Clinical Judgment: Misattributed Lithium Toxicity in Bipolar Disorder with Autoimmune Encephalitis
The Critical Error: Misinterpreting Lithium Levels and Symptoms
The fundamental error in this case was attributing classic neurotoxic symptoms to lithium when the patient actually had autoimmune encephalitis, compounded by improper timing of lithium level measurement that created a falsely elevated result. The 1.7 mEq/L level drawn at 12 hours post-dose represents a peak or mid-interval concentration rather than the standard 12-hour trough, making it clinically meaningless for therapeutic monitoring 1, 2. The true trough level of 1.08 mEq/L at 24 hours was actually therapeutic and appropriate 3.
Why This Case Was Diagnostically Challenging
The Misleading Clinical Picture
Symptom overlap created diagnostic confusion: Slurred speech, nausea, vomiting, and confusion are classic signs of lithium toxicity at levels >1.5 mEq/L, but these identical symptoms occur in autoimmune encephalitis 4, 5.
The corticosteroid confounding factor: High-dose methylprednisolone for MS treatment likely triggered the manic episode, creating a complex clinical scenario where multiple pathologies (steroid-induced mania, MS-related demyelination, and autoimmune encephalitis) presented simultaneously 2.
Historical precedent exists: A documented case from 1978 describes multiple sclerosis masquerading as lithium toxicity in a bipolar patient, where dysarthria and ataxia were incorrectly attributed to therapeutic lithium levels 5.
The Pharmacokinetic Error: Timing of Blood Draw
Why the 1.7 mEq/L Level Was Misleading
Standard lithium monitoring requires 12-hour trough levels drawn immediately before the next dose, not 12 hours after an evening dose when using once-daily dosing 1, 3.
The 12-hour post-dose level captured peak/mid-interval concentration: With once-daily evening dosing at 1200mg, a level drawn 12 hours later (morning) represents a point on the absorption/distribution curve, not steady-state trough 3.
The 24-hour level of 1.08 mEq/L was the true trough: This represents the actual pre-dose concentration and falls within the therapeutic range of 0.8-1.2 mEq/L for acute mania treatment 2, 3.
Pharmacokinetic Principles Violated
Lithium reaches peak serum concentrations 1-4 hours after immediate-release formulations and has a half-life of approximately 24 hours, meaning levels fluctuate significantly throughout the dosing interval 3.
Individual patients may respond at lower concentrations (<0.8 mEq/L), and the relationship between concentration and therapeutic effect varies considerably between patients 3.
The patient's renal function was normal (creatinine 65 μmol/L, approximately 0.74 mg/dL), eliminating lithium accumulation as an explanation for toxicity 4.
The True Diagnosis: Autoimmune Encephalitis
Why Symptoms Were Not Lithium-Related
Autoimmune encephalitis with positive varicella PCR and demyelinated neurons explains all the neurological symptoms: confusion, slurred speech, altered mental status, and potentially nausea/vomiting from increased intracranial pressure 5.
The temporal relationship was misleading: Symptoms appeared 5 days after lithium dose increase, creating false causality, when autoimmune encephalitis was the actual culprit developing independently 5.
MS patients are at increased risk for autoimmune complications: The underlying MS pathology, combined with high-dose corticosteroid treatment, created vulnerability to additional autoimmune phenomena 5.
Clinical Algorithm: How to Avoid This Error
Step 1: Verify Lithium Level Timing and Validity
Always confirm that lithium levels are true 12-hour trough levels drawn immediately before the next scheduled dose, regardless of dosing frequency 1, 3.
For once-daily evening dosing, the trough is drawn the following evening before the next dose, not the following morning 3.
Repeat any lithium level that seems discordant with clinical presentation before making treatment decisions 1.
Step 2: Assess for Alternative Explanations
When neurotoxic symptoms occur at therapeutic lithium levels, immediately consider alternative diagnoses: CNS infections, autoimmune encephalitis, MS exacerbation, metabolic derangements, or drug interactions 5.
In patients with MS or other autoimmune conditions, maintain high suspicion for concurrent autoimmune complications rather than immediately attributing symptoms to medication toxicity 5.
Obtain comprehensive workup including: lumbar puncture with PCR studies, MRI brain, EEG, and autoimmune encephalitis panel when neurological symptoms are disproportionate to lithium levels 5.
Step 3: Recognize High-Risk Clinical Scenarios
Corticosteroid-induced mania in bipolar patients requires aggressive mood stabilization but also increases risk of infectious and autoimmune complications 2.
Combination therapy with lithium plus quetiapine is appropriate for severe mania, but the quetiapine dose of 800mg/day was at the upper limit and could contribute to sedation and confusion independent of lithium 6, 7.
Neuroleptic malignant syndrome (NMS) must be excluded: The combination of lithium, quetiapine, and recent medication changes creates risk for NMS, which presents with confusion, rigidity, and autonomic instability 8.
Critical Pitfalls in This Case
Pitfall 1: Anchoring Bias
The team anchored on "lithium toxicity" based on a single elevated level without considering the timing error or alternative diagnoses 5.
Classic toxicity symptoms at a "toxic" level created confirmation bias, preventing consideration of other etiologies 5.
Pitfall 2: Inadequate Therapeutic Drug Monitoring Knowledge
Failure to recognize that lithium levels vary significantly throughout the dosing interval led to misinterpretation of the 12-hour post-dose value 3.
Not understanding that once-daily dosing requires 24-hour trough levels (drawn before the next evening dose) was the fundamental error 3.
Pitfall 3: Overlooking the Complex Medical Context
The MS diagnosis, high-dose corticosteroids, and recent manic episode created a perfect storm for autoimmune encephalitis that was missed 5.
Stopping lithium prematurely based on a misinterpreted level left the patient without mood stabilization during a critical period 2.
What Should Have Been Done
Immediate Actions When Symptoms Appeared
Repeat lithium level as a true 24-hour trough (which was eventually done and showed 1.08 mEq/L) 3.
Obtain comprehensive neurological workup immediately: LP with PCR panel, MRI brain, EEG, and autoimmune encephalitis antibodies 5.
Continue lithium at reduced dose (e.g., 900mg) rather than stopping completely, given the therapeutic trough level and ongoing manic episode 2, 3.
Rule out NMS with creatine kinase, complete metabolic panel, and careful examination for rigidity given the combination of lithium and quetiapine 8.
Long-Term Management Considerations
Lithium remains appropriate for this patient once the autoimmune encephalitis is treated, as the true trough level was therapeutic and the symptoms were not lithium-related 2, 3.
Maintenance therapy should continue for at least 12-24 months after mood stabilization, with proper trough level monitoring 2.
Regular monitoring every 3-6 months should include: lithium levels (true 12-hour troughs), renal function, thyroid function, and urinalysis 2.
The Bottom Line for Clinical Pharmacists
When evaluating suspected lithium toxicity, always verify the timing of blood draw before attributing symptoms to the medication. In this case, the 1.7 mEq/L level was a mid-interval concentration, not a trough, and the true trough of 1.08 mEq/L was therapeutic 3. The symptoms were caused by autoimmune encephalitis, not lithium 5. This case exemplifies how improper therapeutic drug monitoring combined with anchoring bias can lead to misdiagnosis and inappropriate medication discontinuation in complex patients with multiple comorbidities.