Medical Care
Treatment is often necessary for acute attacks of hypokalemic periodic paralysis but seldom for hyperkalemic periodic paralysis. Prophylactic treatment is necessary when the attacks are frequent.
Dichlorphenamide, a carbonic anhydrase inhibitor, was approved by the FDA in August 2015 for the management of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants. Approval was based on 2 randomized, double-blinded placebo-controlled studies that included 138 patients. Treatment with dichlorphenamide resulted in significantly fewer muscle weakness attacks/week compared with placebo (2.3 to 3.9 fewer attacks/week with hyperkalemic periodic paralysis; 2.2 fewer attacks/week with hypokalemic periodic paralysis). [16]
Hypokalemic periodic paralyses
During attacks, oral potassium supplementation is preferable to IV supplementation. The latter is reserved for patients who are nauseated or unable to swallow. Potassium chloride is the preferred agent for an acute attack (assuming a normal renal function). [17] A reasonable initial dose for a 60-120 kg man (ie, 0.5-1 mEq/kg) is 60 mEq. Typically, 40-60 mEq of K+ raises the potassium concentration by 1.0-1.5 mEq/L, and 135-160 mEq of K+ raises plasma potassium by 2.5-3.5 mEq/L. Aqueous potassium is favored for quicker results. If there is no response in 30 minutes, an additional 0.3 mEq/kg may be given. This should be repeated up to 100 mEq of potassium. Beyond this, monitoring of serum potassium is warranted prior to further supplementation. Typically, one should not exceed a total dose of 200 mEq in a day.
Intravenous potassium is reserved for cardiac arrhythmia or airway compromise due to ictal dysphagia or accessory respiratory muscle paralysis. IV potassium chloride 0.05-0.1 mEq/kg body weight in 5% mannitol as a bolus is preferable to continuous infusion. Mannitol should be used as solvent, as both sodium and dextrose worsen the attack. Only 10 mEq at a time should be infused with intervals of 20-60 minutes, unless in situations of cardiac arrhythmia or respiratory compromise. This is to avoid hyperkalemia at the end of an attack with shift of potassium from intracellular compartment into the blood. Continuous ECG monitoring and sequential serum potassium measurements are mandatory.
For prophylaxis, dichlorphenamide 50-100 mg BID may be considered for the management of primary hypokalemic periodic paralysis. Acetazolamide is an off-label alternative that is administered at a dose of 125-1500 mg/d in divided doses. 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. Spironolactone may cause gynecomastia, but this is less with eplerenone. Blood pressure monitoring is advised. Because these diuretics are potassium sparing, potassium supplements may not be necessary.
Approximately 50% of genotyped patients with HypoPP respond to acetazolamide. Poor response is predicted with substitution of arginine with smaller glycine in the residues of voltage sensors near the extracellular side of the sarcolemma. Almost 60% of patients with common CACNA1S mutations show favorable response to acetazolamide, whereas only 16% of patients with SCN4A mutations benefited from acetazolamide. In both cohorts, this poor response is predicted with substitution of arginine with smaller glycine in the residues of the voltage sensor near the extracellular side of the sarcolemma. [18]
Thyrotoxic periodic paralysis
Treatment consists of controlling thyrotoxicosis and beta-blocking agents. Potassium supplementation, dichlorphenamide, propranolol, and spironolactone may be helpful during the attacks as well as for prophylaxis. Dichlorphenamide 50-100 mg BID or propranolol in doses of 20-40 mg twice a day may be sufficient to control recurrent attacks of periodic paralysis.
Hyperkalemic periodic paralyses
Fortunately, attacks are usually mild and rarely require treatment. Weakness promptly responds to high-carbohydrate foods. Beta-adrenergic stimulants, such as inhaled salbutamol, also improve the weakness (but are contraindicated in patients with cardiac arrhythmias).
