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.

Suggestive Findings

HypoPP should be suspected in individuals who describe episodic paralytic attacks with the following symptoms and signs (Note: Strictly speaking, "periodic" is a misnomer, as the attacks do not occur at regular intervals; "episodic" is a better descriptor.):

• Decreased muscle tone (flaccidity)
• Bilateral, symmetric, ascending (lower limbs affected before upper limbs) paralysis that is more marked in proximal than in distal muscles with sparing of the cranial muscles
• Deep tendon reflexes that are normal or decreased and plantar reflexes that are normal (downward movement of toes)
• Concomitant hypokalemia that is usually pronounced (0.9-3.5 mmol/L)

The typical evolution of symptoms is as follows:

• Rapid installation (over minutes or over hours)
• Duration of several minutes to several days
• Spontaneous recovery

Symptoms tend to occur under the following circumstances:

• At rest after strong physical exertion
• With fever
• At times of mental stress
• On awakening after a carbohydrate-rich meal the previous evening
• After prolonged immobility (e.g., with long-distance travel)

Suspicion for hypoPP is also raised in individuals who have

• A familial history of paralytic attack in earlier generations (father or mother, grandfather or grandmother) and in sibs;
• A personal history of previous spontaneously regressive episodes of paralysis or acute muscle weakness with the above-mentioned characteristics;
• Long-lasting flaccid weakness, especially if the weakness is only moderate and is prevalent in the family.

Establishing the Diagnosis

The diagnosis of hypoPP is established in a proband who meets the consensus diagnostic criteria for primary hypokalemic periodic paralysis as published in a Cochrane review [Sansone et al 2008] and/or with the identification of a heterozygous pathogenic variant in one of the genes listed in Table 1.

Consensus diagnostic criteria

• Two or more attacks of muscle weakness with documented serum potassium <3.5 mEq/L
  OR
• One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum potassium <3.5 mEq/L
  OR
• Three or more of the following six clinical/laboratory features:
  • Onset in the first or second decade
  • Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours
  • The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress)
  • Improvement in symptoms with potassium intake
  • A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation
  • Positive long exercise test (see Clinical Testing Available; pdf)
  AND
• Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse)

In individuals who have had one or more paralytic episodes, several tests can be used to differentiate between primary hypoPP and the other possible causes.

See Clinical Testing Available (pdf) if the diagnosis is less apparent.

Atypical clinical presentation. In some individuals, hypoPP may present solely as long-lasting weakness due to a progressive limb-girdle myopathy with no history of paralytic episodes. The diagnosis may be considered if paralytic episodes are present in family members, whereas in simplex cases (i.e., a single occurrence in a family) the diagnosis is often revealed only after muscle biopsy (see Clinical Description).

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of hypoPP is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of hypoPP has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Large-scale studies of the natural history of primary hypokalemic periodic paralysis (hypoPP) have not been performed. Thus, knowledge of the natural history relies largely on personal observations and on individual cases that have been published with a retrospective description of the individual disease history.

Pattern of attacks. The natural history and expressivity vary greatly over time. Frequency ranges from a single occurrence of a paralytic attack that may be triggered by exceptional circumstances (extreme physical effort, specific medical intervention) to spontaneous recurrent attacks of variable frequency (ranging from multiple attacks daily to less frequent attacks). The pattern of recurrent attacks may be linked more or less to identifiable temporal and behavioral circumstances, and may evolve over years.

Triggers of paralytic attacks. There may be identifiable triggers for paralytic attacks in hypoPP. In cohort studies by Miller et al [2004] and Cavel-Greant et al [2012], affected individuals were given a list of triggers and asked which trigger applied to their own case:

• Cessation of effort following strenuous exercise (e.g., football match) may trigger a paralytic attack. Approximately 67% of affected individuals identified exercise as a trigger.
• Carbohydrate-rich evening meals followed by nocturnal rest may result in an immobilizing paralytic attack in the morning. Approximately 45% of affected individuals identified heavy meals or sweets as a trigger.
• Cold. In ~24%. Re-warming usually recovers muscle strength.
• Stress/excitement/fear/epinephrine. In ~12%. Stress, excitement, or fear results in the body producing epinephrine, which makes episodes of paralysis more likely in some individuals. This appears to be due to the effect of epinephrine in reducing blood potassium.
• Salt intake. In ~11%. One of the most potent triggers of hypokalemic periodic paralysis is consumption of sodium chloride. The salt effect is far less known than the carbohydrate trigger. For many people it is easier to reduce salt than it is to reduce carbohydrates. Many foods contain huge amounts of salt, particularly snacks and tomato sauce. Soda drinks that contain both sodium and sugar are a particular problem.
• Prolonged immobility is a trigger for most affected individuals. "To keep moving" is the general clinical recommendation.
• Use of glucosteroids, especially parenterally, can trigger an attack.
• Anesthesia/ICU. During anesthesia there are many changes that can contribute to paralysis, including cooling, glucose, mannitol, sodium, and certain anesthetics such as succinylcholine, the risk for which requires preventive measures and careful anesthetic follow up (see Management). It is not clear that people with hypoPP are at any increased risk for malignant hyperthermia.
• Alcohol. It is unclear why alcohol sometimes triggers periodic paralysis. It could be from electrolyte imbalance, dehydration, or increased exercise or dietary indiscretion that often accompanies the inebriated state.

Age of onset of paralytic attacks. Three cohort studies have addressed this issue [Sternberg et al 2001, Miller et al 2004, Cavel-Greant et al 2012].

• The age of the first paralytic attack in affected individuals who develop repetitive attacks ranges from age two years to 30 years, with a mean age of onset of 14 years. Occasionally, clinical manifestations can be present at birth [Chabrier et al 2008].
• Disease onset is not likely after age 30 years.
• Age of symptom onset is correlated with sex (younger age of onset for girls than for boys).

Frequency of paralytic episodes

• In a cohort study by Miller et al [2004], the mean frequency of paralytic attacks was seven per month (2/week), with a range of one attack per day to one attack every four months.
• It was formerly assumed that the frequency of attacks peaks and then decreases with age, but in a recent survey only 21% of the patients reported decreased frequency with age [Cavel-Greant et al 2012].

Duration of paralytic episodes

• In the cohort study by Miller et al [2004], the duration of a paralytic episode ranged from one hour to 72 hours, with a mean duration of nearly 24 hours.
• Paralytic episodes may be followed by a period of weakness, obscuring the precise resolution of the attack.

Potassium levels during paralytic episodes

• The mean level of serum potassium during attacks was reported as 1.8 mmol/L in a cohort study by Sternberg et al [2001] and as 2.3 mmol/L in a cohort study by Miller et al [2004]. The lowest reported value was 1.2 mmol/L.
• Occasionally, normal potassium values are noted. The ictal potassium level depends on the pathogenic variant (see Molecular Pathogenesis).

Respiratory involvement and fatal outcome. The involvement of respiratory muscles during paralytic attacks is a rare but life-threatening complication of primary hypoPP. There are three possible life-threatening elements of paralytic attacks:

• Hypokalemia leading to possible cardiac dysrhythmia
• Weakness or paralysis of respiratory muscles leading to acute respiratory insufficiency
• Inability to move that can lead to death if it occurs in a hostile environment (i.e., drowning if the paralytic attack occurs in a swimming pool)

Long-lasting interictal flaccid weakness. Most individuals have normal muscle strength and physical activity during the interictal period (i.e., between paralytic attacks), but in some affected individuals and in some stages of the disease, there may be long-lasting weakness manifesting as abortive paralytic attacks occurring in rapid succession over a long period (weeks, months). Such attacks may respond to treatment with carbonic anhydrase inhibitors or aldosterone inhibitors (see Treatment of Manifestations).

• The frequency of long-lasting interictal muscle weakness is not known with certainty. It was present in all 11 affected individuals from the same family ranging from age 33 to 74 years [Links et al 1990] and in 28% of a study group with a mean age of 39 years (range 8-66 years) [Sternberg et al 2001]. It is suspected that a long-lasting interictal weakness is the result of a permanent increased Na+ uptake of the muscle fibers due to the omega current, the leak current that passes through the voltage sensor domain of an abnormal voltage-gated cation channel.
• From a survey in which participants were recruited by a patient support group, Cavel-Greant et al [2012] found that 90% of 46 individuals (mean age 55 years) with a clinical diagnosis of hypoPP reported fatigue and difficulties with daily activities and mild exercise. Sixty-seven percent of these individuals had incurred injuries due to falls and nearly 50% needed mobility aids.
• As no longitudinal prospective study has been performed, the risk for long-lasting interictal muscle weakness as it pertains to age and the particular pathogenic variant present is unknown.

