Role of tacrolimus in return of hand function after brachial plexus injury in a lung transplantation patient
- 1 Division of Hand Surgery, Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA
- 2 Department of Plastic-, Reconstructive- and Hand Surgery, Radboud University, Nijmegen, the Netherlands
- 3 Department of Pharmacy, Mayo Clinic, Rochester, Minnesota, United States
- 4 Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, United States
- Correspondence to Dr Alexander Y Shin; Shin.Alexander@mayo.edu
Abstract
We report a patient who has been on tacrolimus for bilateral lung transplantation and presented with a brachial plexus injury (BPI), with unusual improvement of lower trunk innervated hand function. The lower trunk injury with resultant left hand paralysis had developed after his sternotomy 18 months ago. He has been treated with tacrolimus as part of his immunosuppression protocol since the surgery, without severe side effects. Physical examination at 18 months demonstrated unusual excellent grip pattern and full opposition of his thumb with slight claw deformity of his ulnar two digits. While the neurotoxic effects of tacrolimus are more emphasised, the neuroregenerative properties have been recently explored. The recovery in this patient is unique and unusual after BPI and is most likely as a result of the low dose tacrolimus treatment.
Background
Tacrolimus, also known as FK506, is a calcineurin inhibitor and used for the prevention of allograft rejection after solid organ transplantation (SOT).1 For over two decades, it has been the cornerstone of modern immunosuppressive therapy after heart, lung, kidney, liver and pancreas transplantation.2 3 There are many controversies regarding its use in peripheral nerve injuries due to the undesirable neurotoxic side effects with an incidence of 10%–28%,4 including peripheral neuropathy, seizures and tremor.5 Recently, the neuroregenerative properties of tacrolimus have received more attention in basic science animal studies.6–10 The binding of tacrolimus to its immunophilin FK506-binding protein 12 and the consequent inhibition of calcineurin were believed to result in promotion of neuroregeneration.10 However, recently, binding to another immunophilin, FK506-binding protein 52 (FKBP-52) receptor, is suggested to stimulate nerve regeneration.11 FKBP-52 is a component of the mature steroid receptor complex, consisting of heat shock protein (HSP-59) and p23.12 13 This protein contains two binding domains, potentially explaining the bimodal dose response of tacrolimus. Only low and high concentrations of tacrolimus have resulted in increased neuroregeneration, whereas intermediate doses were shown not to be effective.9 14 Although basic science research has been providing more insights into the neuroregenerative effect of tacrolimus, no clinical studies exist to support these findings. Only anecdotal data of two successful hand transplantations, treated with tacrolimus, demonstrated enhancement of axonal regeneration and sensation without confirmation of any exams.15 16 Here, we report the functional outcomes of a patient with brachial plexus injury (BPI), treated with tacrolimus, at postoperative 18 months with unusual recovery of hand function.
Case presentation
The patient is a 46-year-old man with a medical history of childhood asthma, and exposure to chemicals and smoke in his work as a fire fighter. His first onset of shortness of breath was in 2007 and gradually exacerbated into exertional shortness of breath. He was diagnosed with interstitial lung disease confirmed by lung biopsy. In 2013, he was noted to have right ventricular enlargement and dysfunction by echocardiogram. His lung disease evolved into oxygen-dependent idiopathic pulmonary fibrosis and he became eligible for a lung transplant. In November 2017, he underwent a successful bilateral pulmonary allotransplantation. Induction therapy was performed with methylprednisolone 400 mg intravenously, tacrolimus 2 mg sublingually and mycophenolate mofetil (MMF) 500 mg intravenously 1 day prior to surgery. Intraoperatively, intravenous methylprednisolone was continued as 750 mg two times (1500 mg total) and converted postoperatively to 125 mg daily intravenously for 4 days. Postoperatively, he was immunosuppressed with oral MMF 500 mg two times a day, while laboratory tests were requested to determine renal recovery. After renal recovery, oral tacrolimus was commenced at 1.5 mg daily.
Tacrolimus treatment and monitoring
Tacrolimus levels were closely followed to maintain trough levels between 6 and 10 ng/mL. The dose of tacrolimus was maintained between 1.0 and 2.5 mg/day over 18 months with slight changes in dose in response to the trough levels. Subtherapeutic levels had occurred two times. To date, no side effects associated with the drug therapy were reported by the patient.
Onset of left arm weakness
Immediately following surgery in November 2017, the patient described severe left arm and hand paralysis. No previous significant neurologic or orthopaedic problems of the left upper extremity or neck were reported. He had complete loss of wrist function and intrinsic muscles of the left hand, consistent with a complete lower trunk injury and partial middle trunk involvement. He had diminished sensation over the ulnar aspect of the left elbow to hand with complete numbness in the C7-T1 distribution of his left hand, including digits 2–5. No sudden onset of pain prior to the weakness was described and brachial plexus neuritis (Parsonage-Turner syndrome) was ruled out.17 His postsurgical weakness was diagnosed as a traction and positioning injury secondary to median sternotomy. Brachial plexopathy after median sternotomy is rare and characterised by motor and predominance of sensory complaint in the lower roots of the plexus.18
Eighteen months after onset of his BPI, he was referred to our brachial plexus clinic for evaluation and treatment. His goal for evaluation was strengthening and improvement of his hand function. The symptoms of numbness in his non-dominant affected left hand had receded to involve only the fourth and fifth digits. Strength had returned with an excellent grip pattern and full opposition of his thumb. Objective outcome measurements of the muscle strength included the modified British Medical Research Council (mBMRC) motor grading19 20 and electromyographic (EMG) testing.
