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In This Article
 »  Abstract
 » Introduction
 » Case Report
 » Discussion
 » Conclusion
 »  References

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 Table of Contents    
DRUG WATCH
Year : 2022  |  Volume : 54  |  Issue : 6  |  Page : 459-461
 

An idiosyncratic reaction of unilateral common peroneal nerve palsy associated with below desired therapeutic range of tacrolimus level in a patient postheart transplantation


1 Department of Cardiothoracic and Vascular Surgery, Heart and Lung Transplant Unit, Fortis Healthcare, Chennai, Tamil Nadu, India
2 Department of Pharmacology, MKCG Medical College and Hospital, Berhampur, Odisha, India

Date of Submission27-Sep-2020
Date of Decision16-Dec-2022
Date of Acceptance19-Dec-2022
Date of Web Publication31-Jan-2023

Correspondence Address:
P Ansuman Abhisek
Department of Pharmacology, MKCG Medical College and Hospital, Berhampur - 760 004, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.ijp_950_20

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 » Abstract 


Tacrolimus (TAC) is a very effective medication in routine use after solid organ transplantation. The potential, but infrequently reported neurological adverse effect of TAC is peripheral neuropathy (PN). This has rarely been reported in heart transplant patients. To the best of our knowledge, the data regarding mononeuropathy of common peroneal nerve presented with foot drop due to low whole blood trough TAC level are very limited in the early days postheart transplantation. An idiosyncratic reaction might be suspected in the early postoperative period, when the whole blood trough levels of TAC fall below or within the desired therapeutic range associated with any adverse events after ruling out other causes. We report a 21-year-old patient, who underwent heart transplantation after a suitable donor was identified, and presented with a new-onset right side foot drop on the 10th postoperative day. According to the WHO-Uppsala Monitoring Center causality assessment scale, the likely culprit agent is TAC. Rapid and progressive improvement of foot drop occurred after stopping it and changed over to cyclosporine.


Keywords: Foot drop, idiosyncratic reaction, immunosupressant, tacrolimus level


How to cite this article:
Srivastava A, Abhisek P A, Pradhan SS. An idiosyncratic reaction of unilateral common peroneal nerve palsy associated with below desired therapeutic range of tacrolimus level in a patient postheart transplantation. Indian J Pharmacol 2022;54:459-61

How to cite this URL:
Srivastava A, Abhisek P A, Pradhan SS. An idiosyncratic reaction of unilateral common peroneal nerve palsy associated with below desired therapeutic range of tacrolimus level in a patient postheart transplantation. Indian J Pharmacol [serial online] 2022 [cited 2023 Mar 26];54:459-61. Available from: https://www.ijp-online.com/text.asp?2022/54/6/459/368847





 » Introduction Top


Nearly, 8000 heart and lung transplantations are effectively performed per annum around the globe, but morbidity, as well as mortality, still pose a matter of serious concern.[1] Tacrolimus (TAC) is a macrolide antibiotic, a metabolite produced by the fungus Streptomyces tsukubaensis. TAC is the preferred option among calcineurin inhibitors (CNIs) because of not only due to its ease of blood level monitoring, but also its slightly greater efficacy.[2] TAC has a strong affinity for an intracellular protein immunophilin (FKBP-12), which leads to TAC-FKBP-12, Ca2+, calmodulin, and calcineurin complex formation.

This complex inhibits T-cell activation by inhibiting the activity of the phosphatase enzyme and preventing dephosphorylation and nuclear translocation of NFAT. Hyperglycemia, hypertension, nephrotoxicity, gastrointestinal symptoms, hyperkalemia neurotoxicity (e.g., tremors, headache, motor disturbances, and seizures), etc., are adverse drug reactions (ADRs) associated with TAC use.[2] Besides lymphocytes, CNIs are also found in abundance in the nervous tissues. CNI moves easily across the blood–brain barrier because of its lipophilic nature.[3] The risk of developing toxicity in the central nervous system from TAC may vary according to the type of solid organ transplant received. In the majority of cases, the CNI-induced neurotoxicity is reversible after discontinuation of the medication.[3] As per our knowledge, reports regarding foot drop associated with low whole blood trough TAC level after early days heart transplantation are sparse. We report a case of foot drop as a result of unilateral common peroneal nerve (CPN) palsy following heart transplantation, and rapid and progressive improvement was noticed after TAC was withdrawn and changed over to cyclosporine.


