Guillain–Barre syndrome-like presentation and thrombotic microangiopathy with calcineurin inhibitor - A case report

Prawash Kumar Chowdhary; Sanjeev Anant Kale; Tarun Kumar Saha; Subho Banerjee

doi:10.4103/ijot.ijot_70_19

CASE REPORT

Year : 2020 | Volume : 14 | Issue : 4 | Page : 369-373

Guillain–Barre syndrome-like presentation and thrombotic microangiopathy with calcineurin inhibitor - A case report

Prawash Kumar Chowdhary¹, Sanjeev Anant Kale¹, Tarun Kumar Saha², Subho Banerjee³
¹ Department of Nephrology, Ramkrishna Care Hospital, Raipur, Chhattisgarh, India
² Department of Nephrology, Apollo Hospital, Secunderabad, Telangana, India
³ KD and Research Center, Civil Hospital Campus, Ahmedabad, Gujarat, India

Date of Submission	14-Dec-2019
Date of Acceptance	07-Jun-2020
Date of Web Publication	30-Dec-2020

Correspondence Address:
Dr. Prawash Kumar Chowdhary
Ramkrishna Care Hospital, Raipur - 492 001, Chhattisgarh
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_70_19

Abstract

A 35-year-old male, 3 months postrenal transplant, presented with acute-onset demyelinating polyneuropathy, diagnosed to have tacrolimus-associated Guillain–Barre syndrome. He recovered within 5–7 days after converting from tacrolimus to cyclosporine (CsA). He developed graft dysfunction after 2 months due to CsA-induced thrombotic microangiopathy. He responded after converting to sirolimus from CsA. The proper knowledge of immunosuppression side effect and its discontinuation in the early period prevents permanent damage.

Keywords: Cyclosporine, Guillain–Barre syndrome, thrombotic microangiopathy

How to cite this article:
Chowdhary PK, Kale SA, Saha TK, Banerjee S. Guillain–Barre syndrome-like presentation and thrombotic microangiopathy with calcineurin inhibitor - A case report. Indian J Transplant 2020;14:369-73

How to cite this URL:
Chowdhary PK, Kale SA, Saha TK, Banerjee S. Guillain–Barre syndrome-like presentation and thrombotic microangiopathy with calcineurin inhibitor - A case report. Indian J Transplant [serial online] 2020 [cited 2021 Jan 22];14:369-73. Available from: https://www.ijtonline.in/text.asp?2020/14/4/369/305433

Introduction

Guillain–Barre syndrome (GBS) is an autoimmune neurological disorder characterized by acute demyelinating changes of the peripheral nervous system that results in an ascending paralysis, leading to severe bilateral symmetric weakness of the limbs.^[1] GBS has been reported following the liver, kidney, heart, lung, and bone marrow transplantation.^[2] Calcineurin inhibitors, especially tacrolimus, have been postulated as one of the potential causes of acute-onset demyelinating sensorimotor polyneuropathy.^[3] Tacrolimus-induced neurotoxicity can be treated either by reducing the dose or by switching the patient to different calcineurin inhibitors; cyclosporine (CsA).^[4],[5] Thrombotic microangiopathy (TMA) has been observed as a side effect of CsA therapy in patients treated with solid organ transplantation, including the kidney.^{[6],[7],[8],[9],[10],[11]} Only a minority of patients with CsA-associated TMA have full clinical picture of hemolytic-uremic syndrome,^[12] and that the diagnosis is frequently not apparent before the renal biopsy is performed. Treatment modalities include stopping CsA^[13],[14] and switching to other calcineurin inhibitors or to a calcineurin inhibitor-free regimen.^[15] We describe the course and treatment of one kidney-transplant recipient diagnosed with GBS-like presentation occurring in association with the use of tacrolimus. Neurotoxicity was treated by switching to CsA. The patient developed CsA-induced TMA. Hence, he was switched over to sirolimus.

