Hypokalemic Periodic Paralysis

Clinical characteristics: Hypokalemic periodic paralysis (hypoPP) is a condition in which affected individuals may experience paralytic episodes with concomitant hypokalemia (serum potassium <3.5 mmol/L). The paralytic attacks are characterized by decreased muscle tone (flaccidity) more marked proximally than distally with normal to decreased deep tendon reflexes. The episodes develop over minutes to hours and last several minutes to several days with spontaneous recovery.

Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often. The major triggering factors are cessation of effort following strenuous exercise and carbohydrate-rich evening meals. Additional triggers can include cold, stress/excitement/fear, salt intake, prolonged immobility, use of glucosteroids or alcohol, and anesthetic procedures. The age of onset of the first attack ranges from two to 30 years; the duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Long-lasting interictal muscle weakness may occur in some affected individuals and in some stages of the disease and in myopathic muscle changes. A myopathy may occur independent of paralytic symptoms and may be the sole manifestation of hypoPP.

Diagnosis/testing: The diagnosis of hypoPP is established in a proband who meets the consensus diagnostic criteria based on a history of attacks of muscle weakness associated with documented serum potassium <3.5 mmol/L during attacks and/or the identification of a heterozygous pathogenic variant in CACNA1S or SCN4A. Of all individuals meeting diagnostic criteria for hypoPP, approximately 30% do not have a pathogenic variant identified in either of these known genes.

In the case of long-lasting interictal flaccid muscle weakness, imaging techniques can inform on the pathogenesis, potential therapy, and prognosis. Muscle ultrasound and muscle 1H-MRI are reliable image techniques with high accuracy for the disease. The weakness can be caused by edemas, fatty muscle degeneration, and muscle atrophy or a combination of these pathologies.

Management: Treatment of manifestations. Treatment varies depending on the intensity and duration of the paralytic attack. Minor attacks may resolve spontaneously. Moderate attacks may be self-treated in a non-medical setting by ingestion of oral potassium salts. Severe attacks typically require more intensive medical management with intravenous potassium infusion, serial measurement of serum potassium concentration, clinical evaluation of possible respiratory involvement, and continuous electrocardiogram monitoring. There is no known curative treatment for hypoPP-related myopathy; physiotherapy may help to maintain strength and motor skills.

Prevention of primary manifestations. The goal of preventive treatment is to reduce the frequency and intensity of paralytic attacks. This may be achieved by avoidance of triggering factors, adherence to a diet low in sodium and carbohydrate and rich in potassium, and with the use of oral potassium supplementation. If dietary intervention and oral potassium supplementation are not effective in preventing attacks, treatment with a carbonic anhydrase inhibitor (acetazolamide or dichlorphenamide) may be necessary. If carbonic anhydrase inhibitors are not tolerated or not effective after prolonged use, alternatives include potassium-sparing diuretics such as triamterene, spironolactone, or eplerenone.

Prevention of secondary complications. Creating a safe environment, getting help in case of paralytic attack, and preventing falls and accidents are critical; an affected person experiencing a paralytic attack must have access to potassium as well as physical assistance and companions must be informed of the risk in order to enable rapid treatment. Anesthetic complications should be prevented by strict control of serum potassium concentration, avoidance of large glucose and salt load, maintenance of body temperature and acid-base balance, and careful use of neuromuscular blocking agents with continuous monitoring of neuromuscular function. It is unknown whether prevention of paralytic attacks also prevents the development of myopathy. Individuals with known pathogenic variants in one of the genes associated with hypoPP who developed myopathy without having experienced episodes of weakness have been reported.

Surveillance. The frequency of consultations is adapted to the individual's signs/symptoms and response to preventive treatment. Periodic neurologic examination with attention to muscle strength in the legs should be performed to detect long-lasting weakness associated with myopathy. For those taking acetazolamide, the following are indicated every three months: complete blood count; electrolytes; and glucose, uric acid, and liver enzyme levels. Renal ultrasound should be performed annually.

Agents/circumstances to avoid. Factors that trigger paralytic attacks (e.g., unusually strenuous effort, carbohydrate-rich meals or sweets, cold, stress/excitement/fear, high salt intake, prolonged immobility, oral or intravenous glucosteroids, certain anesthetic procedures, alcohol) should be avoided when possible.

Evaluation of relatives at risk. When the family-specific pathogenic variant is known, molecular genetic testing of at-risk asymptomatic family members can identify those at risk for unexpected acute paralysis and/or possible anesthetic complications.

Genetic counseling: HypoPP is inherited in an autosomal dominant manner. Most individuals diagnosed with hypoPP have an affected parent. The proportion of cases caused by a de novo pathogenic variant is unknown. Offspring of a proband are at a 50% risk of inheriting the pathogenic variant. Penetrance is about 90% in males and reduced in females. Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.