BASICS
DESCRIPTION
Hypokalemic periodic paralysis is a syndrome characterized by episodes of motor weakness accompanied by low serum potassium levels in between periods of well-being.
EPIDEMIOLOGY
- There are primary and secondary forms. The primary form is genetic and follows an autosomal dominant pattern of inheritance. The secondary forms may complicate a number of medical disorders including, but not limited to, distal renal tubular acidosis, thyrotoxicosis, hyperaldosteronism, nephrotic syndrome, diuretics, laxatives, and medication-induced (theophylline, amphotericin, and steroids).
- Although rare, this is the most common cause of primary periodic paralysis. Prevalence is around 1 in 100,000.
- The primary form usually manifests in the first 2 decades of life and is more common in men than women (displaying incomplete penetrance phenotypes). Late-onset hypokalemic periodic paralysis is usually secondary and is characterized by hypokalemia, which may be persistent in contrast to primary where hypokalemia is periodic.
ETIOLOGY AND PATHOPHYSIOLOGY
Calcium channelopathy impairs muscle depolarization, causing flaccid paralysis. Sodium channelopathies are seen in a smaller subset of patients and cause clinical manifestations by impairing depolarization muscle action potentials.
Genetics
Mutations in genes encoding for calcium (CACNL1A3) and sodium (SCN4A) have been described. Calcium channel mutations are the most common, present in 80% of all primary cases (1).
RISK FACTORS
Attacks are typically triggered by vigorous exercises, stress, and high-carbohydrate meals. Hyperadrenergic drive worsens the hypokalemia by promoting intracellular shift of the K+ ion.
DIAGNOSIS
- The diagnostic criteria for primary paralysis as defined by the European Neuromuscular Centre (ENMC) (2) are as follows:
- Two or more attacks of muscle weakness with documented serum K <3.5 mEq/L
- One attack of muscle weakness in the proband and one attack of weakness in one relative with documented serum K <3.5 mEq/L in at least one attack
- Three of six clinical or laboratory features outlined below
- Onset in the 1st or 2nd decade
- Attack duration (muscle weakness involving one or more limbs) >2 hours
- Positive triggers (high-carbohydrate-rich meal, rest after exercise, stress)
- Improvement with potassium intake
- Positive family history or genetically confirmed skeletal calcium or sodium channel mutation
- Positive McManis exercise test; see section on "Diagnostic Procedures/Other" for details.
- Exclusion of other causes of hypokalemia (renal, adrenal, thyroid dysfunction; renal tubular acidosis; diuretic and laxative abuse)
- Usually, a classic clinical history helps in recognizing the pattern of this disorder. Although a positive family history is helpful in making the diagnosis, the absence of family history does not rule it out (3)[C].
- Recurrent hypokalemic paralysis can cause vacuolar myopathy with permanent weakness, particularly in the large muscles of the upper and lower extremities.
HISTORY
- Episodic attacks of focal or generalized muscle weakness lasting from a few hours to several days
- Typical attacks occur upon waking from sleep or early in the morning.
- Attacks can be provoked by strenuous exercise or high-carbohydrate meals and can occur several hours later or the next morning.
- Cold, stress, upper respiratory infections, high-sodium intake, alcohol, glucocorticoids, diuretics, insulin, or epinephrine may also exacerbate attacks.
- A prodrome of stiff muscles, diffuse myalgia, and fatigue is common.
- Attacks are more common in summer and fall (thyrotoxic hypokalemic periodic paralysis [THPP]).
- Once periodic paralysis is suspected, a thorough history looking for features of secondary causes of recurrent hypokalemia should be obtained before making a diagnosis of primary hypokalemic periodic paralysis.
PHYSICAL EXAM
- Muscle weakness is usually symmetrical and affects lower limbs more than upper and proximal more than distal.
- Muscles of the eyes, face, tongue, pharynx, larynx, diaphragm, and sphincters are rarely involved.
- Deep tendon reflexes are hypoactive.
- Sensation is preserved.
- After years of attacks, persistent proximal weakness may develop.
- Urinary output is decreased during the attack because of intracellular fluid accumulation.
- Patients with THPP may manifest signs of hyperthyroidism (especially systolic hypertension and tachycardia).
- Women with the genetic mutation are less likely to have clinical manifestations than men.
DIFFERENTIAL DIAGNOSIS
- After ruling out secondary causes of hypokalemia and paying close attention to the distribution of muscle weakness, the following may be considered:
- Andersen-Tawil syndrome (triad of periodic paralysis, ventricular dysrhythmias, and dysmorphic features)
- Hyperkalemic or normokalemic periodic paralysis (adynamia episodica)
- Myasthenia gravis
- Lambert-Eaton myasthenic syndrome
- Guillain-Barr © syndrome
- Tick paralysis
- Akinetic epilepsy
- Cataplexy
- Drop attacks
- Episodic ataxia
- Hyperventilation
- Myotonia congenita
- Paramyotonia congenita
- Sleep paralysis
DIAGNOSTIC TESTS & INTERPRETATION
- Mild hypokalemia: ECG may show ST depression, flattened T waves, or presence of U waves.
- Severe hypokalemia: ECG may show peaked P waves, prolonged PR interval, or widened QRS.
- Electromyography (EMG) done during attack usually shows low postexercise compound motor action potential. EMG is usually normal between attacks.
