What labs or diagnostics should be ordered for a patient with a history of seizures, currently taking Phenytoin (phenytoin sodium), who presented to the ER with increased seizure activity, and has a history of smoking and hyperlipidemia?

Laboratory and Diagnostic Workup for Seizure Patient on Phenytoin

Immediate Priority: Phenytoin Level Monitoring

You must order a serum phenytoin level immediately – this is the single most critical test given the patient's breakthrough seizures (6 in 2 days) while on phenytoin therapy 1. Phenytoin serum level determinations are necessary to achieve optimal dosage adjustments, particularly when therapeutic failure is suspected 1.

Why Phenytoin Level is Essential

• Therapeutic range is typically 10-20 mg/L (40-80 μmol/L), though some patients require higher levels for seizure control 2, 3
• Subtherapeutic levels are the most common cause of breakthrough seizures in compliant patients 1
• The patient may be a slow metabolizer (genetically determined) requiring dose adjustment 1
• Smoking status matters: chronic substance use can affect phenytoin metabolism 1

Additional Required Laboratory Tests

Complete Blood Count (CBC) with Differential

• Phenytoin can cause blood dyscrasias including leukopenia, thrombocytopenia, and agranulocytosis 4
• Rapid changes in hematological parameters have been documented with phenytoin therapy 4
• This is particularly important given the acute increase in seizure frequency 4

Comprehensive Metabolic Panel (CMP)

• Liver function tests (AST, ALT, alkaline phosphatase): The liver is the chief site of phenytoin biotransformation; impaired liver function shows early toxicity signs 1
• Serum glucose: Phenytoin inhibits insulin release and can cause hyperglycemia 1
• Electrolytes (sodium, calcium, phosphate): Hypoglycemia and other metabolic causes must be ruled out as seizure triggers 1
• Phenytoin increases metabolism of Vitamin D3, leading to hypocalcemia and hypophosphatemia 1

Lipid Panel

• Given the patient's hyperlipidemia history, check if statins or other lipid medications are being used 1
• Many drugs interact with phenytoin metabolism (both increasing and decreasing levels) 1

Neuroimaging Considerations

Brain imaging (CT or MRI) should be performed in the ED setting when feasible for patients with increased seizure frequency, even with known seizure history 5. While guidelines allow deferred outpatient neuroimaging with reliable follow-up, the acute change in seizure pattern (6 seizures in 2 days) warrants urgent evaluation to exclude:

• New structural lesions
• Hemorrhage
• Tumor progression
• Other acute pathology 5

Drug Interaction Assessment

Critical Medication Review

Review all current medications for interactions that may decrease phenytoin levels 1:

• Carbamazepine (decreases phenytoin)
• Chronic alcohol abuse (decreases phenytoin)
• Calcium-containing antacids (interferes with absorption) 1

Check for medications that may increase phenytoin levels and cause paradoxical seizures from toxicity 1, 4:

• H2-antagonists, omeprazole
• Sulfonamides, isoniazid
• Acute alcohol intake
• Amiodarone, fluoxetine, sertraline 1

Additional Monitoring Based on Clinical Presentation

If Phenytoin Level is Supratherapeutic (>20 mg/L or 80 μmol/L)

• Free (unbound) phenytoin level – protein binding is 90-95%, and free levels better predict toxicity 6, 3
• Paradoxical seizures can occur with phenytoin toxicity (decreased seizure threshold at high levels) 4
• Look for signs of phenytoin encephalopathy: cognitive impairment, cerebellar signs (ataxia, nystagmus) 6

If Phenytoin Level is Subtherapeutic (<10 mg/L or 40 μmol/L)

• Consider compliance issues
• Assess for malabsorption or drug interactions 1
• Patient may require higher maintenance doses (some need 200-700 mg/day to maintain therapeutic levels) 5

Common Pitfalls to Avoid

• Don't assume compliance without checking levels – even compliant patients can have subtherapeutic levels due to individual metabolism differences 1
• Don't ignore the smoking history – chronic substance use affects phenytoin metabolism 1
• Don't delay imaging – acute change in seizure frequency (from baseline to 6 in 2 days) suggests possible new pathology 5
• Don't forget to check free phenytoin if total level is borderline – protein binding varies and free levels are more clinically relevant 6, 3