Hypokalemic Periodic Paralysis– Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- Hypokalemic periodic paralysis (HPP) is a channelopathy characterized by episodic skeletal muscle weakness in the setting of a transient decrease in serum potassium (K) levels (1,2). There are 2 forms:
- Familial hypokalemic periodic paralysis (FHPP), classified as type 1 or type 2 (see Etiology)
- Hypokalemic periodic paralysis with thyrotoxicosis (thyrotoxic hypokalemic periodic paralysis [THPP])
- System(s) affected: Endocrine/Metabolic; Musculoskeletal; Nervous
- Synonym(s): Paroxysmal myoplegia
- Predominant age: Onset of disease in late childhood or adolescence (FHPP), early adulthood (THPP). Onset >35 years of age is extremely rare (1,2).
- Age of onset depends on type of genetic mutation; earlier for type 1 FHPP by an average of 6 years (3).
- Predominant sex: FHPP, Male > Female (3:1) (2); THPPs, Male > Female (20:1)
- THPP typically affects Asian males; rare in Caucasians (4,5)
- 1/100,000 FHPP (estimated) (1,4)
- 4.3–13% of thyrotoxic Asian males develop THPP (5).
- Male (1,2)
- Age <35
- Family history (FHPP)
- Asian (THPP)
- FHPP: Autosomal dominant; incomplete penetrance in females (see Etiology) (1,2)
- THPP: Identifiable mutation in 1/3 of cases in 1 series, sporadic (6)
- See Medication (prevention of attacks) and Diet.
- FHPP: Genetic counseling; 50% risk of transmitting abnormal gene to offspring and 50% chance of affected siblings
- NINDS Familial Periodic Paralyses Information Page: http://www.ninds.nih.gov/disorders/periodic_paralysis/periodic_paralysis.htm
- Exact pathogenesis unknown (1,2,3)
- Microelectrode studies show abnormal depolarization of skeletal muscle membrane (-50–60 mV instead of normal -90 mV) in presence of hypokalemia.
- Depolarization inactivates voltage-gated Na channels, preventing action potential propagation.
- Cardiac and smooth muscles are not directly affected.
- Contractile apparatus is normal.
- Hypokalemia is caused by intracellular K shift; total body K is normal (i.e., hypokalemia not a result of K loss).
- Pathogenesis of FHPP and THPP are likely different, as hyperthyroidism doesn’t worsen FHPP.
- FHPP is caused by 1 of several point mutations in skeletal muscle voltage-gated calcium channels (type 1 FHPP) or sodium channels (type 2 FHPP) (3,7).
- 70% of mutations causing FHPP are in the calcium channel; 10–15% in the sodium channel.
- THPP is associated with a mutation in a voltage-gated potassium channel in 1/3 of cases (6).
Commonly Associated Conditions
THPP: Hyperthyroidism (1,2,4)
- Support by stabilizing ABCs if necessary (1,2)[C].
- Signs and symptoms are mostly neuromuscular (paresis) but can include cardiac (arrhythmias) and endocrine (hyperthyroidism in THPP only) (1,2)[C].
- Episodic attacks of focal or generalized muscle weakness lasting from a few hours to several days (1,2,3)[C]
- Typical attack occurs upon waking from sleep or in the early morning.
- Attacks usually provoked by strenuous exercise the day previous, also high-carbohydrate meals.
- Cold, stress, upper respiratory infections, high Na intake, alcohol, glucocorticoids, diuretics, insulin, or epinephrine may also exacerbate attack.
- Attacks more common in summer and fall (THPP)
- Prodrome of stiff muscles, diffuse aching, fatigue is common (5)
- Myalgias may be present.
- Limb muscle weakness: Lower extremity muscles affected more than upper; proximal muscles affected more than distal (1,2)[C]
- Muscle weakness usually symmetric
- Muscles of the eyes, face, tongue, pharynx, larynx, diaphragm, and sphincters rarely involved
- Hypoactive deep tendon reflexes
- Sensation preserved
- Strength between attacks usually near normal
- After years of attacks, patient may develop persistent proximal weakness.
- Patients with THPP may manifest signs of hyperthyroidism (especially systolic hypertension and tachycardia).
Diagnostic Tests & Interpretation
- Mild hypokalemia: Electrocardiogram (ECG) may show S-T depression, flattened T waves, or presence of U waves (2,4,7)[C].
- Severe hypokalemia: ECG may show peaked P waves, prolonged P-R interval, or widened QRS.