 » Case Report Top


Preoperative course in hospital

A 21-year-old male, having weight of 42 kg, a known case of dilated cardiomyopathy, was diagnosed 5 years back. He presented with complaints of breathlessness and was admitted to the hospital for further evaluation. Global hypokinesia of left ventricular (LV), severe LV dysfunction (ejection fraction - 16%), severe pulmonary arterial hypertension, and right ventricle dysfunction (+) tricuspid annular plane systolic excursion: 1.2 cm were revealed from echocardiogram. The right heart hemodynamic study showed a pulmonary vascular resistance of 2.48 wood units and cardiac output of 4.0 L/min and was on milrinone of 0.375 μg/kg/min. A routine pretransplant workup was done. He was found to be suitable for heart transplantation and registered in the state transplant registry. After a suitable donor was identified, he was taken for transplantation under high risk.

Postoperative course in the hospital

On the day of surgery, the patient was shifted to the trauma intensive care unit with inotropic supports of injection milrinone 0.75 μg/kg/min, injection adrenaline 0.2 μg/kg/min, and nitric oxide 20 ppm with stable hemodynamics. He started receiving induction immunosuppression therapy with an injection of basiliximab 20 mg and an injection of methylprednisolone from the intraoperative period, which was gradually tapered and converted to tablet wysolone 40 mg/day, which was tapered gradually to 5 mg as well. On postoperative day (POD) 0, the patient had hemodynamic instability along with LV dysfunction. Suspecting rejection, the patient was started on pulse steroid along with intra-aortic balloon pump (IABP) support to support the left ventricle. On POD 1, mycophenolate mofetil 2 g/day and TAC 3 mg/day were started and echo showed improved ventricular function and his hemodynamics stabilized. The patient was gradually weaned off the ventilator and was extubated on POD 2. His inotropes were gradually weaned to minimal support and IABP was removed. The patient was hemodynamically stable, off inotropes and the screening echo showed good biventricular function with minimal pericardial effusion. He was shifted to the ward on POD 9. On POD 10, the patient developed acute-onset right-sided weakness of the foot, toe dragged while walking due to loss of extension of toes and was unable to hold the foot straight across due to loss of eversion of the foot (signs of foot drop due to paralysis of muscles of the anterior compartment of the leg as steppage gait and foot slap gait), could not able to stand on the heel. There was no associated motor weakness or sensory loss in the lower limbs. There was no history of trauma, backache, and addictions. His blood pressure was 118/76 mmHg. Suspecting TAC as a contributing factor, TAC whole blood trough level was found to be 9.2 ng/ml (by electrochemiluminescence immunoassay Roche Cobas e411 analyzer) (reference range in the 1st 3 months after transplant is 10–15 ng/ml) cytochrome 3A5 assessment was not done.[2] There was no sign of improvement 1 week after being continued TAC with decreased doses (2 mg/day). Since his foot drop did not improve, neurologist's opinion was obtained and he was started on intravenous (IV) immunoglobulin. The nervous system examination was normal except for the right foot drop (power 1/5 of the dorsiflexor group of muscles). Viral markers were found to be negative. Serum Vitamin B12 as well as an electrolyte, metabolic disturbances status, appeared to be normal. Magnetic resonance imaging of both spine and brain screening was normal. Nerve conduction study revealed grossly reduced distal motor response amplitude at the right CPN, which suggests axonopathy with the normal study of the other side. TAC was stopped on the neurologist's advice and cyclosporine was started at 200 mg/day. Then, he received a second dose of injection basiliximab. Surveillance for rejection was done by endomyocardial biopsy, which showed no rejection. Over the next few days, his general condition was improved as well as rapid, progressive improvement of foot drop, and physiotherapy was continued. He recovered and was discharged after 1 month.