In severe attacks, therapeutic measures that reduce hyperkalemia are utilized. Continuous ECG monitoring is always needed during the treatment. Dichlorphenamide 50-100 mg BID is indicated for hyperkalemic periodic paralysis. Thiazide diuretics and carbonic anhydrase inhibitors are used as prophylaxis. Thiazide diuretics have few short-term side effects; they are tried as first-line treatment. Occasionally, thiazide diuretics may result in paradoxical hypokalemic weakness, which responds to potassium supplementation.
Paramyotonia congenita
Because weakness is uncommon, treatment is aimed at reducing myotonia. While the above-mentioned diuretics can be tried, they are often not effective. Mexiletine has been shown to be helpful but is contraindicated in patients with heart block.
Potassium-associated myotonia
Treatment with mexiletine or a thiazide diuretic may reduce the severity of the myotonia.
Andersen-Tawil syndrome
A combination of amiodarone and acetazolamide resulted in a long-lasting improvement in one study. [19]
Implantation of a cardiac defibrillator has rarely been performed.
Carbonic anhydrase inhibitors are used for preventing periodic paralysis.
Potassium supplementation prevents periodic paralysis and also reduces cardiac arrhythmia, shortening the QT interval.
For the control of cardiac symptoms, β-blockers or calcium channel blockers may be used.
Flecainide has been shown to be successful in treating bidirectional ventricular tachycardia, ventricular ectopy, and tachycardia-induced cardiomyopathy. [20]
Surgical Care
Malignant hyperthermia susceptibility has been noted in HypoPP with calcium channel mutations. It is prudent to monitor all patients with periodic paralysis for this complication.
Diet
See the list below:
-
Hypokalemic periodic paralyses: Low-carbohydrate and low-sodium diet may decrease the frequency of attacks.
-
Hyperkalemic periodic paralyses: Glucose-containing candy or carbohydrate diet with low potassium may improve the weakness.
-
Mutations in periodic paralysis.
Tables
- Table 1. Primary Periodic Paralysis (modified from Jurkat-Rott and Lehmann-Horn [1] )
- Table 2. Distinguishing Features Among the Common Forms of Periodic Paralyses
- Table 3. Differential Diagnosis of Secondary Periodic Paralyses
- Table 4. Differential Diagnosis of Other Entities Causing Acute Generalized Weakness
- Table 5. Medical Conditions Associated With Hypokalemia
- Table 6. Diagnostic Studies of Hypokalemic and Hyperkalemic Periodic Paralyses
- Table 7. Electrophysiological Patterns to Exercise Testing
Disease |
Gene |
Protein |
Inheritance |
Mutation |
HyperPP |
SCN4A |
Nav1.4 |
Dominant |
Gain |
NormoPP |
|
|
|
Gain (ω-pore) |
Paramyotoniacongenita |
Gain |
|||
HypoPP Type II |
Gain (ω-pore) |
|||
HypoPP Type I |
CACNA1S |
Cav1.1 |
Dominant |
Gain (ω-pore) |
ThyrotoxicPP |
KCNJ18 |
Kir2.18 |
Dominant |
Loss |
Andersen-Tawil syndrome |
KCNJ2 |
Kir2.1 |
Dominant |
Loss |
Syndrome |
Age of Onset |
Duration of Attack |
Precipitating Factors |
Severity of Attacks |
Associated Features |
Hyper-kalemic periodic paralyses |
First decade of life |
Few minutes to less than 2 h (mostly less than 1 h) |
Low carbohydrate intake (fasting) Cold Rest following exercise Alcohol Infection Emotional stress Trauma Menstrual period |
Rarely severe |
Perioral and limb paresthesias Myotonia frequent Occasional pseudo-hypertrophy of muscles |
Hypo-kalemic periodic paralyses |
Variable -Childhood to third decade Majority of cases before 16 years |
