Hypokalaemic Periodic Paralysis

Synonym: HOKPP

It is inherited in a typical autosomal dominant pattern with a penetrance that is almost 100% in males, but rather lower in females.
Around a third a cases give no family history and so may be spontaneous mutations.

• It tends to present in the second decade of life but may be in the first decade with more severe disease and the third decade in milder cases. The majority present before 16 years of age.
• The attacks are intermittent and infrequent initially but may increase in frequency until attacks occur almost daily.
• The frequency declines by the age of 30 and it rarely occurs after the age of 50 years.

Signs and symptoms

• Weakness may range from slight transient weakness of an isolated muscle group to severe generalised weakness.
  • The muscles that are constantly active, particularly heart, diaphragm and other muscles of ventilation are spared.
  • Muscles supplied by the cranial nerves tend to be spared too.
• Severe attacks begin in the morning. There has often been strenuous exercise or a high carbohydrate meal on the previous day.
• Patients awake with marked symmetrical weakness, often with truncal involvement:
  • Mild attacks are frequent and involve only a limited group of muscles, and may be unilateral, partial, or affecting just one muscle.
  • This may predominantly affect the legs.
  • Sometimes extensor muscles are affected more than flexors.
• The duration of weakness can vary from a few hours to a week but it seldom exceeds 72 hours.
• Urinary output is reduced during an attack as water is retained within the muscle cells.

Interictal features

• Between attacks, myotonia may occur but this is unusual. Myotonic lid lag may be observed between attacks.
• Permanent muscle weakness may be seen later in the course of the disease and this may become severe. Hypertrophy of the calves has been observed. Proximal muscle wasting, rather than hypertrophy, may be seen in patients with permanent weakness.

Aggravating and relieving factors

The condition can be precipitated by insulin or glucose infusion:

• Glucose will cause the endogenous release of insulin that causes both glucose and potassium to move into cells.
• This would also explain the precipitation of an attack by high carbohydrate meals.

Attacks can be aborted by administration of potassium or by exercise.

• Hyperkalaemic periodic paralysis (HYPP) is very similar clinically.² It is also an autosomal dominant condition causing paralytic attacks but with high rather than low potassium during an attack and myotonia is more commonly seen.
• Another variant that is genetically determined, apparently from mutation on the 1 chromosome, is thyrotoxic periodic paralysis in which hypokalaemic paralysis is associated with thyrotoxicosis.³
• Secondary hypokalaemia will cause weakness and there are a number of causes:
  • Hyperaldosteronism
  • Conn's syndrome
  • Bartter's syndrome
  • Excessive consumption of licorice
  • Renal loss, especially with renal tubular acidosis
  • Alimentary loss with chronic diarrhoea or purgative abuse
  • Excessive alcohol consumption
  • Drugs (especially amphotericin B)
  • Barium poisoning

Between attacks parameters may be normal.

• During an attack the plasma potassium level is decreased, although it may not fall below the normal or reference range.
• Urine output is low with elevated urine levels of sodium, potassium, and chloride.
• There is a fall in serum phosphate levels whilst CPK is elevated during an attack.
• It may be possible to distinguish the primary condition from secondary periodic paralysis from potassium loss by the ratio of urinary creatinine to potassium (CRP).⁴ In molar terms, if the CRP exceeds 2.5 there is secondary potassium loss
• The ECG may show sinus bradycardia with evidence of hypokalemia, including flattening of T waves, U waves in leads II, V2, V3, and V4, and ST segment depression.

Provocation testing

Provocative testing can be employed but general precautions for such testing are important for safety:

• A doctor should be present during testing.
• It should be performed in a setting where intensive care such as ventilation may be provided if required with facilities for rapid electrolyte and glucose testing and correction.
• Do not test patients with serum potassium disturbances, diabetes mellitus, or renal or cardiac dysfunction.
• There must be close monitoring of the ECG.

The first step is an oral glucose loading test:

• Glucose is given orally at a dose of 1.5 g/kg to a maximum of 100 g over a period of 3 minutes with or without 10 to 20 units of subcutaneous insulin.
• Muscle strength is tested every 30 minutes.
• Electrolytes are measured every 30 minutes for 3 hours and every hour for the next 2 hours.
• Weakness is usually detected within 2 or 3 hours.

If the test is negative the next step is an intravenous glucose challenge. This is not without danger of severe hypoglycaemia.

An alternative is an intra-arterial adrenaline test or an exercise test has also been described:⁵

• There is a greater than normal increase in compound muscle action potential amplitude during 2 to 5 minutes of intermittent strong voluntary contraction of the tested muscle.
• This is followed by a progressive decline in amplitude, which is most rapid during the first 20 minutes after exercise.
• This test does not help identify the type of periodic paralysis.

During attacks

Oral potassium is preferred to IV but the latter may be required for patients who are unable to swallow:

• Oral potassium salts at a dose of 0.25 mEq/kg should be given every 30 minutes until the weakness improves.
• Continuous ECG monitoring and serial potassium measurements are essential.

Prophylaxis

• Acetazolamide may be used at a dose of 125 to 1500 mg/day in divided doses.
• A recent Cochrane review found dichlorphenamide was significantly better than placebo for prophylaxis in HOKPP or HYPP.⁶
• Potassium-sparing diuretics like triamterene (25-100 mg/d) and spironolactone (25-100 mg/d) are second-line drugs to be used in patients in whom the weakness worsens or in those who do not respond to carbonic anhydrase inhibitors.
• As these diuretics are potassium sparing, potassium supplements may not be necessary.

There is no evidence base for the management of HOKPP in pregnancy.⁷

If the condition is not treated, fixed proximal muscle weakness may occur.

A few deaths have been reported, mostly due to aspiration pneumonia or inability to clear secretions.

Attacks can be minimised by a very low sodium diet and avoidance of meals that are high in carbohydrate.