unremarkable. Urine dipstick testing showed a normal urinary pH, hence excluded renal tubular acidosis (Table 1). Her serum potassium on admission was 1.9 mmol/L. She was immediately treated with continuous slow infusion of KCL through a large intravenous peripheral cannula. In the initial 6 h, 20 mEq of KCL was administered, subsequently, oral potassium (10% potassium chloride oral solution USP; Brand name: Potklor; Manufacturer: Walter Bushnell, India; 15 mL = 20 mEq) was provided three times daily. She was advised to take oral potassium (15 mL twice a day) once her symptoms resolved entirely in the next 7 days. Symptoms did not recur during the remaining part of pregnancy and delivery. She delivered a premature baby vaginally at 36 weeks of gestation. Parenteral opioid was given as labour analgesia. The baby required admission to the intensive care unit due to a poor APGAR score. She was told to discontinue oral potassium supplement in the postpartum period and was advised to take it (15 mL once daily) whenever weakness recurs. Both mother and baby were healthy at one year follow-up.

Discussion

Acute onset flaccid paralysis is not rare and several neurological, metabolic and endocrine disorders can result in a systematic approach to acute muscle weakness (Figure 1). All women in this series had normal GCS (15/15) and there was no evidence of respiratory, cranial nerve or sensory involvement. Furthermore, all women had had at least one episode of similar muscle weakness unrelated to pregnancy. Three women did not seek intervention and their symptoms resolved spontaneously, while one woman required potassium supplementation in her previous pregnancy. Therefore, we began investigating targeted electrolytes (both serum and urine) and blood gas analysis. Anti-nuclear antibody and thyroid function were obtained to rule out Sjogren syndrome-related renal tubular acidosis and thyroid dysfunction-associated hypokalaemia.^8,9 Two women had episodes of vomiting and serum thiamine level was normal in those two patients. A low serum thiamine may precipitate Wernicke encephalopathy. HPP and Wernicke encephalopathy may have similar symptoms.¹⁰ However, magnetic resonance imaging is required for definitive diagnosis of Wernicke encephalopathy.¹⁰ All women were therefore diagnosed with primary hypokalemic periodic paralysis. Genetic analysis was not considered as all relevant investigations ruled out majority of the causes of hypokalemic paralysis.² However, genetic analysis may be required occasionally in primary HPP, and it should be considered in hyperkalaemic periodic paralysis, Andersen-Tawil syndrome, Gitelmann syndrome and Bartter syndrome.^2,11 Hyperkalaemic paralysis was unlikely as all women in our series were characterised by flaccid paralysis and severe hypokalaemia while hyperkalaemic paralysis is characterised by stiffness and normo- or hyperkalaemia. Moreover, Andersen–Tawil syndrome is characterised by peculiar faces and skeletal deformities.²

Figure 1.

Diagnostic approach to acute-onset muscle weakness during pregnancy. CT: computed tomography; GCS: Glasgow Coma Scale, CSF: Cerebrospinal Fluid, GI: Gastrointesinal, MRI: magnetic resonance imaging.

To our knowledge, this is the largest case series of primary HPP presenting during pregnancy. Primary HPP is caused by mutations in calcium and/or sodium channels and clinical presentation is generally identical in both types of mutation. Diagnosis in most cases is based on clinical findings, and serum potassium measurement during the episodes, but can be confirmed by genetic testing. Nearly 60% of cases are due to a missense mutation in the calcium channel gene, and 15–20% of cases are caused by a mutation in the sodium channel gene.¹² Women may not have an identifiable mutation in either of these two genes. Phenotypic mapping and data entries in OMIM (Online Mendelian Inheritance in Man) database may help clinicians and researchers in counselling and designing studies to find the exact nature of mutation and molecular basis of the disease. Additionally, if a mutation is found, it might be advisable for family members to undergo genetic testing. Primary HPP is an autosomal dominant disorder and it is frequently reported in men during the second or third decades of life.² However, sporadic variants are not uncommon in males of Asiatic origin.² It has been rarely reported in females of Asiatic descent. Unlike primary HPP, secondary HPP is accompanied by acid-base and other electrolytes abnormalities.¹³ Increased potassium requirements during pregnancy, exercise and high carbohydrate diets and higher renal or gastrointestinal loss may precipitate paralysis in both primary and secondary HPP.⁶ A higher transcellular shift of potassium due to insulin, beta-agonist and bicarbonate therapy may also precipitate both phenotypes of HPP.