Case Report

A 35-year-old male, haplomatch with father as the donor, underwent live-related renal transplantation. Native kidney disease was unknown. Cytomegalovirus status of the donor and recipient was positive for immunoglobulin IgG but negative for IgM. He was induced with three doses of Solu-Medrol. His maintenance immunosuppressants were tacrolimus, Mycophenolate mofetil (MMF), and wysolone. The postoperative course was uneventful, and he was discharged on the 10^th postoperative day. During discharge, his serum creatinine was 1.2 mg/dL, and tacrolimus trough level was 6.21 ng/L. Gradually, his prednisolone dose was tapered to 5 mg/day. Three months posttransplantation, he presented with acute progressive weakness of both lower limbs and loose motions. On examination, the tone was decreased in both lower limbs, with muscle power 2/5. Deep tendon reflex was absent, with impaired joint position sensation up to the ankle. Nerve conduction study was suggestive of demyelination of both lower limb motor nerves and normal sensory potential [Figure 1]. MRI of lumbosacral spine doesnot showed much defect as shown in [Figure 2]. His serum electrolytes and renal function were deranged (Serum potassium 2.8mEq/L, serum magnesium 0.81mg/dl and serum creatinine 3.8mg/dl) [Table 1]. Blood and urine cultures were negative for bacterial and fungal organism. Serum cytomegalovirus deoxyribonucleic acid by polymerase chain reaction was negative. Stool for culture sensitive was negative; cerebrospinal fluid study was normal. Neuroviral panels by qualitative polymerase chain reaction were done in the cerebrospinal fluid, which was negative (adenovirus, enterovirus, Epstein–Barr virus, human herpes virus 7, human herpes virus 6, herpes simplex virus 1 and 2, parvovirus B19, varicella zoster virus, and cytomegalovirus). Tacrolimus level was high (15.30 ng/L). Fluid balance and dyselectrolemia were normalized. For loose motion, the patient was treated with ciprofloxacin and metronidazole. Tacrolimus dose was reduced. Repeat tacrolimus level was done after 4 days which was 8.2 ng/L. Renal function showed some improvement, but no neurological improvement was seen. Transplant biopsy was done, and no evidence of tacrolimus toxicity or rejection was observed (Banff score 2013 update: i0, ti0, t0, v1, mm0, g2, cg0, ci0, ct1, ah1, ptc2) [Figure 3]. Tacrolimus was stopped and CsA was started. After 5 days, his neurological defect started improving. He was discharged with mild persistent left foot drop and serum creatinine 1.48 mg/dL. He was on irregular follow-up. After 2 months when he came for follow-up, serum creatinine was 3.4 mg/dL. CsA level was 131.29 ng/L. Donor-specific antibody (DSA) was negative [Table 2]. Complement levels were not reduced (C3 – 168 mg/dL and C4 – 36 mg/dL). Peripheral smear examination showed no evidence of schistocytes or thrombocytopenia. Graft biopsy was suggestive of TMA (Banff score 2013 update: i1, ti1, t0, v0, mm0, g0, cg0, ci1, ct1, cv2, ah2, ptc0) [Figure 4]. CsA was stopped and sirolimus was started. Serum creatinine was gradually improved to 2.1 mg/dL. Now, he is in follow-up with us for 2 years with serum creatinine between 1.7 and 2 mg/dL.

Figure 1: Nerve conduction study nerve conduction study was suggestive of demyelination of both lower limb motor nerves and normal sensory potential

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Figure 2: Magnetic resonance imaging of the patients

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Figure 3: Transplant biopsy of patient in the first admission

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Figure 4: transplant biopsy of patient in second admission, suggestive of thrombotic microangiopathy

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Table 1: Investigation details of patient during first admission

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Table 2: Investigation details of patient during second admission

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Discussion

We describe a case of GBS-like presentation attributed to tacrolimus use after renal transplantation. GBS is an uncommon disease with a worldwide incidence of 1 or 2 cases per 100,000/year.^[16] A review of the literature that included all cases of GBS in transplant recipient found only thirty cases of GBS occurring after solid organ transplantation (13 liver, 6 heart and lung, and 11 kidney-transplant recipients). In the majority of these reports, male patients are affected more frequently than females, and the onset of symptoms occurred within 3 months to 1 year of the transplant.^[17] Our patient is a male patient and develops GBS after 3-month postrenal transplant.

