Hypokalemic Periodic Paralysis

Hypokalemic Periodic Paralysis 

Hypokalemic periodic paralysis (HPP) is a rare neuromuscular disorder caused by a muscle ion channel defect, resulting in painless muscle weakness with associated low potassium blood levels.

Total-body muscle weakness may occur periodically with either a true potassium deficit or, more commonly, a potassium shift intracellularly.

Synonyms

• Periodic paralysis
• Hypokalemic nonperiodic paralysis
• Cavare disease
• HPP

Epidemiology & Demographics

Here is the incidence and epidemiology of Hypokalemic Periodic Paralysis

• •Hypokalemic Periodic Paralysis has an incidence of 1:100,000.
• •Autosomal-dominant inheritance.
• •One third of cases are new mutations.
• •Majority of new cases develop in patients with thyrotoxicosis.
• •Clinical penetrance is often incomplete but more commonly expressed in men.
• •Anderson syndrome is a rare variant of Hypokalemic Periodic Paralysis and has an incidence of 1:1,000,000. Patients are at risk for cardiac arrhythmias because the potassium-channel mutation is also expressed in cardiac muscle.

What are the Symptoms of Hypokalemic Periodic Paralysis – Physical Findings & Clinical Presentation

• •The usual onset of Hypokalemic Periodic Paralysis begins during adolescence as transient episodes of generalized weakness without muscle-tone loss.
• •Attacks vary in frequency and length. Most commonly lasting several hours but can last up to days.
• •Attacks may be provoked by rest after vigorous exercise, stress, or high-carbohydrate meals. The resulting increase in epinephrine and/or insulin leads to an intracellular shift of potassium and low serum potassium.
• •Attacks have also been known to be provoked by cold, alcohol, lack of sleep, emotional stress, beta-2 receptor agonists, diuretics, corticosteroids, insulin, glucocorticoids, viral illness, menstruation, and pregnancy.
• •Legs are generally affected more than arms, and proximal more than distal muscles.
• •Most commonly symptoms occur in the morning after waking.
• •Consciousness as well as ocular, bulbar, and respiratory muscles are spared.
• •Patients may develop chronic progressive proximal myopathy around age 50, most pronounced in proximal upper and lower extremities as well as pelvic girdle.
• •Frequency of attacks and weakness begin to decrease around age 50 yrs.

What causes Hypokalemic Periodic Paralysis?

• •Hypokalemic Periodic Paralysis is caused by mutations in transmembrane voltage-gated ion channels of the skeletal muscle or endoplasmic reticulum.
• •Most common mutation is in the alpha-1 subunit of the dihydropyridine-sensitive calcium channel in skeletal muscle. Exact mechanism for causing hypokalemia is not currently known.
• •Another cause is a mutation in the skeletal muscle sodium channel (SNC4A). This produces an anomalous gating pore current leading to abnormal depolarization.
• •The final common pathway is low extracellular potassium concentration. This causes a transient membrane depolarization, which inactivates voltage-gated sodium and calcium channels. These channels are no longer capable of generating action potential essential for muscular contraction.

 How is this condition diagnosed?

• •Established family history of HPP often requires no further diagnostic evaluation.
• •If no family history, hypokalemia during an attack and the exclusion of alternative syndromes is sufficient to establish the diagnosis.
• •Serum potassium will normalize between attacks in HPP so evaluation must occur during an attack.

Differential Diagnosis

• •Thyrotoxicosis
• •Andersen syndrome
• •Hyperkalemic periodic paralysis
• •Normokalemic periodic paralysis
• •Myasthenia gravis
• •Secondary hypokalemia unrelated to channelopathy
• •Guillain-Barré syndrome
• •Transverse myelitis
• •Tick paralysis
• •Botulism
• •Barium poisoning
• •Metabolic myopathy

Workup

Serum potassium levels establish the diagnosis and guide treatment of Hypokalemic Periodic Paralysis.

Laboratory Tests

• •Mean serum potassium level during attacks has been reported as 2.4 mmol/L.
• •T3, T4, TSH levels to exclude thyrotoxic periodic paralysis resulting from hyperthyroidism.
• •Rule out secondary causes of hypokalemia (thyrotoxicosis, diuretic use, vomiting, diarrhea, hyperaldosteronism, distal tubular renal acidosis).
• •Serum electrolyte measurement.
• •Genetic testing is available for the majority of common mutations.
• •When genetic testing is negative, provocative testing with ACTH, exercise, or insulin and glucose are high-risk options for evaluation.

Other Tests

• •Electrocardiogram (ECG) must be performed to evaluate for prolonged QT or QU interval which would be suggestive of Andersen syndrome.
• •During an HPP attack, ECG may demonstrate signs of hypokalemia including ST depression, T wave depression, increased U wave. Arrhythmias are uncommon with HPP but have been reported.
• •Electromyography may help distinguish the etiology of hypokalemia during an attack.

Acute General Treatment

• •Oral potassium chloride: 1 mEq/kg up to 200 mEq every 24 hours until relief of symptoms. Avoid slow release formulation.
• •Hypokalemia must be confirmed prior to therapy as hyperkalemia can also cause periodic paralysis
• •Treatment may lead to hyperkalemia as potassium moves back out of cells so potassium levels and ECG should be monitored for 24 hours.

Chronic Treatment

• •Avoidance of potassium-lowering pharmaceuticals, high-carbohydrate foods, bicarbonate and potassium-lowering diuretics, and strenuous physical exercise has been demonstrated to prevent attacks.
• •Nonpharmacologic treatments include a low sodium and carbohydrate diet and avoiding hyperosmolar states (dehydration, hyperglycemia).
• •Some patients may need potassium supplements, potassium-sparing diuretics, and carbonic anhydrase inhibitors chronically to maintain sufficient serum potassium levels to prevent attacks.
• •Carbonic anhydrase inhibitors, specifically acetazolamide and dichlorphenamide, have shown utility in relieving symptoms. However, there is potential for exacerbating hypokalemic attack in patients with diabetes via intracellular potassium shift.

Disposition

• •Patients treated with oral potassium are at risk for hyperkalemia following an attack as intracellular potassium redistributes into the extracellular space. Potassium levels may require intermittent monitoring for 24 hours after treatment.
• •Patients with new-onset hypokalemia or suspected new-onset HPP may be admitted for further diagnostic workup.

Pearls & Considerations

Serum potassium levels reflect extracellular potassium, which is only 2% of total body potassium stores. Low serum potassium levels during an attack typically represent intracellular shift rather than total-body depletion.

Patient & Family Education

NIH: https://rarediseases.info.nih.gov/diseases/6729/hypokalemic-periodic-paralysis

Seek Additional Information

• Statland J.M., et al.: Review of the diagnosis and treatment of periodic paralysis. Muscle Nerve 2018; 57 (4): pp. 522-530.
• Sung C.C., et al.: Etiologic and therapeutic analysis in patients with hypokalemic nonperiodic paralysis. Am J Med 2015; 128: pp. 289-296.