Continuing Education Activity

Hyperkalemic periodic paralysis is a rare condition presenting as temporary periods of severe muscle weakness or paralysis. To treat this condition appropriately, it is important for clinicians to diagnosis this condition in a timely fashion and provides the patient with the appropriate care and referrals. This activity reviews the evaluation and treatment of hyperkalemic periodic paralysis and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the presentation of a patient with hyperkalemic periodic paralysis.
• Explain the pathophysiology of hyperkalemic periodic paralysis.
• Outline the management considerations for patients with hyperkalemic periodic paralysis.

Introduction

Periodic paralysis is a group of inherited diseases that present as episodic muscle weakness and paralysis. Hyperkalemic Periodic Paralysis (HYPP, HyperKPP) is a rare condition that begins in childhood and can continue until middle adulthood or may even last into late adulthood. It presents as muscle weakness, ranging from mild weakness to paralysis. During these episodes, it is common to have higher than normal blood levels of potassium.[1] [Level 5]

The condition is caused by a mutation in the SCN4A gene that codes for voltage-gated sodium channel Na1.4. Several diagnostic modalities exist in assisting diagnosis, such as genetic testing, although they are not always definitive. Treatment for HYPP is both proactive and reactive, with avoidance of triggers being the mainstay of therapy. It is important to diagnosis this condition quickly and accurately as long-term complications, including weakness and fatigue, can lead to a decrease in the quality of life.

Etiology

Hyperkalemic periodic paralysis is caused by a point mutation in the SCN4A gene.[2] [Level 5] This gene encodes proteins responsible for sodium transport in skeletal muscles.[3] [Level 4]

Epidemiology

There is an estimated prevalence of 1 to 200,000 cases, affecting women and men equally, making this condition quite rare.[4]

Pathophysiology

The SCN4A protein is responsible for the control of sodium influx into skeletal muscles that aid in contraction. Mutant SCN4A protein channels malfunction by allowing too much sodium into skeletal muscles by staying open too long or not staying closed long enough. This additional influx of sodium triggers a release of intracellular potassium from the skeletal muscles. Subsequently, this change in ion transport impairs a muscle's ability to contract, leading to weakness or paralysis.[3]

History and Physical

Patients typically present in the first or second decade of life with intermittent bouts of weakness or paralysis in the hips, shoulders, and back triggered by diet, stress, or exercise. Attacks are generally intermittent and last 15 minutes to 1 hour. Affected individuals may also present with paratonia (muscle stiffness or inability to relax muscles). Approximately 50% of affected individuals will present with weakness or paralysis before age 10. The attacks initially are uncommon; however, they increase in intensity and frequency until the fifth decade of life, at which point there is a steep decline. Common triggers are potassium-rich foods, a cold environment, and rest after physical activity. Attacks may last from 15 minutes to 1 hour. Individuals over 40 years of age commonly report permanent muscle weakness, with a third of individuals developing chronic progressive myopathy.[5] [Level 5]

Evaluation

Diagnosis is initially guided by the clinical presentation of the affected individual. This includes intermittent paralysis and/or paratonia after certain triggers. Diagnosis is based primarily on several criteria, which include a history of transient episodes of weakness, ictal serum potassium levels, electromyography, and exclusion of secondary causes. The proposed diagnostic criteria are as follows: 2 or more attacks of weakness with serum potassium greater than 4.5 mEq/L or 1 attack in the patient with a relative with 1 attack with serum potassium greater than 4.5 mEq/L. 

