In a patient on several antiepileptic drugs who develops hyponatremia, which drug is most likely responsible and what is the appropriate management?

Hyponatremia in Patients on Multiple Antiepileptic Drugs

Oxcarbazepine and carbamazepine are the most likely culprits for hyponatremia in patients on multiple antiepileptic drugs, with oxcarbazepine carrying the highest risk, followed by carbamazepine, valproate, and levetiracetam. 1, 2

Most Likely Offending Agents

High-Risk Antiepileptic Drugs

• Oxcarbazepine causes clinically significant hyponatremia (sodium <125 mmol/L) in 2.5% of treated patients, typically within the first 3 months of therapy, though it can occur after more than 1 year of treatment. 1

• Carbamazepine has a 9.63-fold increased odds of hospitalization due to hyponatremia when newly initiated (≤90 days), and a 7.97-fold increased risk during ongoing treatment. 2

• Levetiracetam shows a 9.76-fold increased odds of hyponatremia-related hospitalization with newly initiated treatment, though the risk decreases with ongoing use. 2

• Valproate demonstrates a 4.96-fold increased odds of hyponatremia when newly initiated, with moderate risk during ongoing treatment. 2

• Phenytoin carries a 4.83-fold increased odds of hyponatremia with new initiation, though the association is moderate compared to oxcarbazepine and carbamazepine. 2

Lower-Risk Alternatives

• Lamotrigine and gabapentin have the lowest risk of hyponatremia both during initiation and ongoing treatment, making them advantageous alternatives in patients at risk of developing hyponatremia. 2

• Gabapentin shows only a 1.61-fold increased odds with new initiation and an adjusted OR of 0.83 during ongoing treatment, indicating minimal risk. 2

Mechanism of Hyponatremia

• Oxcarbazepine and carbamazepine cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH), leading to water retention and dilutional hyponatremia. 1, 3

• The mechanism involves interference with normal electrolyte balance, with the specific pathway varying by drug but commonly involving inappropriate ADH secretion despite low plasma osmolality. 3, 4

Clinical Presentation and Monitoring

Symptom Recognition

• Acute hyponatremia (<48 hours) presents with delirium, seizures, decerebrate posturing, and cerebral edema with potential uncal herniation. 3

• Chronic hyponatremia (>48 hours) manifests as lethargy, dizziness, weakness, headache, nausea, and confusion, with symptoms often being nonspecific. 3, 5

• Even mild chronic hyponatremia is associated with cognitive impairment, gait disturbances, increased falls (23.8% vs 16.4% in normonatremic patients), and higher fracture rates (23.3% vs 17.3% over 7.4 years). 5

Monitoring Protocol

• Serum sodium levels should be measured during maintenance treatment with oxcarbazepine, particularly if the patient receives other medications known to decrease sodium levels or develops symptoms suggesting hyponatremia (nausea, malaise, headache, lethargy, confusion, increased seizure frequency). 1

• Most patients who developed hyponatremia in clinical trials were asymptomatic but were frequently monitored, and some required dose reduction, discontinuation, or fluid restriction. 1

Management Algorithm

Step 1: Identify the Offending Agent

• Review all antiepileptic medications, prioritizing oxcarbazepine, carbamazepine, levetiracetam, and valproate as the most likely causes based on timing of initiation and known risk profiles. 1, 2

• Consider that newly initiated drugs (≤90 days) have higher odds of causing hyponatremia than ongoing treatments, though oxcarbazepine maintains high risk throughout treatment. 2

Step 2: Assess Severity and Symptomatology

• Classify hyponatremia as mild (130-134 mEq/L), moderate (125-129 mEq/L), or severe (<125 mEq/L) to guide urgency of intervention. 6

• Patients with sodium <125 mEq/L and severe symptoms (delirium, confusion, impaired consciousness, ataxia, seizures) require emergency treatment with 3% hypertonic saline. 6, 5

