• Hypokalemic periodic paralysis (HPP) is a channelopathy characterized by episodic skeletal muscle weakness in the setting of a transient decrease in serum potassium (K) level. 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; Neuromuscular
• 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.
• Age of onset depends on type of genetic mutation; earlier for type 1 FHPP by an average of 6 years (1)
• Predominant sex: FHPP, Male > Female (3:1); THPPs, Male > Female (20:1)
• THPP typically affects Asian males; rare in Caucasians (2,3)

Prevalence

• ∼1/100,000 FHPP (estimated) (2)
• 4.3–13% of thyrotoxic Asian males develop THPP (3).

• Male gender
• Age <35
• Family history (FHPP)
• Asian race (THPP)

Genetics

• FHPP: Autosomal dominant; incomplete penetrance in females (see “Etiology”)
• THPP: Identifiable mutation in 1/3 of cases in 1 series, sporadic (4)

• See “Medication” (prevention of attacks) and “Diet.”
• FHPP: Genetic counseling; 50% risk of transmitting abnormal gene to offspring and 50% chance of affected siblings
• National Institute of Neurological Disorders and Stroke (NINDS) Familial Periodic Paralyses Information Page: http://www.ninds.nih.gov/disorders/periodic_paralysis/periodic_paralysis.h...

• 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.
• New research suggests that “gating pore current” combined with a reduction in K_ir is sufficient to explain the pathologic muscle membrane depolarization observed in paralytic attacks of HPP (5,6).
• 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).

• FHPP type 1 is caused by mutations in skeletal muscle voltage-gated calcium channel genes. FHPP type 2 is caused by mutations in sodium channel genes (1,7).
• The most common mutations identified in about 60–70% of patients with FHPP are in the calcium channel gene (CACNA1S); 10–15% are in the sodium channel gene (SCN4A).
• THPP is associated with a mutation in a voltage-gated potassium channel gene (Kir2.6) in 1/3 of cases (4).

THPP: Hyperthyroidism (2)

Signs and symptoms are mostly neuromuscular (paresis), but on rare occasions can also include cardiac (arrhythmias) and endocrine (hyperthyroidism in THPP only).

• Episodic attacks of focal or generalized muscle weakness lasting from a few hours to several days
• Typical attacks occur upon waking up from sleep or in the early morning.
• Attacks are usually provoked by strenuous exercise or high-carbohydrate meals, often several hours later or the next morning.
• Cold, stress, upper respiratory infections, high Na intake, alcohol, glucocorticoids, diuretics, insulin, or epinephrine may also exacerbate attacks
• Attacks are more common in summer and fall (THPP).
• Prodrome of stiff muscles, diffuse aching, and fatigue is common (3).
• Myalgias may be present.

• Limb muscle weakness: Lower extremity muscles are affected more than upper; proximal muscles are affected more than distal.
• Muscle weakness is usually symmetric.
• Muscles of the eyes, face, tongue, pharynx, larynx, diaphragm, and sphincters are rarely involved.
• Deep tendon reflexes may be hypoactive.
• Sensation is preserved.
• Strength between attacks is usually near normal.
• After years of attacks, persistent proximal weakness may be present.
• Patients with THPP may manifest signs of hyperthyroidism (especially systolic hypertension and tachycardia).

• Mild hypokalemia: ECG may show S-T depression, flattened T waves, or presence of U waves.
• 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 is usually normal between attacks.
• Genetic testing (DNA sequencing) helps to differentiate type 1 from type 2 FHPP (Ca-channel vs. Na-channel mutations).

Lab

• Low serum potassium (as low as 1 mEq/L [1 mmol/L]) is a hallmark.
• Urine potassium is usually low as well.
• Serum phosphorous may be low.
• Serum creatine kinase level is normal or slightly increased.
• Acid–base balance is normal.
• Urine K/creatinine ratio is low (<2).
• T₃, T₄, free thyroid index are elevated, and thyroid-stimulating hormone (TSH) is decreased in THPP; may be only mildly abnormal (3).
• Hypercalciuria and hypophosphaturia are characteristic features of THPP.

Imaging Thyroid scans using radioiodine (THPP only)

Diagnostic Procedures/Other

• During an acute attack, serum potassium level needs to be checked, both for diagnosis and to guide treatment.
• When high clinical suspicion but negative genetic testing, provocative testing can be done with 2 g/kg (50–100 g) PO glucose and/or 10 units SC regular or fast-acting insulin.
• Monitor closely for insulin-precipitated hypoglycemia.
• Patient should have cardiac monitoring during testing.
• Provocative testing with glucose and insulin can be risky. Safer alternative for diagnosis is monitoring for weakness and hypokalemia after exercise (30 minutes on a treadmill) or ACTH administration (80–100 IU IM).
• EMG may help confirm the diagnosis or discriminate between types of periodic paralysis.
• Negative tests do not exclude the diagnosis.

