Can tacrolimus (immunosuppressive agent) cause neurotoxicity?

Tacrolimus-Induced Neurotoxicity: Clinical Presentation and Management

Tacrolimus can definitely cause neurotoxicity, which ranges from mild symptoms like tremors and paresthesias to severe manifestations including posterior reversible encephalopathy syndrome (PRES), seizures, and coma. 1, 2

Clinical Presentation of Tacrolimus-Induced Neurotoxicity

• Neurotoxicity presents with a spectrum of symptoms including tremors, paresthesias, headache, insomnia, anxiety, agitation, language disturbances, and motor dysfunction 2, 3
• Severe manifestations include PRES, delirium, seizures, and coma 1
• Neurotoxicity can occur even when tacrolimus blood levels are within therapeutic range (5-20 ng/mL) 4, 5
• Symptoms may develop within days to months after initiating tacrolimus therapy 6, 7

Risk Factors for Tacrolimus Neurotoxicity

• Hypomagnesemia, hyponatremia, and electrolyte imbalances significantly increase risk 7, 8
• Hypertension and hypocholesterolemia are associated with higher risk 8
• Concurrent use of high-dose steroids (methylprednisolone) may exacerbate neurotoxicity 8
• Autoimmune hepatitis as underlying disease has been identified as a significant risk factor (p=0.0311) 7
• White blood cell count elevation has been observed in pediatric patients with tacrolimus-induced encephalopathy 6

Diagnostic Approach

• Obtain tacrolimus trough levels immediately when neurotoxicity is suspected 2
• Perform neurological assessment to grade severity of symptoms 2
• For moderate to severe symptoms, obtain MRI of brain with and without contrast 2
• Consider EEG for assessment of seizure activity 2
• Brain MRI may show hyperintense lesions on T2-weighted images, particularly in the pontine tegmentum or occipital white matter 4, 8

Management Algorithm

1. For mild symptoms (tremors, paresthesias):

   • Reduce tacrolimus dose to achieve lower therapeutic levels 2, 3
   • Monitor tacrolimus levels more frequently until stabilized 2
   • Correct any electrolyte abnormalities, particularly magnesium and sodium 7

2. For moderate to severe symptoms (seizures, encephalopathy, PRES):

   • Consider temporary discontinuation of tacrolimus 1, 2
   • Switch to alternative immunosuppressant (e.g., cyclosporine) if symptoms persist 6, 7
   • Initiate anticonvulsant therapy if seizures are present 4
   • Avoid medications that can cause CNS depression unless needed for seizure management 2

3. For refractory cases:

   • Consider switching to mycophenolate mofetil-based regimen, which has no neurotoxic effects 8
   • Consult neurology for specialized management 2

Monitoring and Prevention

• Regular monitoring of tacrolimus blood levels is essential, with recommended trough levels between 5-15 ng/mL for most transplant recipients 3, 2
• Monitor serum potassium, magnesium, sodium, glucose, renal function, and hepatic function 3, 2
• Consider lower target tacrolimus levels in patients with risk factors for neurotoxicity 5
• Avoid concurrent use of medications that increase tacrolimus levels through CYP3A4 inhibition 1

Prognosis

• Most patients experience resolution of neurologic symptoms after dose reduction or discontinuation of tacrolimus 8
• Some patients may develop permanent neurological damage despite dose reduction or discontinuation 8
• In pediatric liver transplant recipients, tacrolimus can be safely resumed after a median of 8 months from onset of neurotoxicity without recurrence of symptoms 6

Important Pitfalls to Avoid

• Do not dismiss neurologic symptoms in patients with therapeutic tacrolimus levels, as neurotoxicity can occur even within normal concentration ranges 4, 5
• Avoid abrupt discontinuation of tacrolimus without planning alternative immunosuppression strategy, as this may increase risk of transplant rejection 5
• Do not overlook correction of electrolyte abnormalities, particularly hypomagnesemia and hyponatremia, which can exacerbate neurotoxicity 7
• Recognize that tacrolimus-induced neurotoxicity may increase hospital and ICU length of stay 7