What is the appropriate workup and treatment for a patient presenting with periodic paralysis, considering potential inherited forms and triggers such as diet or exercise?

Workup and Treatment of Periodic Paralysis

For a patient presenting with periodic paralysis, immediately check serum potassium, thyroid function, and obtain a detailed family history, then initiate dichlorphenamide 50 mg twice daily for primary periodic paralysis or treat the underlying cause for secondary forms.

Initial Diagnostic Workup

Essential Laboratory Testing

• Serum potassium level during an attack is the single most critical test to differentiate hypokalemic from hyperkalemic periodic paralysis 1, 2
• Thyroid function tests (TSH, free T4, free T3) must be obtained in all patients, as thyrotoxic periodic paralysis accounts for up to 10% of thyrotoxic patients and is particularly prevalent in Asian or Hispanic males 1
• Comprehensive metabolic panel including electrolytes, bicarbonate, blood urea nitrogen, and creatinine to assess for renal tubular acidosis and other metabolic causes 2
• Arterial blood gas if renal tubular acidosis is suspected based on low bicarbonate 2

Critical History Elements

• Family history is essential, as primary periodic paralysis follows autosomal dominant inheritance with males affected three times more often than females 1, 3
• Timing of attacks: Primary hypokalemic periodic paralysis typically occurs at night after vigorous exercise 1
• Dietary triggers: Consumption of high-carbohydrate foods frequently precipitates attacks in hypokalemic periodic paralysis 3
• Medication history: Certain drugs including dexamethasone-containing combinations can provoke attacks 4
• Duration of symptoms: Primary periodic paralysis typically presents with shorter attack duration (mean 18 hours) compared to secondary forms (mean 60 hours) 2

Distinguishing Primary from Secondary Causes

Primary periodic paralysis (57% of cases) characteristics: 2

• Predominantly young males (mean age 28 years)
• Positive family history in multiple blood relatives 3
• Shorter symptom duration (mean 18 hours)
• Triggered by exercise and high-carbohydrate meals 1, 3

Secondary periodic paralysis (43% of cases) must be excluded: 2

• Thyrotoxicosis (50% of secondary cases) - check TSH, free T4, free T3
• Gastrointestinal losses (20%) - infective diarrhea, Crohn's disease
• Renal tubular acidosis Type I (10%) - check bicarbonate, urine pH
• Primary hyperaldosteronism/Conn's syndrome (10%) - check aldosterone, renin
• Older age at presentation (mean 38.7 years) and longer attack duration (mean 60 hours) suggest secondary causes 2

Advanced Diagnostic Testing

• Muscle biopsy shows characteristic vacuolar myopathy with T-tubule dilation on electron microscopy in primary hypokalemic periodic paralysis, but is rarely necessary for diagnosis 3
• Genetic testing for CACN1AS (calcium channel) or SCN4A (sodium channel) mutations confirms primary periodic paralysis but should not delay treatment 3

Treatment Algorithm

Acute Attack Management

For hypokalemic periodic paralysis attacks:

• Administer oral potassium chloride 40-120 mEq immediately 1
• Monitor cardiac rhythm, as both hypokalemia and rapid potassium replacement can cause arrhythmias 1
• Avoid intravenous glucose, which can worsen hypokalemia by driving potassium intracellularly 4

For hyperkalemic periodic paralysis attacks:

• Administer oral carbohydrates to drive potassium into cells 1
• Avoid potassium supplementation 1

Preventive Pharmacotherapy

Dichlorphenamide is the FDA-approved first-line preventive treatment for both hypokalemic and hyperkalemic periodic paralysis: 5, 6

Dosing regimen:

• Treatment-naïve patients: Start dichlorphenamide 50 mg twice daily 5
• Patients previously on acetazolamide: Use 20% of the acetazolamide dose as the dichlorphenamide dose 5
• Dose adjustment: Reduce for tolerability as needed; mean effective doses are 82-96 mg/day 5
• Time to steady state: 10 days of twice-daily dosing 5

Evidence for dichlorphenamide efficacy:

• In hypokalemic periodic paralysis, dichlorphenamide reduced attacks by 2.2 per week versus placebo (p=0.02), with only 2 patients experiencing acute worsening on dichlorphenamide versus 11 on placebo (p=0.02) 5, 6
• In hyperkalemic periodic paralysis, dichlorphenamide reduced attacks by 2.3-3.9 per week versus placebo (p=0.006-0.08) 5, 6
• No patients on dichlorphenamide withdrew for acute worsening compared to multiple placebo patients 5, 6

Treatment of Secondary Causes

For thyrotoxic periodic paralysis:

• Treat underlying hyperthyroidism definitively with antithyroid medications, radioactive iodine, or thyroidectomy 1
• Attacks resolve once euthyroid state is achieved 1
• Potassium supplementation during acute attacks, but definitive thyroid treatment is curative 1

For other secondary causes:

• Treat underlying condition (Crohn's disease, renal tubular acidosis, Conn's syndrome) 2
• Correct electrolyte abnormalities 2

Critical Pitfalls to Avoid

• Do not misdiagnose as Guillain-Barré Syndrome: Periodic paralysis should be ruled out before initiating GBS therapy, as the flaccid paralysis can be mistaken for GBS 2
• Do not administer glucose-containing IV fluids in hypokalemic periodic paralysis, as this worsens hypokalemia through insulin-mediated potassium shift into cells 4
• Do not overlook thyrotoxicosis: Up to 10% of thyrotoxic patients develop periodic paralysis, particularly Asian or Hispanic males 1
• Do not delay treatment while awaiting genetic testing results, as clinical diagnosis and empiric dichlorphenamide therapy are appropriate 1, 3
• Do not use antiviral monotherapy - this statement applies to Bell's palsy, not periodic paralysis, and the Bell's palsy evidence provided is not relevant to this question 7

Monitoring and Follow-up

• Monitor serum potassium levels regularly during treatment 5
• Assess attack frequency weekly to evaluate treatment response 5, 6
• Screen for carbonic anhydrase inhibitor side effects including paresthesias, metabolic acidosis, and kidney stones 5
• Long-term follow-up is essential, as some patients develop progressive fixed weakness requiring ongoing management 3