• For severely symptomatic hyponatremia, administer bolus hypertonic saline to increase serum sodium by 4-6 mEq/L within 1-2 hours, but not exceeding 10 mEq/L in the first 24 hours to avoid osmotic demyelination syndrome. 5

Step 3: Discontinue or Switch the Offending Drug

• Discontinue oxcarbazepine or carbamazepine if identified as the cause, as serum sodium generally normalizes within a few days without additional treatment. 1

• Switch to lamotrigine or gabapentin, which have the lowest risk of hyponatremia during both initiation and ongoing treatment. 2

• Avoid cross-hypersensitivity: approximately 25-30% of patients with hypersensitivity reactions to carbamazepine will experience similar reactions with oxcarbazepine. 1

Step 4: Determine Volume Status and Treat Accordingly

• Categorize patients as hypovolemic, euvolemic, or hypervolemic hyponatremia, as this determines the specific treatment approach. 6, 4

• Hypovolemic hyponatremia is treated with normal saline infusions to restore intravascular volume. 6, 4

• Euvolemic hyponatremia (often SIADH) requires fluid restriction to 1 L/day as first-line treatment, with salt tablets or vaptans for refractory cases. 6, 5

• Hypervolemic hyponatremia is managed by treating the underlying cause (heart failure, cirrhosis) and implementing free water restriction to 1-1.5 L/day. 6, 4

Step 5: Correct Sodium Safely

• The maximum correction rate must not exceed 8 mmol/L in any 24-hour period to prevent osmotic demyelination syndrome, a rare but severe neurological complication that can cause parkinsonism, quadriparesis, or death. 7, 5

• High-risk patients (advanced liver disease, alcoholism, malnutrition, prior encephalopathy) require even more cautious correction at 4-6 mmol/L per day. 7

• Use calculators to guide fluid replacement and avoid overly rapid correction, which occurs in 4.5-28% of patients treated with hypertonic saline. 6, 5

Common Pitfalls and Caveats

Drug Selection Errors

• Failing to recognize that oxcarbazepine has the highest risk of hyponatremia among antiepileptics can lead to continued use of the offending agent. 1, 2

• Assuming all antiepileptics carry equal hyponatremia risk ignores the significantly lower risk profile of lamotrigine and gabapentin. 2

Monitoring Failures

• Not monitoring sodium levels during the first 3 months of oxcarbazepine or carbamazepine therapy misses the highest-risk period for hyponatremia development. 1

• Overlooking mild chronic hyponatremia (130-135 mEq/L) as clinically insignificant ignores its association with falls, fractures, and cognitive impairment. 5

Correction Errors

• Correcting chronic hyponatremia faster than 8 mmol/L in 24 hours risks osmotic demyelination syndrome, which typically manifests 2-7 days after rapid correction with dysarthria, dysphagia, oculomotor dysfunction, and quadriparesis. 7, 5

• Using hypertonic saline in asymptomatic or mildly symptomatic patients when fluid restriction or drug discontinuation would suffice exposes patients to unnecessary risk of overcorrection. 6, 5

Treatment Delays

• Delaying treatment while pursuing a complete diagnostic workup in severely symptomatic patients can lead to cerebral edema and hyponatremic encephalopathy. 6

• Failing to discontinue the offending antiepileptic drug promptly when hyponatremia is identified prolongs the electrolyte disturbance unnecessarily. 1

Special Considerations

• Hyponatremia is associated with longer hospital stays, increased mortality, and is the most common electrolyte disorder, affecting approximately 5% of adults and 35% of hospitalized patients. 3, 5

• The risk of hyponatremia is lower during ongoing treatment compared to newly initiated therapy for most antiepileptics, though oxcarbazepine maintains high risk throughout. 2

• Patients taking multiple medications that decrease sodium levels (diuretics, SSRIs, NSAIDs) require particularly close monitoring when on high-risk antiepileptics. 1, 4