What are the types, diagnostic steps, acute treatment, and preventive management for primary periodic paralysis?

Primary Periodic Paralysis: Types, Diagnosis, and Management

Types of Primary Periodic Paralysis

Primary periodic paralyses are hereditary channelopathies caused by mutations in skeletal muscle ion channel genes, presenting as episodic flaccid weakness with distinct subtypes based on serum potassium levels during attacks. 1

Main Subtypes

• Hypokalemic Periodic Paralysis Type 1 (HypoPP1): Caused by mutations in the calcium channel gene CACNA1S, characterized by low serum potassium during attacks 2

• Hypokalemic Periodic Paralysis Type 2 (HypoPP2): Caused by mutations in the sodium channel gene SCN4A, also presenting with hypokalemia during episodes 2

• Hyperkalemic Periodic Paralysis (HyperPP): Associated with SCN4A mutations, presenting with elevated or normal potassium during attacks 1, 3

• Normokalemic Periodic Paralysis (NormoPP): SCN4A mutations causing attacks without significant potassium changes 2

• Andersen-Tawil Syndrome (ATS): Caused by KCNJ2 mutations, distinguished by the triad of periodic paralysis, cardiac arrhythmias (particularly ventricular), and dysmorphic features including skeletal and craniofacial anomalies 2

• Paramyotonia Congenita von Eulenburg: Another SCN4A-related disorder with cold-induced myotonia and weakness 1

Diagnostic Approach

Clinical Evaluation

Look specifically for episodic flaccid weakness affecting one or more limbs, lasting several hours to days, with preserved consciousness and no sensory involvement. 1

• Document attack duration (typically hours to days, not minutes) 1
• Identify specific triggers: vigorous exercise, cold exposure, potassium-rich foods, emotional stress, carbohydrate-rich meals, glucocorticosteroids, insulin, diuretics, or pregnancy 1, 4
• Assess for associated features: myotonia (especially with cold in paramyotonia congenita), cardiac arrhythmias, or dysmorphic features suggesting ATS 2
• Measure serum potassium during an attack to classify the subtype 2

Laboratory and Electrodiagnostic Studies

• Serum potassium during attacks: Critical for subtype classification; measure immediately when weakness occurs 2
• ECG during hypokalemic episodes: Look for U-waves, QRS widening, and arrhythmias 4
• Electromyography (EMG): Shows diffuse myopathic discharge patterns 2
• Muscle biopsy: May reveal tubular aggregates, particularly helpful when diagnosis is uncertain 2

Genetic Testing

• CACNA1S gene: Test for HypoPP1 2
• SCN4A gene: Test for HypoPP2, HyperPP, NormoPP, and paramyotonia congenita 2
• KCNJ2 gene: Test when ATS is suspected (periodic paralysis plus cardiac arrhythmias and/or dysmorphic features) 2
• Genetic testing confirms diagnosis but is not mandatory for treatment initiation 2

Acute Treatment During Attacks

Hypokalemic Periodic Paralysis

Administer potassium supplementation cautiously, using both oral and intravenous routes, while monitoring closely for rebound hyperkalemia due to intracellular potassium sequestration rather than true depletion. 4

• Oral potassium supplementation is preferred initially 4
• Add intravenous potassium if oral route is insufficient or patient cannot swallow 4
• Critical warning: Hypokalemia in periodic paralysis results from intracellular sequestration, not total body depletion; aggressive repletion can cause iatrogenic hyperkalemia within 24 hours 4
• Monitor serum potassium every 2-4 hours during repletion 4
• Expect paralysis to resolve within 24 hours of potassium normalization 4

Hyperkalemic Periodic Paralysis

• Mild exercise may abort early attacks 1
• Ingestion of carbohydrates can help terminate attacks 1
• Calcium gluconate for severe hyperkalemia with cardiac manifestations 1
• Salbutamol (beta-2 agonist) to shift potassium intracellularly 1

Preventive Management

Pharmacological Prevention

Dichlorphenamide (DCP) is the most effective preventive agent for both hypokalemic and hyperkalemic periodic paralysis, significantly reducing attack frequency and severity. 5, 3

• Dichlorphenamide dosing: Start low and titrate based on response; the largest controlled trial demonstrated significant reduction in attack rates (P = 0.02 for HypoPP, P = 0.006 for HyperPP) 5
• In the pivotal trial, 11 of 13 HypoPP patients who showed treatment preference chose DCP over placebo 5
• For HyperPP, 15 of 16 patients preferred DCP over placebo 5

Alternative carbonic anhydrase inhibitors:

• Acetazolamide: Demonstrated improvement in muscle strength in HypoPP patients 3
• Use when dichlorphenamide is unavailable or not tolerated 3

For refractory HypoPP:

• Thiazide diuretics may be beneficial 1
• Potassium-sparing agents should be avoided in HyperPP 1

Non-Pharmacological Prevention

Implement strict trigger avoidance as first-line prevention alongside medication. 1

• Dietary modifications for HypoPP: Avoid high-carbohydrate meals, limit potassium-rich foods if they trigger attacks 1
• Dietary modifications for HyperPP: Avoid potassium-rich foods (bananas, oranges, tomatoes), avoid fasting 1
• Avoid glucocorticosteroids, including illicit use for bodybuilding (documented trigger) 4
• Avoid insulin and diuretics when possible 1
• Prevent vigorous exercise followed by rest; encourage mild continuous activity instead 1
• Avoid cold exposure in paramyotonia congenita 1
• Counsel regarding pregnancy risks and need for close monitoring 1

Special Considerations for Andersen-Tawil Syndrome

• Cardiac monitoring is essential due to risk of ventricular arrhythmias 2
• Patients may develop permanent fixed myopathy over time, requiring long-term strength monitoring 2
• Genetic counseling is particularly important given the multisystem involvement 2

Monitoring and Long-term Management

• Regular follow-up to assess attack frequency and medication efficacy 3
• Periodic ECG monitoring, especially in ATS and during hypokalemic episodes 4
• Patient education about trigger avoidance and early recognition of attacks 1
• Family screening when hereditary forms are identified 2