Pathological Findings

• Muscle biopsy may show atrophy, vacuoles, or tubular aggregates (vacuolar myopathy) (7)[C].
• Vacuolar myopathy is more likely in proximal muscles and is more common in FHPP than THPP.

• Andersen-Tawil syndrome (triad of periodic paralysis, ventricular dysthymias, and dysmorphic features)
• Hyperkalemic or normokalemic periodic paralysis (adynamia episodica)
• Secondary hypokalemia (laxative or diuretic use, diarrhea, vomiting, renal or adrenal disease, clay ingestion, barium poisoning)
• Myasthenia gravis
• Guillain-Barré syndrome
• Tick paralysis
• Akinetic epilepsy
• Cataplexy
• Drop attacks
• Episodic ataxia
• Hyperventilation
• Myotonia congenita
• Paramyotonia congenita
• Presyncope
• Sleep paralysis

Support by stabilizing airway, breathing, circulation (ABCs) if necessary. Hypokalemia must be confirmed prior to treatment.

First Line Acute attack:

• Goal is normalization of serum potassium
• Oral potassium chloride (KCl): 0.2–0.4 mEq/kg (up to 30 mEq), repeated q30min depending on response of ECG, serum K+, muscle strength (1)[C]
• In life-threatening situations can give 10–20 mEq/h IV KCL (not in dextrose solution); frequent ECG and potassium monitoring is necessary
• PO or IV propranolol (THPP only); PO dose is 3 mg/kg (2)[C]

Second Line

• Prevention of attacks in FHPP:
  • Acetazolamide: Usual dose 250 mg b.i.d. (type 1 FHPP or Ca-channel mutation only) (1,7)[B]. Acetazolamide can be cautiously tried in patients with type 2 FHPP or Na-channel mutation but it may precipitate attack (7)[C]
  • Dichlorphenamide: 50 mg b.i.d. is an alternative to acetazolamide
  • Spironolactone: 100 mg daily as a supplement to carbonic anhydrase inhibitor, or as an alternative
• Prevention of attacks in thyrotoxic hypokalemic periodic paralysis (2)[C]:
  • Antithyroid medications (propylthiouracil or methimazole), radioactive ablation of thyroid (2)[C]
  • Treat underlying thyrotoxicosis with nonselective β-adrenergic blocking agent (propranolol and others). Symptoms do not occur if patient is euthyroid.
• Contraindications:
  • Acetazolamide: Marked hepatic or renal dysfunction, hypersensitivity, adrenal failure, hyperchloremic acidosis, low serum Na, THPP
  • Propranolol: Cardiogenic shock, sinus bradycardia, second- or third-degree heart block, congestive heart failure, bronchial asthma, hypersensitivity
• Precautions and adverse reactions:
  • Infusion of IV or PO KCl must be monitored to avoid potentially fatal hyperkalemia (2)[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 (2)[B].
  • Acetazolamide may cause fatigue, malaise, metallic taste, diarrhea, and may precipitate or worsen paralysis in patients with type 2 FHPP (2)[C].
  • Propranolol: Use with caution if impaired hepatic or renal function, Raynaud’s, diabetes mellitus, second- or third-trimester pregnancy
• Possible drug interactions:
  • Acetazolamide: High-dose aspirin, amphetamines, methenamine
  • Propranolol: Phenothiazines, calcium channel blocker

General Measures

• Mild hypokalemia or weakness: Outpatient K correction with close follow-up
• Severe hypokalemia or weakness: Inpatient K correction with cardiac monitoring

Issue for Referral THPP: May need thyroid ablation

Paralysis is often precipitated by surgery; therefore, close monitoring is warranted.

Initial Stabilization May need respiratory support (rarely) and/or cardiac monitoring (usually done)

Admission Criteria Severe weakness, hypokalemia with ECG findings, arrhythmias, respiratory compromise, need for IV KCl or propranolol

Discharge Criteria Resolution of symptoms

As tolerated, mild exercise may help.

Patient Monitoring

• Follow serum K and electrolytes (if on acetazolamide).
• Follow thyroid function tests (if on propranolol or antithyroid drugs).

Avoid high-carbohydrate, high-Na foods (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 (1)[C].
• Thyroid ablation resolves attacks (THPP only).

• Cardiac arrhythmias
• Respiratory collapse

• Lin SH, Chu P, Cheng CJ, et al. Early diagnosis of thyrotoxic periodic paralysis: Spot urine calcium to phosphate ratio. Crit Care Med. 2006;34(12):2984–9.
• Sansone V, Meola G, Links TP, et al. Treatment for periodic paralysis. Cochrane Database Syst Rev. 2008:CD005045.

359.3 Periodic paralysis

G72.3 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 10–30 mEq, q30min, with cardiac monitoring and frequent serum K. If TSH is low, add propranolol, 3 mg/kg.

Kinga K. Tomczak, MD, PhD
Rinat Jonas, MD

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