Tacrolimus induced common peroneal nerve palsy (CPN) in a Nigerian in the early postoperative post-transplant period: a case report

¹Nephrology Unit, Department of Medicine, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria, ²Nephrology Unit, Department of Medicine, Zenith Medical and Kidney Centre, Abuja, Nigeria, ³Department of Clinical Research, Zenith Medical and Kidney Centre, Abuja, Nigeria

^&Corresponding author
Adegboyega Emmanuel Faponle, Nephrology Unit, Department of Medicine, Zenith Medical and Kidney Centre, Abuja, Nigeria

Introduction    

Neurologic complications are possible complications from the use of tacrolimus (TAC). This could include headaches, tremors, confusion, paraesthesia and insomnia. However, not too common or reported is the common peroneal nerve affectation with subsequent foot drop following the use of tacrolimus in the early post-transplant period [1]. We report a case of unilateral CPN palsy presenting as foot drop following renal transplantation in our facility, with subsequent only after tacrolimus (TAC) was completely discontinued and successfully replaced by cyclosporine.

Patient and observation     

Patient information: a 54-year-old man with end-stage renal disease secondary to hypertensive nephropathy had living related kidney transplantation in our facility. The prior history before transplantation did not suggest any neurological issues. There was no evidence of peripheral or autonomic neuropathy in the pre-operative period.

Clinical findings: the early post-transplant period was uneventful. He was induced with intravenous anti-thymocyte globulin. He was then commenced on included oral Tacrolimus 0.2 mg/kg/d at two divided doses (4 mg twice daily with a target tacrolimus trough level of between 7-12 ng/l), oral prednisone 40 mg/d which was gradually tapered down in the succeeding weeks and mycophenolate mofetil one gram twice daily.

Timeline: he tolerated well until discharge two weeks post-op. He represented 3 days with complaints of focal seizures over the left leg and subsequent foot drop of the left limb.

Diagnostic assessment: serum TAC level was 4.52 ng/mL (target concentration 7-12 ng/mL) during this period. A thorough neurologic examination revealed power of 0-1/5 in the dorsiflexor group of muscles. There was no associated sensory loss or any other neurologic deficit. Magnesium was consistently within normal range 0.8 mmol/l (normal range 0.7 - 1.1 mmol/l), cholesterol 4.5 mmol/l (2.3 - 5.2 mmol/l), sodium 137mmol/l (135 - 155 mol/l). Magnetic resonance imaging (MRI) of brain only revealed multi-sinusitis. The carotid Doppler revealed mild to moderate atherosclerosis. Acute stroke was initially considered and a stroke protocol with physiotherapy was instituted. However, focal seizures remained unabated despite the use of Leviracetam.

Therapeutic intervention: he was also switched to the Advagraf (tacrolimus, one daily dosing) but was of no benefit. Subsequently, Tacrolimus was switched to cyclosporine.

Follow-up and outcomes: over the next few days, he showed rapid and progressive improvement, as evidenced by resolution of focal seizures and improvement in the power of the dorsiflexors of the left limb. He recovered fully and was discharged home after 2 weeks.

Patient perspective: the patient expressed gratitude for the relief of symptoms that he felt following the intervention. He was initially scared that the condition will be irreversible, the resolving symptoms made him happy.

Informed consent: a written informed consent was obtained from the patient.

Discussion     

Tacrolimus (previously known as FK506) is a potent macrolide antibiotic, widely used for immunosuppression following solid organ transplantation, including kidney transplantation [2]. Unsurprisingly, much attention is centered on graft function post-transplantation. However, neurological complications are a significant and under-reported cause of graft recipient´s morbidity [3]. Immunosuppressive agents are an important contributor to these complications [4]. About 10-30% of posttransplant patients managed with calcineurin inhibitors (CNIs) develop a wide range of neurotoxicities, which includes tremors, paraesthesias and polyneuropathies. These findings are more commonly seen with TAC than cyclosporine. Other neuropsychiatric complications noted are catatonia and psychosis. These complications tend to occur commonly in the early post-operative period [3,5]. In a prospective study by Eidelman et al. [2], major neurological complications were found in 5.4% of the patients studied. These findings were noticed within the first month after transplantation, and associated with high plasma tacrolimus levels. Ayres et al. [6], in a retrospective study on 50 patients with orthotopic liver transplantation, found 2 cases of disabling peripheral neuropathy. However, the tacrolimus assay level was found to be within normal level in both cases, the symptoms resolved completely following cessation of tacrolimus. Other attributable explanation for these neurological complications post-surgery includes nerve compression with or without lengthy duration of surgery, intraoperative hypotension and supine positional [1,3].

We however reported a rather rare case of CPN palsy following kidney transplantation. Our reported case improved only after discontinuation of tacrolimus; few cases of this finding have been reported so far. Due to the rarity of this condition, the precise mechanism of CPN palsy is unknown. There are however possible pathogenic explanations: presence of possible central white matter lesions from injury to both the major and minor vessels, causing ischemic injury and local secondary toxicity in the white matter [7,8]. This might also explain the focal seizures noticed in our patient. This mechanism of neurotoxicity of CNIs is most likely idiosyncratic, particularly when there is failure of response to dose reduction even with tacrolimus levels within the desired therapeutic range [9]. In our patient, there was only full recovery following replacement of tacrolimus with cyclosporine. Another important contributor to the early onset of neurotoxicity is the high trough levels of tacrolimus, surprisingly our patient had suboptimal levels during the period of neurotoxicity [10]. The toxic effects resulting from an abnormal metabolism of tacrolimus by liver enzyme on CYP3A4 is also a possibility [11]. Other pathogenic mechanisms include electrolyte and metabolic disturbances (hypomagnesemia, hypercholesterolaemia, hypo/hypernatremia), fluid overload and high blood pressure. However, available studies did not find a clear relationship between hypocholesterolaemia or hypomagnesaemia and neurotoxicity in patients on tacrolimus [2,12,13].

The type of solid organ transplantation received also determines the risk of neurotoxicity. The risk is lowest with renal transplantation, while major neurological side effects are commonest in patients who received liver transplantation [2,8]. Surprisingly, even though tacrolimus and cyclosporine have similar immunosuppressive mechanisms of action, switching from tacrolimus to cyclosporine sometimes improve the tacrolimus-induced CPN adverse effects. In our patient, switching to cyclosporine resulted into resolution of his symptoms [14]. Possible explanation for this improvement is the clearance of tacrolimus and its metabolites following the switch to cyclosporine. Other treatment options include reducing the dose of tacrolimus, and converting to a calcineurin inhibitor-free immunosuppressive regimen (sirolimus, everolimus or betalecept) [1].

Conclusion     

this case illustrates that CPN palsy is a potential but reversible side effect of tacrolimus use in renal allograft recipients. Therefore, patients should be monitored for neurotoxicity and when such an event occurs, prompt switching to cyclosporine or a calcineurin inhibitor-free immunosuppressive regimen is advised.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All the authors have read and agreed to the final manuscript.

References