Myopathy. The development of more permanent fixed weakness due to myopathic muscle changes (fibrosis and fatty replacement) appears to vary widely from one individual to another. The myopathy may occur independent of paralytic attacks. Rarely, early signs of myopathy (e.g., Achilles' tendon shortening or scoliosis) may be present in childhood – possibly the result of more severe pathogenic variants.

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.

Muscle histology. Typically, a muscle biopsy is not performed in the evaluation for hypoPP and histologic findings associated with the myopathy in hypoPP may depend on the specific pathogenic variant. In individuals with the p.Arg528His CACNA1S variant, the usual finding is vacuoles. Two male members of a family with the p.Arg672Gly SCNA4 variant presented only with tubular aggregates [Sternberg et al 2001].

Weakness without paralytic attacks. In some individuals, hypoPP may present solely with long-lasting weakness due to a progressive limb-girdle myopathy with no history of paralytic episodes.

Additional symptoms that can co-occur with hypokalemic periodic paralysis. People with genetically proven hypoPP often have other symptoms in addition to the paralysis:

• Pain (by some reports, more commonly associated with sodium-triggered episodes)
• Cramps

Among the 30% of people who appear to have hypoPP but do not have pathogenic variants in either of the genes known to be associated with hypoPP, the following are often noted:

• Migraines
• Heart rhythm abnormalities
• Attention deficit disorder (ADD, ADHD)
• Relative insensitivity to the local anesthetic lidocaine and "dental anxiety"
• Severe premenstrual syndrome

Genotype-Phenotype Correlations

There are no clear cut genotype-phenotype correlations for either of the genes known to be associated with hypoPP.

Penetrance

In general, the penetrance of this disorder is high (≥90%) in males and reduced in females. An exception to this occurs with pathogenic variants with an arginine-to-glycine substitution for which high penetrance in males and females is noted [Kim et al 2005, Wang et al 2005, Winczewska-Wiktor et al 2007].

Nomenclature

Names for hypokalemic periodic paralysis no longer in use include the following:

• Cavaré-Romberg syndrome
• Cavaré-Westphal syndrome
• Cavaré-Romberg-Westphal syndrome
• Westphal's disease
• Westphal's neurosis

Hypokalemic periodic paralysis was formerly most often known as Westphal's disease, as Karl Friedrich Otto Westphal (1833-1890) first described extensively and convincingly the main characteristics of the disease, which had previously been described as "periodic palsy" by Musgrave in 1727, Cavaré in 1853, and Romberg in 1857. Hartwig reported a case of palsy with muscle inexcitability provoked by rest after exercise in 1875. Westphal described a simplex case (i.e., single occurrence in a family); it was not until 1887 that a dominant pedigree was described by Cousot.

Familial versus sporadic hypoPP. Hypokalemic periodic paralysis may be familial (f-hypoPP) or sporadic (s-hypoPP), meaning that the affected individual has no known family history of hypoPP. Sporadic cases may be the result of a de novo variant, of pathogenic variants with incomplete penetrance in other family members with the variant, or of other as-yet unexplained factors. Pathogenic variants in the same genes may lead to either f-hypoPP or s-hypoPP.

HypoPP1 versus hypoPP2. HypoPP1 and hypoPP2 are hypokalemic periodic paralysis linked respectively to CACNA1S and SCN4A pathogenic variants. Some authors use the terms "hypoPP type 1" and "hypoPP type 2." However, this could wrongly suggest that there are two clinical types of hypoPP. In fact, hypoPP1 and hypoPP2 are not distinct clinically.

Prevalence

The prevalence of hypoPP is unknown but thought to be approximately 1:100,000 [Statland et al 2018]. However, a demographic survey in England, relying on the data of the national specialist channelopathy service, reported a minimum point prevalence of 0.13:100,000 (95% CI 0.10-0.17) [Horga et al 2013].