The onset and pattern of muscle weakness in primary HPP cannot be differentiated from secondary HPP.¹⁴ Nonetheless, unlike secondary HPP, primary HPP has a quicker recovery profile.^14,15

Two women were treated with oral potassium supplementation (60 mmol/day) while two women were treated with intravenous potassium infusions when symptomatic. Additionally, women were prescribed low carbohydrate and high protein diet throughout the pregnancy. Acetazolamide or spironolactone was not used during the pregnancy in our series. Muscle power returns back to normal within 4–7 days in all women. We prescribed oral potassium (40 mEq) during the remaining period of pregnancy once the symptoms subsided. Potassium can be used chronically as maintenance therapy to decrease the frequency and severity of attacks over time. However, no dosing regimen is available and finding the correct dose requires some trial and error. Diuretics are not helpful during acute attacks.¹⁶ Acetazolamide and dichlorphenamide may be used as first-line therapy along with potassium supplementation.^17,18 However, acetazolamide may occasionally worsen the attacks. If acetazolamide worsens then another carbonic anhydrase inhibitor such as dichlorphenamide would not be helpful. Nevertheless, patients responsive to acetazolamide or who have become refractory to acetazolamide may be benefitted from dichlorphenamide.¹⁶ In non-pregnant individuals, epleronone and spironolactone can be safely used in combination with potassium as maintenance therapy.^2,16 However, the dose of potassium needs to be adjusted, and frequent monitoring of serum potassium is required to prevent hyperkalaemia. Spironolactone is generally regarded as contra-indicated in pregnancy due to its anti-androgenic properties and the risk this may pose to male fetuses, however, it is occasionally used. Eplerenone lacks these anti-androgenic properties so may become of more use in pregnancy in the future. Notably, bumetanide has been trialled in mouse models of HPP with calcium and sodium mutations with reasonable success. Bumetanide is an inhibitor of Na-K-2Cl cotransporter and prevents paradoxical depolarisation in HPP.¹⁹

Symptoms in the women described did not recur during pregnancy, delivery or lactation, once on regular supplementation. We noticed electrocardiographic features of hypokalaemia (flattened T waves, U waves and QT prolongation) in one woman only. None of the women showed cardiac rhythm disturbance and hemodynamic instability during symptomatic period or delivery. Serum magnesium was normal in all women so no additional magnesium supplementation was required. Women were advised to undergo delivery in a hospital setting. None of the women had preterm labour.

Labour-induced stress may precipitate hypokalaemic paralysis and so it is important to ensure adequate pain control all women.²⁰ One women required caesarean delivery due to previous caesarean delivery and cephalopelvic disproportion, while another required vacuum extraction. Muscle power remained normal (5/5) during all stages of labour and during the postpartum period.

Oral potassium administration appears sufficient to treat primary HPP. However, intravenous potassium may be required in patients with severe muscle weakness. Moreover, intravenous potassium administration requires large-bore venous access, slow administration, adequate dilution and frequent monitoring. We did not notice a higher potassium level (>4 mEq/lit) with the current oral or intravenous dosing regimen.

All the babies and mothers were healthy at 1-year follow-up. There had been no episodes of periodic paralysis in the mothers and none of the babies required hospitalisation. Oral potassium supplements (15 mL = 20 mEq/day) were advised whenever muscle weakness recurs and women were advised to seek medical assistance if this occurred.

Conclusions

A focussed history and targeted laboratory investigation are needed to diagnose primary hypokalaemic periodic paralysis. Early administration of oral or intravenous potassium becomes crucial in improving the fetomaternal outcomes. Adequate labour pain control and careful selection of drugs at the time of delivery are required to prevent an acute change in potassium levels.

Footnotes

Consent for publication

All patients provided written informed consent for publication of data.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Not applicable.

Guarantor

Ajay Kumar Jha.

Contributorship

Nivedita Jha helped with intellectual content, study design, writing and approving manuscript for publication. Divya Mecheril Balachandran: Helped in conceptualization, extraction of data, interpretation, and preparation and approval of final draft of manuscript. Molly Mary Thabah: Helped in conceptualization, extraction of data, interpretation, and preparation and approval of final draft of manuscript. Ajay Kumar Jha: Helped in conceptualization, extraction of data, interpretation, and preparation and approval of final draft of manuscript.

ORCID iDs

Nivedita Jha

Ajay Kumar Jha

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