 » Discussion Top


Nearly 10%–28% of patients, who develop some form of neurotoxicity are treated with CNIs.[4] CNI-induced neurotoxicity includes mild symptoms which occur in 20%–40% of patients in the form of tremors, followed by headache, insomnia, photophobia, paresthesia, rarely peripheral neuropathy, and major complications, such as confusion, followed by seizures, cortical blindness, posterior reversible encephalopathy syndrome, and coma that occurs in 5%–8% of patients. It can be early (<2 months) or late (>2 months) in on set. Risk factors associated with this patient include previous seizures/cerebrovascular disease, hypertension, cholesterol levels <100 mg/dl, use of IV methylprednisolone, hypomagnesemia, high CNI levels, aluminum overload, electrolyte imbalances, and fluid overload.[5],[6] However, the risk factors associated with this patient were not established.

Our patient had developed a foot drop on the 10th POD. The exact mechanism of foot drop involving CPN with respect to TAC is still not known. The pathogenesis may correspond to lesions in central white matter, where injury to both the major as well as minor vasculature may lead to hypoperfusion or ischemia followed by secondary toxicity locally in the white matter.[4] No relationship between the serum CNI levels and the occurrence of the severity of neurologic symptoms is noted.[7]

Lack of response to dose reduction with respect to foot drop, addressed the possibility of idiosyncrasy, particularly when the serum level of TAC is within the desired therapeutic range or below as evident from our study.[6],[7] Improvement was noticed after the discontinuation of TAC and its replacement with cyclosporine.[7] As we did not estimate our patient for genetic polymorphisms such as CYP3A5, ABCB1, and MDR1 gene mutation and he was not under any medications which might be cytochrome p450 enzyme inducer or inhibitor as well as concentration to dose ratio of TAC was below normal limits, preclude these possibilities.

WHO-Uppsala Monitoring Center causality assessment scale suggests TAC as a probable/likely cause of unilateral foot drop in our patient. However, by the Naranjo ADR probability algorithm, the score obtained was 3, which suggests TAC as a suspected possible cause of unilateral foot drop. As far as severity is concerned, the modified Hartwig and Siegel scale suggests that the ADR is moderate in severity (level 4a). If preventability is concerned, the modified Schumock and Thornton scale suggests that the ADR is not preventable in nature.


 » Conclusion Top


The incidence of unilateral common peroneal axonopathy due to TAC though less frequently encountered may be relevant. Although CPN occurs with high serum drug levels of serum TAC level, physicians need to be watchful as it even can occur at or below the therapeutic levels. Patients scheduled for organ transplantation should receive a proper neurological assessment. Early identification and immediate attention to dose reduction or replacing the drug can avert the serious potentially irreversible adverse effect.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Sikma MA, van Maarseveen EM, van de Graaf EA, Kirkels JH, Verhaar MC, Donker DW, et al. Pharmacokinetics and toxicity of tacrolimus early after heart and lung transplantation. Am J Transplant 2015;15:2301-13.  Back to cited text no. 1
    
2.
Krensky A, Azzi J, Hafler D. Immunosuppressants and Tolerogens. 13th ed. New York: Mc Graw Hill education; 2018.  Back to cited text no. 2
    
3.
Gupta AK, Bahri N. Isolated diplopia associated with calcineurin inhibitor therapy in a patient with idiopathic membranous nephropathy: A case report. BMC Nephrol 2016;17:116.  Back to cited text no. 3
    
4.
Al Masri O, Fathallah W, Quader S. Recovery of tacrolimus-associated brachial neuritis after conversion to everolimus in a pediatric renal transplant recipient – Case report and review of the literature. Pediatr Transplant 2008;12:914-7.  Back to cited text no. 4
    
5.
Thanikachalam DK. Foot drop in a renal transplant recipient A case report and review of literature. Univ J Med Med Sci 2016;2: Available from: http://ejournal-tnmgrmu.ac.in/index.php/medicine/article/view/614/202. [last accessed on 2023 Jan 20].  Back to cited text no. 5
    
6.
Jain A, Mathew PJ, Modi M, Mangal K. Unilateral common peroneal nerve palsy following renal transplantation: A case report of tacrolimus neurotoxicity. J Postgrad Med 2011;57:126-8.  Back to cited text no. 6
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7.
Chegounchi M, Hanna MG, Neild GH. Progressive neurological disease induced by tacrolimus in a renal transplant recipient: Case presentation. BMC Nephrol 2006;7:7.  Back to cited text no. 7
    




 

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