Primary Periodic Paralysis (PPP) Diagnosis and Management

Primary Periodic Paralysis PPP is a complex and challenging condition

Delayed and missed diagnoses

Primary Periodic Paralysis PPP can be difficult to diagnose. While usually inherited, it sometimes presents as a de novo mutation.1
  • Misdiagnosis and delays in diagnosis are common because symptoms:
    • Are often nonspecific and patients have varying clinical presentations1-3
    • Can mimic a variety of more common diseases, from psychiatric conditions to cardiovascular disorders1-3
  • The diagnostic journey from the first symptom until a confirmed diagnosis can take more than 20 years1,3
    • In a survey of 94 patients over age 18 diagnosed with hyperkalemic periodic paralysis, patients reported seeing an average of 4 healthcare professionals; however, some saw as many as 10 before they were finally diagnosed1
  • Patients also reported undergoing a range of diagnostic studies, including blood tests, electromyographies (EMGs), electrocardiograms (ECGs), compound muscle action potentials (CMAP), and genetic testing before their diagnosis was confirmed1,4

PPP: The Diagnostic Journey—A new algorithm for diagnosing PPP

In January 2019, Strongbridge Biopharma sponsored an expert roundtable on PPP. The meeting brought together a group of expert clinicians and researchers specializing in neuromuscular disorders, representing a variety of academic institutions and teaching hospitals across the nation. Their discussion resulted in a protocol that has the potential to shorten the time to diagnosis and improve outcomes for patients impacted by PPP.

Read the Whitepaper

A multidimensional assessment is required

Because Primary Periodic Paralysis PPP is so often difficult to diagnose, multiple levels of evaluation and testing should be included.4,5

Findings that suggest hyperkalemic periodic paralysis4
  • A history of at least 2 attacks of flaccid weakness (limbs, eyes, throat, breathing muscles, trunk)
  • Disease manifestations before 20 years of age
  • A family history; however, absence does not preclude diagnosis
  • Onset or worsening of an attack resulting from oral potassium intake
  • Absence of cardiac arrhythmia between attacks
  • EMG with reduced motor units or silence during attacks
  • CMAP with a greater than normal increase during exercise followed by a progressive decline in amplitude
  • Hyperkalemia with serum potassium >5 mmol/L or an increase of at least 1.5 mmol/L during attacks; normal between attacks
  • Elevated serum creatine kinase (CK) concentration during attacks
Findings that suggest hypokalemic periodic paralysis5
  • A history of episodes of flaccid paralysis with spontaneous recovery
  • A family history consistent with autosomal dominant inheritance
  • Low serum concentration of potassium (<3.5 mmol/L) during attacks, but not between
  • Precipitating factors, such as rest after strenuous exertion or prolonged immobility

Although genetic testing can help confirm a suspected diagnosis, the absence of a genetic alteration does not preclude diagnosis4,5

  • In hyperkalemic periodic paralysis, SCN4A is primarily associated
    • If no pathogenic variant is identified, sequencing of KCNJ2 and CACNA1S may be considered
  • In hypokalemic periodic paralysis, 3 genes have been associated; all encode subunits of ion channels that are primarily expressed in skeletal muscle cells
    • CACNA1S (60% of patients)
    • SCN4A (20% of patients)
    • KCNJ18 (3.5% of patients)

Management strategies for Primary Periodic Paralysis PPP

Considerations in hyperkalemic periodic paralysis4
Treatment of attacks
Attacks may be minimized with:
  • Mild exercise and/or oral ingestion of carbohydrates, inhalation of salbutamol, or intravenous calcium gluconate
Managing attacks (medical and non-medical approaches)
Attacks may be managed by:
  • Prescribing medications such as KEVEYIS
  • Eating meals rich in carbohydrates
  • Avoiding potassium-rich medications and foods, fasting, strenuous work, and exposure to cold
Prevention of secondary complications
Depolarizing anesthetic agents should be avoided during surgery
  • These include potassium, suxamethonium, and anticholinesterases
  • These may aggravate myotonia and can interfere with intubation and mechanical ventilation
Considerations in hypokalemic periodic paralysis5
Treatment of attacks
Attack intensity and duration may be managed by:
  • Taking oral potassium salts as needed for mild-to-moderate attacks
  • Intensive management for severe attacks (intravenous potassium infusion, serial measurement of serum potassium concentration, evaluation of possible respiratory involvement, and continuous ECG monitoring)
Managing attacks (medical and non-medical approaches)
Attacks may be managed by:
  • Prescribing medications such as KEVEYIS
  • Counseling patients to avoid triggers; follow a low-sodium, low-carbohydrate, high-potassium diet; and take oral potassium supplementation
Prevention of secondary complications
Complications can be avoided by:
  • Creating a safe home environment to prevent falls and accidents
  • Taking steps to prevent anesthetic complications (ie, malignant hyperthermia)
Strongbridge is now partnering with Invitae to offer no-cost genetic testing to appropriate patients. Learn more.