In addition, 3 of the 6 following clinical or laboratory features can also assist in making a diagnosis: symptom onset before age 30; attacks must last less than 2 hours, identifiable triggers, myotonia, family history, confirmed genetic testing for sodium channel mutation in the SCN4A, or positive McManis short exercise test.[6][Level 4] Additionally, other causes must be excluded.[5]

Historically, provocative tests were utilized to establish a diagnosis. However, due to the risk of inducing severe attacks, they are no longer recommended. Muscle biopsy is not recommended due to the lack of specific findings as well as the lack of influence on management.[7] [Level 5]

Treatment / Management

The treatment approach should include both management of acute attacks and the prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels through diet, diuretics, and carbonic anhydrase inhibitors. Attacks may be treated at the onset of weakness with mild physical activity, oral intake of carbohydrate-rich foods, salbutamol inhalation, or intravenous calcium gluconate.[8] [Level 3]

Individuals may prevent attacks by consuming frequent carbohydrate-rich meals, a thiazide diuretic, or a carbonic anhydrase inhibitor. Individuals should avoid potassium-rich medications and foods, fasting, strenuous work, and exposure to cold to prevent attacks. Surveillance methods include scheduled evaluation of neurologic status. Individuals who develop permanent muscle weakness may require life long thiazide diuretics and interval MRI of proximal leg muscle every 1 to 3 years.

Prophylactic treatment necessitates serum potassium levels twice yearly to avoid diuretic complications and annual evaluation of thyroid function. It is imperative to avoid factors that may precipitate an episode. These include the ingestion of potassium-rich food or medications, prolonged fasting, intense physical activity, cold environment, and depolarizing anesthetic agents that may be used during general anesthesia.[5] [Level 5]

Differential Diagnosis

As hyperkalemic periodic paralysis presents in childhood, adult-onset of clinically similar symptoms suggests other etiology either as Andersen-Tawil syndrome or other acquired hyperkalemic periodic paralysis.[9] [Level 5] Common hereditary disorders that cause hyperkalemia include adrenal insufficiency, recessive infantile hypoaldosteronism, pseudohypoaldosteronism type 1, and pseudohypoaldosteronism type 2. Additionally, any individual may suffer from periodic paralysis secondary to acquired sustained hyperkalemia.[10][11] Moreover, a case of hyperkalemic periodic paralysis associated with multiple sleep-onset REM periods with concomitant daytime sleepiness has been reported in the literature, although the genetic analysis was not conducted.[12] [Level 4]

Prognosis

The possible long-term sequelae confer a poor prognosis for those affected with this condition. Although the episodic frequency classically decreases with age, the literature suggests that only 21% of those affected report this improvement. Of affected individuals, 68% have reported permanent weakness, 82% have reported muscle pain, and up to 89% have reported fatigue.[13] [Level 5]

Complications

Long term complications from hyperkalemic periodic paralysis can range from minimal to severe life long symptoms that can decrease quality of life. They can include pain, fatigue, stiffness, weakness, injuries, and depression.[13] [Level 5] 

Secondary complications are of concern for general anesthesia as commonly used drugs can cause depolarizing effects on the musculature, which can worsen myotonic reactions inducing spasms and stiffness. This can have detrimental effects on respiratory muscles. Glucose infusion, maintenance of normal body temperature, and low serum potassium should be maintained to prevent these complications.[14][15]

Consultations

Consultation with a neurologist who is familiar with the diagnosis and management of hyperkalemic periodic paralysis is advised.

Deterrence and Patient Education

Appropriate evaluation and genetic counseling remain the cornerstone of patient education for individuals with hyperkalemic periodic paralysis and their families. It is relevant to evaluate asymptomatic relatives of affected individuals allowing the appropriate preventative measures to be taken prior to adverse events.[5] [Level 3]

Enhancing Healthcare Team Outcomes

An interdisciplinary team can improve the quality of care and patient outcomes by coordinating efforts to provide comprehensive care. Firstly, it is important that primary care physicians are familiar with the disease presentation and pathogenesis of hyperkalemic periodic paralysis.  Once the correct diagnosis has been made, it is important to provide the correct treatment and preventative measures. It is important to make the patient aware of the different triggers of the condition. A referral to a knowledgeable registered dietician is necessary as a component of preventative measures entails consuming and avoiding certain foods.

A consultation with a geneticist is also necessary to evaluate the risk for future generations or asymptomatic relatives of the affected individual. Lastly, physical activity plays an integral role in the long-term management of potential complications, which may necessitate a visit to a physical therapist.  As evident, for optimal treatment of this condition, it is imperative to have an interdisciplinary approach with shared decision-making and open communication.