- Electromyography (EMG) done during attack usually shows low postexercise compound motor action potential; pattern may help diagnose type 1 vs type 2 FHPP.
- EMG usually normal between attacks
- Genetic testing (DNA sequencing) to differentiate type 1 from type 2 FHPP (Ca channel vs Na channel mutations)
- Low serum K (as low as 1 mEq/L [1 mmol/L]) is hallmark (1,8)[C]
- Low serum phosphorous also found
- Urine K usually low
- Serum creatine kinase level normal or slightly increased
- Acid-base balance normal
- Urine K/creatinine ratio low (<2)
- Elevated T3, T4, free thyroid index, and decreased thyroid-stimulating hormone (TSH) in THPP; may be only mildly abnormal (5)
- Hypercalciuria and hypophosphaturia are characteristic features of THPP (9)[B].
Thyroid scans using radioiodine (THPP only)
- Provocative testing with 2g/kg (50–100 g) p.o. glucose and 10–20 units SC regular or fast-acting insulin (2)[C]
- If no weakness in 2–3 hours, may repeat with 2–8 g of p.o. Na and 50–100 g p.o. glucose, followed by exercise and/or insulin)
- Monitor closely for insulin-precipitated hypoglycemia.
- Patient should have cardiac monitoring during testing.
- Negative test does not exclude diagnosis.
- Muscle biopsy may show atrophy, vacuoles, or tubular aggregates (vacuolar myopathy) (7)[C].
- Vacuolar myopathy more likely in proximal muscles and more common in FHPP than THPP
- Akinetic epilepsy (1,2,4)
- Andersen-Tawil syndrome (triad of periodic paralysis, ventricular dysthymias, and dysmorphic features)
- Drop attacks
- Episodic ataxia
- Guillain-Barré syndrome
- Hyperkalemic or normokalemic periodic paralysis (adynamia episodica)
- Myasthenia gravis
- Myotonia congenita
- Paramyotonia congenita
- Secondary hypokalemia (laxative or diuretic use, diarrhea, vomiting, renal or adrenal disease, clay ingestion, barium poisoning)
- Sleep paralysis
- Tick paralysis
Support by stabilizing ABCs if necessary.
- Acute attack:
- Goal is normalization of serum potassium
- Oral potassium chloride (KCl): 0.2–0.4 mEq/kg, repeated q15–30 min depending on response of ECG, serum K+, muscle strength (usual total dose: 40 mEq) (2,3)[C]
- In life-threatening situation or if vomiting, give IV KCl in mannitol or normal saline (5% glucose IV may worsen situation). Usual dose: 10–20 mEq/h, with frequent monitoring K and ECG (8,10)[B]. (Watch for rebound hyperkalemia.)
- p.o. or IV propranolol (THPP only); p.o. dose is 3 mg/kg (4,8,11)[C]
- Prevention of attacks in FHPP:
- Oral KCl, 10–20 mEq and titrated to clinic effect (2,3,7)[C]
- Acetazolamide (Diamox): 125–1,000 mg/d divided per day to b.i.d. (type 1 FHPP or Ca-channel mutation only) (1,2,3,7)[B]
- Acetazolamide can be cautiously tried in patients with type 2 FHPP or Na-channel mutation but it may precipitate attack (7)[C].
- Prevention of attacks in thyrotoxic hypokalemic periodic paralysis (4,8,11)[C]:
- Treat underlying thyrotoxicosis with nonselective β-adrenergic blocking agents (propranolol [Inderal] and others). Symptoms do not occur if patient is euthyroid.
- Acetazolamide: Marked hepatic or renal dysfunction, hypersensitivity, adrenal failure, hyperchloremic acidosis, low serum Na, THPP
- Propranolol: Cardiogenic shock, sinus bradycardia, 2nd- or 3rd-degree heart block, congestive heart failure, bronchial asthma, hypersensitivity
- Precautions and adverse reactions:
- Infusion of IV or p.o. KCl must be monitored to avoid potentially fatal hyperkalemia (1,4,8,11)[B].
- Rebound hyperkalemia may occur in patients who receive >90 mEq KCl in 24 hours and in patients with THPP who receive KCl and propranolol (1,4,8,11)[B].
- Acetazolamide may cause fatigue, malaise, metallic taste, diarrhea, and may precipitate or worsen paralysis in patients with type 2 FHPP (1,4)[C].