Among transplant recipients, GBS has been mostly associated with cytomegalovirus infection and recent immunization.^[17],[18] Tacrolimus is postulated as a possible and rare cause of GBS in this population. Bronster et al. described a patient developing a subacute form of demyelinating sensorimotor polyneuropathy 4 months after liver transplantation. The authors concluded that the neurological findings were caused by tacrolimus, and the patients improved after drug discontinuation.^[19] Similarly, Kaushik et al. described a patient developing Miller–Fisher variant of GBS in a liver-transplant recipient. In this report, the authors used the Naranjo probability scale and postulated a probable relationship between the clinical manifestation and tacrolimus therapy.^[20]

Falk et al. described a lung-transplant recipient developing GBS with autonomic dysfunction in association with CsA.^[21] Our patient does not have autonomic dysfunction, and his neurological symptoms improved after switching from tacrolimus to CsA. The symmetric ascending presentation and failure to respond with the reduction of tacrolimus dose and responded after stopping tacrolimus favor the diagnosis of GBS over tacrolimus polyneuropathy in our patients.

The optimal treatment of acute demyelinating polyurethane associated with tacrolimus in transplant recipient is unknown. Several reports of liver- and renal-transplant patients treated with intravenous immunoglobulin (IVIG) and/or plasmapheresis show that these therapies are successful and result in neurological improvement, although other reports of tacrolimus-induced polyneuropathy also suggest that discontinuation of the drug results in similar improvement.^[22] Labate et al. described demyelinating neuropathy in a heart-transplant recipient and showed neurological improvement after the discontinuation on tacrolimus.^[23] Sharma et al. did not show neurological improvement after the discontinuation of tacrolimus, although, due to the severity of weakness, they initiated plasma exchange soon after tacrolimus discontinuation and did not wait after drug discontinuation.^[24] Our patient did not have severe life-threatening weakness, such as respiratory paralysis; we gave adequate time after discontinuation of tacrolimus and observed a remarkable neurological improvement.

De novo TMA can affect 3%–14% of kidney-transplant recipients.^{[25],[26],[27]} Although the association between TMA and CsA is well established, the medical literature on CsA-associated TMA in renal allograft is abundant.^{[11],[28],[29]} Our patient develops CsA-induced TMA, as his initial graft biopsy done 2 months back did not show any evidence of TMA. TMA can be observed in the context of vascular and antibody-mediated rejection. Renal biopsy done did not show any evidence of rejection. His DSA was negative. Genetic analysis was not done to rule out complement-mediated TMA.

Most reports of transplant-associated TMA have recommended a dose reduction or complete withdrawal of calcineurin inhibitors.^[13],[14] Although this maneuver often leads to the resolution of the TMA, the risk of rejection is increased, especially in the early posttransplant period.

In our patient, as he has developed tacrolimus-induced GBS, we preferred to convert it into sirolimus. This also did not occur at the expense of acute rejection, and to date, the patient enjoys excellent allograft function. The temporal course of events characterized by progressive graft dysfunction and TMA which reversed on stopping CsA points to the possible causative role of CsA in inducing TMA.

Conclusion

We conclude that GBS after organ transplantation is rare. If undiagnosed, these conditions may lead into severe disability; therefore, we feel that transplant physician must be aware of the possible association between tacrolimus and GBS. The optimal treatment of GBS associated with tacrolimus is unknown, although drug discontinuation may result in improvement in some patients, while most reports suggest that the use of IVIG and/or plasmapheresis may be helpful and safe in organ-transplant recipient with severe symptoms.

CsA-induced TMA is a devastating complication, which can lead to progressive renal damage. In most patients, CsA-associated TMA remained confined to the kidney with little or no systemic evidence of the thromboangiopathic process. Therefore, we recommend that any significant and persistent elevation in the serum creatinine that is > 0.5 mg/dL above the baseline should be worked up with a graft biopsy. Rather than reducing the dose of calcineurin inhibitors or switching from one calcineurin inhibitors to the other, we recommend the use of sirolimus which has an advantage of reducing the risk of recurrent TMA, while providing adequate prophylaxis from acute rejection.

Declaration of patient consent

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

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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