KEVEYIS is indicated for the treatment of primary hyperkalemic periodic paralysis, primary hypokalemic periodic paralysis, and related variants.

Important Safety Information

  • Hypersensitivity to dichlorphenamide or other sulfonamides
  • Concomitant use of KEVEYIS and high-dose aspirin
  • Severe pulmonary disease, limiting compensation to metabolic acidosis caused by KEVEYIS
  • Hepatic insufficiency: KEVEYIS may aggravate hepatic encephalopathy
Warnings and Precautions

Hypersensitivity and Other Life-Threatening Reactions

  • Fatalities associated with the administration of sulfonamides have occurred because of adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.
  • Pulmonary involvement can occur in isolation or as part of a systemic reaction.
  • Discontinue KEVEYIS at the first appearance of skin rash or any sign of immune-mediated or other life-threatening adverse reaction.

Concomitant Use of Aspirin or Other Salicylates

  • Carbonic anhydrous inhibitors, including KEVEYIS, can cause metabolic acidosis, which can increase the risk of salicylate toxicity.
  • Anorexia, tachypnea, lethargy, and coma have been reported with concomitant use of dichlorphenamide and high-dose aspirin.
  • Concomitant use of KEVEYIS and high-dose aspirin is contraindicated. Use with caution and carefully monitor in patients receiving low-dose aspirin.


  • KEVEYIS increases potassium excretion and can cause hypokalemia.
  • The risk of hypokalemia is greater when KEVEYIS is used in patients with conditions associated with hypokalemia (e.g., adrenocortical excess, renal tubular acidosis type 1 and 2), and in patients receiving other drugs that may cause hypokalemia (e.g., loop diuretics, thiazide diuretics, laxatives, antifungals, penicillin, and theophylline).
  • Baseline and periodic measurements of serum potassium are recommended.
  • If hypokalemia develops or persists, consider reducing the dose or discontinuing KEVEYIS and correction of potassium levels.

Metabolic Acidosis

  • KEVEYIS can cause hyperchloremic non-anion gap metabolic acidosis.
  • Concomitant use of KEVEYIS with other drugs that cause metabolic acidosis may increase the severity of acidosis.
  • Concomitant use of KEVEYIS in compensated patients with respiratory acidosis, such as in advanced lung diseases, may lead to respiratory decompensation.
  • Baseline and periodic measurements of serum bicarbonate during KEVEYIS treatment are recommended.
  • If metabolic acidosis develops or persists, consider reducing the dose or discontinuing KEVEYIS.


  • KEVEYIS increases the risk of falls; risk is greater in the elderly and with higher doses.
  • Consider dose reduction or discontinuation of KEVEYIS in patients who experience falls while treated with KEVEYIS.
Pregnancy and Lactation

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is not known in humans whether dichlorphenamide is excreted in human milk; exercise caution when administered to a nursing woman.

Adverse Reactions

The most common adverse reactions seen in clinical trials (incidence ≥ 10% and greater than placebo) include paresthesias, cognitive disorder, dysgeusia, and confusional state.


  1. Charles G, Zheng C, Lehmann-Horn F, Jurkat-Rott K, Levitt J. Characterization of hyperkalemic periodic paralysis: a survey of genetically diagnosed individuals. J Neurol. 2013;260:2606-2613.
  2. Arya SN. Periodic paralysis. Journal, Indian Academy of Clinical Medicine. 2002;3:374-382.
  3. Cavel-Greant D, Lehmann-Horn F, Jurkat-Rott K. The impact of permanent muscle weakness on quality of life in periodic paralysis: a survey of 66 patients. Acta Myol. 2012;31:126–133.
  4. Weber F, Jurkat-Rott K, Lehmann-Horn F. Hyperkalemic Periodic Paralysis. NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. 2016.
  5. Vicart S, Sternberg D, Arzel-Hezode M, et al. Hypokalemic Periodic Paralysis. NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health. 2014.