- Propranolol: Use with caution if impaired hepatic or renal function, Raynaud’s, diabetes mellitus, 2nd- or 3rd-trimester pregnancy
- Possible drug interactions:
- Acetazolamide: High-dose aspirin, amphetamines, methenamine
- Propranolol: Phenothiazines, calcium channel blocker
- Acute attack: None
- Prevention of attacks in FHPP: Spironolactone (Aldactone): 25–200 mg/d (1)[C]; dichlorphenamide is an alternative to acetazolamide (12)
- Prevention of attacks in THPP: Antithyroid medications (propylthiouracil or methimazole), radioactive ablation of thyroid (4,8)[C]
- Mild hypokalemia or weakness: Outpatient K correction with close follow-up
- Severe hypokalemia or weakness: Inpatient K correction with cardiac monitoring
Issues for Referral
THPP: May need thyroid ablation
Paralysis is often precipitated by surgery, and therefore close monitoring is warranted.
May need respiratory support (rarely) and/or cardiac monitoring (usually done)
Severe weakness, hypokalemia with ECG findings, arrhythmias, respiratory compromise, need for IV KCL or propranolol
Only as needed to administer IV KCL in mannitol or normal saline (5% glucose IV may worsen situation) or IV propranolol (see below) (1,4,11)[C]
Resolution of symptoms
As tolerated, mild exercise may help (2,3,7)[C]
- Follow serum K and electrolytes (if on acetazolamide).
- Follow thyroid function tests (if on propranolol or antithyroid drugs).
Avoid high-carbohydrate, high-Na foods (2,3,7)[C].
- Strenuous exercise in combination with high-carbohydrate or high-Na meals may provoke attack.
- Attacks are also provoked by cold, stress, and alcohol.
- Attack frequency usually lessens with age.
- Up to 2/3 of patients develop persistent proximal weakness (3).
- Thyroid ablation resolves attacks (THPP only).
- Cardiac arrhythmias
- Respiratory collapse
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2. Lehmann-Horn F, Rüdel R. Channelopathies: the nondystrophic myotonias and periodic paralyses. Semin Pediatr Neurol. 1996;3:122–39.
3. Venance SL, Cannon SC, Fialho D, et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain. 2006;129:8–17.
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5. Kung AW. Thyrotoxic Periodic Paralysis: A Diagnostic Challenge. J Clin Endocrinol Metab. 2006.
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7. Fontaine B, Fournier E, Sternberg D, et al. Hypokalemic periodic paralysis: a model for a clinical and research approach to a rare disorder. Neurotherapeutics. 2007;4:225–32.
8. Manoukian MA, Foote JA, Crapo LM. Clinical and metabolic features of thyrotoxic periodic paralysis in 24 episodes. Arch Intern Med. 1999;159:601–6.
9. Lin SH, Chu P, Cheng CJ, et al. Early diagnosis of thyrotoxic periodic paralysis: Spot urine calcium to phosphate ratio* Crit Care Med. 2006.
10. Lu KC, Hsu YJ, Chiu JS, et al. Effects of potassium supplementation on the recovery of thyrotoxic periodic paralysis. Am J Emerg Med. 2004;22:544–7.
11. Lin SH, Lin YF. Propranolol rapidly reverses paralysis, hypokalemia, and hypophosphatemia in thyrotoxic periodic paralysis. Am J Kidney Dis. 2001;37:620–3.
12. Tawil R, McDermott MP, Brown R, et al. Randomized trials of dichlorphenamide in the periodic paralyses. Working Group on Periodic Paralysis. Ann Neurol. 2000;47:46–53.
Sansone V, Meola G, Links TP, et al. Treatment for periodic paralysis. Cochrane Database Syst Rev. 2008:CD005045.
See Also (Topic, Algorithm, Electronic Media Element)
Guillain-Barré Syndrome; Hyperthyroidism; Hypokalemia; Myasthenia Gravis
359.3 Periodic paralysis
240093008 hypokalemic periodic paralysis (disorder)
- Hypokalemic periodic paralysis should be suspected when a young, otherwise healthy male presents complaining of weakness on awakening, especially after exercising or eating a high carbohydrate meal, and serum K is low, but he has no vomiting or diarrhea.
- Serum K, ECG, and TSH tests should be done immediately.
- The usual immediate therapy is to cautiously administer oral KCL 10–20 mEq, q15–30 min, with cardiac monitoring and frequent serum K. If TSH is low, add propranolol, 3 mg/kg.