Few hours to almost a week Typically no longer than 72 h |
Early morning attacks after previous day physical activity High-carbohydrate meal, Chinese food, alcohol Cold, change in barometric pressure or humidity Fever, upper respiratory tract infections Lack of sleep, fatigue Menstrual cycle |
Severe Complete paralysis |
Occasional myotonic lid lag Myotonia between attacks rare Unilateral, partial, monomelic Fixed muscle weakness late in disease |
Potassium- associated myotonia |
First decade |
No weakness |
Cold Rest after exercise |
Attacks of stiffness can be mild to severe |
Muscle hypertrophy |
Para-myotonia congenita |
First decade |
2-24 h |
Cold |
Rarely severe |
Pseudo-hypertrophy of muscles Paradoxical myotonia Fixed weakness rare |
Thyrotoxic periodic paralyses |
Third and fourth decades |
Few hours to 7 d |
Same as hypokalemic PP Hyper-insulinemia |
Same as hypokalemic PP |
Fixed muscle weakness may develop Hypokalemia during attacks |
Hypokalemic |
Hyperkalemic |
Urinary potassium-wasting syndromes
|
|
Alcohol |
Addison disease Chronic renal failure Hyporeninemic Hypoaldosteronism |
Drugs - Amphotericin B, barium |
Ileostomy with tight stoma |
Renal tubular acidosis |
Potassium load |
GI potassium-wasting syndromes
|
Potassium-sparing diuretics |
Disorder |
Pattern and Distribution of Weakness |
Transient ischemic attacks |
Follow CNS distribution (ie, hemiparetic) May have sensory symptoms and signs |
Sleep attacks |
Occur at onset or termination of sleep Last only minutes |
Myelopathy
|
Sensory symptoms Presence of a sensory level Sphincter involvement |
Myasthenia gravis Lambert-Eaton myasthenic syndrome |
Subacute in onset Associated autonomic symptoms in LEMS Hyporeflexia in LEMS Abnormal repetitive nerve stimulation Presence of distinct antibodies |
Peripheral neuropathy of acute onset
|
Pattern of weakness Absent stretch reflexes |
Toxins
|
Clinical presentation |
Urine K/C Ratio |
Acid Base Status |
Other Associated Features |
Medical Conditions |
< 1.5 |
Metabolic acidosis |
|
Lower GI loss – Laxative abuse, diarrhea |
< 1.5 |
Metabolic alkalosis |
Normal BP |
Surreptitious vomiting |
>1.5 |
Metabolic acidosis |
|
DKA, type 1 or type 2 distal RTA |
>1.5 |
Metabolic alkalosis |
Normal BP |
Diuretic use, Bartter syndrome, Gitelman syndrome |
≥1.5 |
Metabolic alkalosis |
Hypertension |
Primary aldosteronism, Cushing syndrome, renal artery stenosis, congenital adrenal hyperplasia, apparent mineralocorticoid excess, Liddle syndrome |
|
Hypokalemic PP |
Hyperkalemic PP |
Serum potassium |
Mildly depressed; may reach 1-5 mEq/L |
Increases from baseline but may not increase beyond normal range |
Serum CPK |
Moderately elevated during attacks |
Mildly elevated during attacks |
ECG |
Bradycardia Flat T waves, U waves, ST-segment depression |
Tall T waves |
|
Para- myotonia Congenita |
Hyper- kalemic Periodic Paralysis |
Hypo- kalemic Periodic Paralysis |
Electrophysiological pattern |
I |
IV |
V |
Channel mutations |
Sodium T1313M, R1448C |
Sodium T704M |
Calcium R528H |
Short Exercise Test: |
|
|
|
Post exercise myotonic potentials |
Yes |
No |
No |
CMAP amplitude change after First trial |
Increase or decrease |
Increase |
No |
CMAP amplitude change after second and third trial |
Gradual increase |
Gradual increase |
No |
Long Exercise Test: |
|
|
|
Immediate change of CMAP amplitude |
Decrease |
Increase |
No |
Late change of CMAP amplitude |
Decrease |
Decrease |
Decrease |
Modified from Fournier et al, 2004. [15] |
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