What is the management approach for a patient with normal lithium levels experiencing seizures?

Management of Seizures in Patients with Normal Lithium Levels

Lithium can cause neurotoxicity and seizures even at therapeutic serum levels, so normal lithium levels do not exclude lithium as the causative agent—clinical diagnosis based on symptoms takes precedence over laboratory values. 1

Critical Recognition: Lithium Neurotoxicity Despite Normal Levels

The fundamental principle here is that lithium toxicity is a clinical diagnosis, not a laboratory diagnosis. 1 Several key mechanisms explain seizures with normal lithium levels:

• Delayed CNS accumulation: Lithium persists in brain tissue long after serum levels normalize, with protracted influx and efflux from the central nervous system creating a lag between serum and brain concentrations. 2
• Therapeutic-level neurotoxicity: Case reports document severe neurotoxicity, including seizures, occurring at lithium levels as low as 0.8 mEq/L (well within the 0.6-1.2 mEq/L therapeutic range). 1
• EEG changes precede clinical symptoms: Electroencephalographic correlates of lithium neurotoxicity can appear even when serum levels are normal, showing epileptiform discharges activated by therapeutic lithium concentrations. 2, 3

Immediate Evaluation and Management

Laboratory Assessment

• Check serum glucose and sodium immediately as these are the most common metabolic abnormalities causing seizures and must be corrected urgently. 4, 5
• Obtain lithium level even if recently checked, as drug interactions (particularly with diuretics like Moduretic) can precipitate toxicity. 6
• Pregnancy test for all women of childbearing age, as this affects antiepileptic drug selection. 4, 5
• Extended electrolyte panel including calcium, magnesium, and phosphate, especially given lithium's renal effects and potential concurrent diuretic use. 5

Neuroimaging Decision

Perform emergent CT head without contrast if any of the following are present: 4

• Persistent altered mental status beyond expected postictal period
• New focal neurological deficits
• Patient has not returned to baseline within several hours
• Immunocompromised state
• Age over 40 years
• Recent head trauma

Electroencephalography

Obtain EEG urgently in this specific clinical scenario because: 6

• EEG is indispensable for diagnosing non-convulsive status epilepticus, which can occur with lithium toxicity even at normal levels. 6
• Epileptiform discharges may be present on EEG despite normal serum lithium, confirming lithium-induced neurotoxicity. 2, 3
• EEG findings predict increased risk of seizure recurrence and guide treatment decisions. 4

Acute Seizure Management

If Actively Seizing

• Benzodiazepines first-line for active seizures or status epilepticus. 4
• Second-line agents: phenytoin/fosphenytoin, valproate (30 mg/kg), or levetiracetam if seizures continue after benzodiazepines. 4
• Avoid phenytoin if possible in lithium-associated seizures, as the combination may worsen neurotoxicity. 2

Lithium Management Decisions

Do not restart lithium immediately after levels normalize, as this case series demonstrates that premature reinitiation (even when serum levels are therapeutic) can precipitate severe delayed neurotoxicity including catatonia and seizures. 7

Consider holding lithium entirely if: 7

• Recent overdose or intoxication within the past 2 weeks
• New neurological symptoms (slurred speech, ataxia, tremor, confusion)
• EEG shows epileptiform activity
• Seizure occurred despite therapeutic levels

Disposition and Follow-up

Admission Criteria

Admit the patient if any of the following apply: 4

• Persistent abnormal neurological examination
• Abnormal investigation results requiring inpatient management
• Has not returned to clinical baseline
• Suspected lithium neurotoxicity regardless of serum level
• Immunocompromised status requiring lumbar puncture after CT. 5

Outpatient Management (Only if ALL criteria met)

• Returned completely to baseline neurological status
• Normal neurological examination
• Normal glucose and sodium
• Reliable follow-up arranged within 24-48 hours
• No high-risk features for structural lesions. 4

Common Pitfalls to Avoid

• Never assume normal lithium levels exclude lithium toxicity—clinical symptoms trump laboratory values. 1
• Do not restart lithium as soon as levels normalize—allow at least 2 weeks for CNS clearance after suspected neurotoxicity. 2, 7
• Do not miss drug interactions, particularly with diuretics, NSAIDs, and ACE inhibitors that can precipitate toxicity at therapeutic doses. 6
• Do not skip EEG in lithium patients with seizures, as non-convulsive status epilepticus may be present without obvious clinical signs. 6
• Do not fail to check for concurrent metabolic derangements (hyponatremia, hypoglycemia) that lithium may mask or exacerbate. 4, 5

Risk Stratification for Recurrence

Early seizure recurrence risk is highest in the first 6 hours (85% of recurrences occur within this window), with mean time to recurrence of 90 minutes. 4 However, lithium-associated seizures have different kinetics due to prolonged CNS persistence, requiring extended observation even with normal serum levels. 2