- Genetic testing (DNA sequencing) helps to differentiate type I from type II FHPP (calcium channel vs. sodium channel mutations).
- Urine potassium and the potassium-to-creatinine ratio are low (<2.5). The transtubular potassium gradient also is low (<3). Serum phosphorous may be low.
- Serum creatine kinase level is normal or slightly increased during attacks.
- Acid-base balance is normal.
- In THPP, T3, T4, and free thyroid index are elevated, and thyroid-stimulating hormone is decreased.
- Hypercalciuria and hypophosphaturia are also observed.
Diagnostic Procedures/Other
- During an acute attack, whether primary or secondary, serum potassium level must be checked, both for diagnosis and to guide treatment.
- When clinical suspicion is high but genetic testing is negative, provocative testing can be pursued.
- Provocative testing can be achieved using insulin and glucose (risky, needs cardiac monitoring) or with ACTH or a treadmill test with demonstration of hypokalemia and loss of muscle power.
- EMG during an acute attack shows absent myotonic discharges on needle insertion. Demonstration of decrease in compound muscle action potential with continued exercise is also helpful. This is known as the McManis exercise test.
- Negative tests do not exclude the diagnosis; clinical features can be diagnostic as demonstrated in the ENMC criteria.
- An effort must be made to rule out reversible secondary causes. This includes, but is not limited to, complete medication reconciliation, thyroid studies, checking a BMP and ABG, and if indicated, hormone studies for aldosteronism.
TREATMENT
GENERAL MEASURES
- Reconfirm the low potassium levels. Needs ICU monitoring during correction of the hypokalemia. Management can be divided into acute and chronic stages.
- In acute state-potassium supplementation in a monitored environment after confirming the diagnosis of hypokalemia; oral potassium supplementation 10 to 20 mEq/hr is recommended. Because the pathology involves a shift in potassium ions, one may see a posttreatment hyperkalemia. Incremental administration of potassium is recommended with monitoring of posttreatment potassium levels.
- Of note is the fact that hyperkalemia can also lead to paralysis. Hence, close monitoring of the potassium levels is essential (4,5)[C].
- When intravenous potassium supplements are being used, dextrose-containing intravenous fluids should be avoided as they may worsen hypokalemia by promoting insulin-mediated intracellular potassium shifts.
ISSUES FOR REFERRAL
Often, specialist inputs from nephrology and endocrinology are helpful.
ONGOING CARE
- Chronic management plan involves preventive strategies such as a low-carbohydrate diet and avoiding high-intensity exercises.
- A Cochrane review suggests that although there is still lack of quality evidence, carbonic anhydrase inhibitors may be useful in decreasing the frequency and severity of attacks in the chronic phase (3)[A].
- Potassium-sparing diuretics have been used with some success in primary paralysis (6)[C].
- Bumetanide has been useful for some animal models (7).
- Interestingly, bumetanide has shown effectiveness in decreasing attack frequency in mice but human data is pending.
DIET
A diet low in sodium and carbohydrates and rich in potassium is recommended in preventing future attacks.
COMPLICATIONS
Besides causing morbidity issues temporarily, repeated episodes may cause permanent weakness by causing vacuolar myopathy. If associated with prolonged QTc, it may cause sudden death especially as a part of Andersen-Tawil syndrome.
REFERENCES
11 Fontaine B, Lapie P, Plassart E, et al. Periodic paralysis and voltage-gated ion channels. Kidney Int. 1996;49(1):9-18.22 Sansone V, Meola G, Links TP, et al. Treatment for periodic paralysis. Cochrane Database Syst Rev. 2008;(1):CD005045.33 Kung AW. Clinical review: thyrotoxic periodic paralysis: a diagnostic challenge. J Clin Endocrinol Metab. 2006;91(7):2490-2495.44 Ahlawat SK, Sachdev A. Hypokalaemic paralysis. Postgrad Med J. 1999;75(882):193-197.55 Lin SH. Thyrotoxic periodic paralysis. Mayo Clin Proc. 2005;80(1):99-105.66 Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. 2006;129(Pt 1):8-17.77 Suetterlin K, M ¤nnikk ¶ R, Hanna MG. Muscle channelopathies: recent advances in genetics, pathophysiology and therapy. Curr Opin Neurol. 2014;27(5):583-590.
ADDITIONAL READING
- Finsterer J. Primary periodic paralyses. Acta Neurol Scand. 2008;117(3):145-158.
- Fontaine B, Vale-Santos J, Jurkat-Rott K, et al. Mapping of the hypokalaemic periodic paralysis (HypoPP) locus to chromosome 1q31-32 in three European families. Nat Genet. 1994;6(3):267-272.
- Lin SH, Lin YF, Chen DT, et al. Laboratory tests to determine the cause of hypokalemia and paralysis. Arch Intern Med. 2004;164(14):1561-1566.
CODES
ICD10
G72.3 Periodic paralysis
ICD9
359.3 Periodic paralysis
SNOMED
Familial hypokalemic periodic paralysis (disorder)
CLINICAL PEARLS
- Although hypokalemic periodic paralysis is associated with low potassium levels, it may exist with normal potassium levels.
- Secondary causes are more common than primary, and therefore, a thorough search for reversible causes is mandatory before pursuing invasive testing and genetic studies.
- Cautious correction of potassium levels because rebound hyperkalemia is common and by itself can cause paralysis.