How should I manage a 26‑year‑old man with epilepsy on Keppra (levetiracetam) 750 mg twice daily who has had four generalized tonic‑clonic seizures, severe rhabdomyolysis, and acute kidney injury with markedly reduced renal function?

Management of Seizures, Rhabdomyolysis, and Acute Kidney Injury in a Patient on Levetiracetam

Immediately discontinue levetiracetam and switch to an alternative antiepileptic drug, as the medication is the likely cause of both the rhabdomyolysis (CK 9000) and acute kidney injury (CrCl 14), while simultaneously initiating aggressive fluid resuscitation and renal replacement therapy for the severe kidney dysfunction.

Immediate Seizure Management

Acute Seizure Control

• Administer intravenous lorazepam 4 mg at 2 mg/min immediately if the patient is actively seizing, which terminates status epilepticus in approximately 65% of cases 1
• Have airway equipment immediately available before benzodiazepine administration due to respiratory depression risk 1
• If seizures persist after adequate benzodiazepine dosing, escalate immediately to a second-line agent 1

Second-Line Anticonvulsant Selection (Avoiding Levetiracetam)

Given the suspected levetiracetam-induced toxicity, choose from these alternatives:

• Valproate 20-30 mg/kg IV over 5-20 minutes (preferred option): achieves 88% seizure control with 0% hypotension risk, making it the safest alternative 1
• Fosphenytoin 20 mg PE/kg IV at maximum rate of 150 PE/min: 84% efficacy but requires continuous cardiac monitoring due to 12% hypotension risk 1
• Phenobarbital 20 mg/kg IV over 10 minutes: 58.2% efficacy but higher risk of respiratory depression and hypotension 1

Do not reload or continue levetiracetam given the strong temporal association between high-dose levetiracetam administration and the development of rhabdomyolysis with acute kidney injury 2, 3, 4.

Management of Levetiracetam-Induced Rhabdomyolysis and AKI

Evidence for Levetiracetam Causality

• Multiple case reports document levetiracetam causing rhabdomyolysis with CK elevations ranging from 21,936 to 30,000 IU/L, with significant CK reduction (often >50%) occurring within 24-48 hours of drug discontinuation 2, 3, 5, 4
• A nearly identical case of a 26-year-old male on levetiracetam 750 mg twice daily who developed status epilepticus, received 4 g IV loading dose, and subsequently developed AKI with creatinine reaching 12.2 mg/dL has been reported, with renal recovery occurring only after switching to valproic acid 2
• The temporal relationship—AKI developing within 1-2 days of levetiracetam initiation or dose escalation—strongly supports drug causality 2, 6, 4

Aggressive Fluid Resuscitation Protocol

• Initiate immediate high-volume intravenous crystalloid resuscitation targeting urine output >200-300 mL/hour to prevent myoglobin-induced tubular injury 7
• For severe rhabdomyolysis (CK >15,000 IU/L), volumes greater than 6 liters per day are required to prevent acute kidney injury progression and need for renal replacement therapy 7
• Monitor hourly urine output via bladder catheterization and maintain urine pH ≥6.5 through alkalinization if needed 7
• Perform repeated bio-assessment combining plasma myoglobin, CK, and potassium measurements to detect hyperkalemia and monitor rhabdomyolysis resolution 7

Renal Replacement Therapy Considerations

• With CrCl of 14 mL/min (severe renal impairment), this patient meets criteria for urgent nephrology consultation and likely requires renal replacement therapy 7
• Indications for emergent dialysis in this context include: severe metabolic acidosis, hyperkalemia refractory to medical management, volume overload, or uremic complications 7
• The management of kidney injury following rhabdomyolysis has no specific unique features beyond standard acute kidney injury protocols 7

Antiepileptic Drug Dosing Adjustments for Severe Renal Impairment

Levetiracetam Dosing (If Continued—NOT Recommended Here)

The FDA label and guidelines specify renal dose adjustments 8, 9:

Creatinine Clearance	Dosage	Frequency
<30 mL/min (Severe)	250-500 mg	Every 12 hours
ESRD on dialysis	500-1,000 mg	Every 24 hours with supplemental dose post-dialysis

However, given the strong suspicion of levetiracetam-induced toxicity in this case, continuing this medication—even at adjusted doses—is contraindicated 2, 3, 4.

Alternative Anticonvulsant Dosing in Renal Failure

• Valproate: does not require renal dose adjustment, making it an excellent choice for this patient 1
• Phenytoin/Fosphenytoin: protein binding is altered in renal failure (increased free fraction), requiring monitoring of free phenytoin levels rather than total levels 9
• Phenobarbital: requires dose reduction and extended dosing intervals in severe renal impairment 1

Monitoring and Follow-Up

Short-Term Monitoring (First 48-72 Hours)

• Serial CK measurements every 12-24 hours: expect significant decline (>50%) within 24-48 hours of levetiracetam discontinuation if drug-induced 2, 4
• Daily serum creatinine and electrolytes: monitor for hyperkalemia, metabolic acidosis, and renal recovery 7
• Continuous cardiac monitoring: for dysrhythmias related to hyperkalemia or second-line anticonvulsant administration 1
• Urine output monitoring: maintain >200 mL/hour during aggressive hydration phase 7

Renal Recovery Assessment

• Renal function recovery from levetiracetam-induced AKI typically occurs over 2-4 weeks, though some patients may have persistent mild impairment as a new baseline 2
• Laboratory and clinical evaluation should occur within 3 days (no later than 7 days) after any RRT session if dialysis is initiated, followed by regular assessments 7
• Weekly assessment of pre-dialysis serum creatinine and 24-hour urine collection for creatinine/urea clearance if patient remains on RRT 7

Critical Pitfalls to Avoid

• Do not attribute the rhabdomyolysis solely to seizure activity: while seizures can cause mild CK elevation, the magnitude (CK 9000) and temporal association with high-dose levetiracetam strongly suggest drug causality 2, 3, 4
• Do not continue levetiracetam at any dose: multiple case reports demonstrate that rhabdomyolysis and AKI resolve only after drug discontinuation, not with dose reduction 2, 5, 4
• Do not delay fluid resuscitation: retrospective studies show that patients who develop AKI had longer time to initiate volume resuscitation compared to those who did not 7
• Do not use neuromuscular blockers alone for ongoing seizures, as they only mask motor manifestations while allowing continued electrical seizure activity and brain injury 1

Long-Term Seizure Management

• Once acute kidney injury resolves and renal function stabilizes, transition to oral maintenance anticonvulsant therapy with the chosen alternative agent (valproate preferred given safety profile) 1
• Avoid reintroduction of levetiracetam given the severe adverse reaction 2, 3, 4
• Arrange outpatient neurology follow-up for optimization of long-term seizure control and monitoring for seizure recurrence 1
• Consider outpatient EEG to assess for ongoing epileptiform activity once clinically stable 1