NeurometPlus

Incidence

Although its exact prevalence is unknown, hypokalemic periodic paralysis is estimated to affect 1 in 100,000 people. Men tend to experience symptoms of this condition more often than women. This condition is inherited in an autosomal dominant pattern.

Clinical Characteristics

Hypokalemic periodic paralysis is a condition that causes episodes of extreme muscle weakness typically beginning in childhood or adolescence. Most often, these episodes involve a temporary inability to move muscles in the arms and legs. Mutations in the CACNA1S or SCN4A gene can cause hypokalemic periodic paralysis. Mutations in the CACNA1S or SCN4A gene alter the usual structure and function of calcium or sodium channels. The altered channels are \\\"leaky,\\\" allowing ions to flow slowly but continually into muscle cells, which reduces the ability of skeletal muscles to contract. Attacks cause severe weakness or paralysis that usually lasts from hours to days. Some people may have episodes almost every day, while others experience them weekly, monthly, or only rarely. Attacks can occur without warning or can be triggered by factors such as rest after exercise, a viral illness, or certain medications. Often, a large, carbohydrate-rich meal or vigorous exercise in the evening can trigger an attack upon waking the following morning. Although affected individuals usually regain their muscle strength between attacks, some develop persistent muscle weakness later in life. People with hypokalemic periodic paralysis typically have reduced levels of potassium in their blood (hypokalemia) during episodes of muscle weakness. A small percentage of people with the characteristic features of hypokalemic periodic paralysis do not have identified mutations in the CACNA1S or SCN4A gene. In these cases, the cause of the condition is unknown. 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. The duration of paralytic episodes ranges from one to 72 hours with an average of nearly 24 hours. Some individuals have only one episode in a lifetime; more commonly, crises occur repeatedly: daily, weekly, monthly, or less often.

Precipitants

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.

Provocation Tests

No provocation tests are suggested. However specific exercise tests can assist with the diagnosis of periodic paralyses and nondystrophic myotonias [Fournier et al 2004]:
A. Short exercise test (SET). SET consists of recording evoked compound muscle action potential (CMAP) every ten seconds over one minute after a short effort (5-12 seconds) [Streib 1987]. B. Long exercise test (LET). LET consists of recording evoked CMAP over 30-45 minutes, every one to two minutes and then every five minutes, after a long effort (2-5 minutes, with brief 3- to 4-second rest periods every 15-45 seconds) [McManis et al 1986].
Five patterns (I-V) of abnormal responses to SET and/or LET in periodic paralyses and nondystrophic myotonias have been described [Fournier et al 2004]. Genetically defined
periodic paralyses specifically result in:
1. Pattern IV (no or rare myotonic discharges, increase of CMAP on SET, immediate increase and late marked decrease in LET), more commonly seen in the hyperkalemic type
OR
2. Pattern V (no myotonic discharges, normal response to SET, no immediate increase but late marked decrease in LET), more commonly seen in the hypokalemic type.
A false negative normal pattern may be noted in some individuals who have a pathogenic variant, especially in asymptomatic individuals or those who have not recently had a paralytic attack [Tengan et al 2004].
A decrease of at least 30% in CMAP amplitude and surface on LET is diagnostic for HOKPP. A decrease of less than 30% and greater than 20% is less specific and may indicate a different dï‚·iagnosis. This decrease corresponds to pattern IV (with initial increment) and pattern V.

Diagnostic Procedures

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. Consensus diagnostic criteria include: 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: 1. Onset in the first or second decade. 2. Duration of attack (muscle weakness involving ≥1 limbs) longer than two hours. 3. The presence of triggers (previous carbohydrate rich meal, symptom onset during rest after exercise, stress). 4. Improvement in symptoms with potassium intake. 5. A family history of the condition or genetically confirmed skeletal calcium or sodium channel mutation and 6. Positive long exercise test.
AND
Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse)
Of all individuals meeting diagnostic criteria for hypoPP, approximately 30% do not have a pathogenic variant identified in either of these known genes.