On physical examination of the brachial plexus, besides a positive Horner’s and neuropathic pain over the C8-T1 distribution, normal strength (mBMRC grade 5) was reported of his upper trunk and middle trunk (C7), except for the flexor digitorum profundus (FDP) of digits II and III (mBMRC grade 3), flexor digitorum superficialis (mBMRC grade 3), flexor pollicis longus (mBMRC grade 3+), flexor pollicis brevis (mBMRC grade 3−), abductor pollicis brevis (mBMRC grade 3−), opponens pollicis (mBMRC grade 3−) and lumbricals (I and II, mBMRC grade 3−). All radial-innervated muscles, including triceps, brachioradialis, wrist and finger extensors, reported mBMRC grade 5. Besides the flexor carpi ulnaris (mBMRC grade 5), the other distal ulnar innervated muscles reported weak (flexor digitorum profundus, mBMRC grade 3) to traces of muscle strength (abductor digiti minimi mBMRC grade 0, adductor pollicis 1, opponens digiti minimi 0, dorsal interosseous I–IV 1, proximal interosseous I–III 0 and lumbricals III and IV 0). There was significant intrinsic weakness of the interossei muscles and clawing of his fourth and fifth digits was reported as well. A positive Wartenberg sign was reported, consistent with his recovering C8-T1 BPI. Tip-to-tip pinch was difficult. Sensory examination reported dense sensory loss in the fourth and fifth digits of his left hand with two point sensation of 10 mm.
Investigations
EMG testing reported reduced left median and ulnar compound muscle action potentials with slow nerve conduction velocities. The left ulnar sensory response was reported to be absent. The left medial antebrachial cutaneous sensory nerve action potential amplitudes were reduced compared with the right side. These findings were consistent with a partial recovery of the lower trunk.
Magnetic resonance imaging (MRI) of the left brachial plexus reported moderate diffuse T2 hyperintensity of the lower elements of the brachial plexus. No focal mass or evidence of an active process was reported at this time.
Plan and follow-up
The main goal of the patient was for strengthening of his hand. There were no tendon transfers that could reliably restore his grip strength. An anti-claw splint was proposed to investigate if a static anti-claw procedure would improve his function. His unusual nerve recovery for a lower trunk postganglionic stretch injury was considered to be as a result of tacrolimus. We elected for continued follow-up and are hopeful he will continue to recover.
Discussion
The incidence of BPI has been increased over the last years due to increasing number of high-speed motor-vehicle accidents.21 These injuries are devastating as clinical options to reconstruct the nerve injury gap are still limited. The goals of surgical reconstruction after BPI are complex as they include multiple point of views, including the surgeon’s, the patient’s and society’s perspective.22 However, gain of motor function has been one of the primary common goals. Clinically, little to no hand function has been gained after comparable lower trunk brachial plexus injuries secondary to the distance the nerve needs to regenerate and the time-dependent degradation of the motor endplate. As a result of consistently poor functional outcomes after treatment of lower trunk injuries, alternatives to nerve grafting are currently the mainstay to return hand function. These alternatives typically include tendon transfer, free functioning muscle transfers or distal nerve transfers.23 In Kline and Judice’s large series, 17 patients with severe lower trunk stretch injuries were grafted with no patient regaining any ulnar or hand related function.24 The result obtained in this patient’s left hand after 18 months, including his grip strength and opposition of his thumb, is highly unusual and most likely attributable to his tacrolimus immunosuppression. Although one may argue the possibility of a transient neuropraxic injury, the likelihood of this is incredibly low as neuropraxic injuries have moderate to complete recovery within 6 months,25 which is not been the case in our patient.
There are no previous cases reported with similar improvement of hand function after BPI, confirmed with physical examination over time. The present patient has been maintained with a triple-drug immunosuppressive regimen (MMF, prednisone and tacrolimus) for his bilateral lung transplantation without severe side effects. The neurotoxic effects that have been published in the past reported higher doses of tacrolimus treatment, ranging between 0.3 and 5 mg/kg daily with trough levels up to 48.1 ng/mL.5 26 In our case, the doses ranged between 1 and 2.5 mg daily (=0.03 mg/kg at highest) and followed up by trough levels never higher than 12.3 ng/mL. Interestingly, it has been reported that the peripheral neuropathy improved after discontinuation or reducing the dose of the drug.5
Itraconazole is one of the ‘azole’ antifungals commonly used to prevent invasive fungal infections post lung transplantation,27 in this case dosed as 300 mg oral two times a day. The dose of tacrolimus in this patient was adjusted lower in response to its interaction with Itraconazole. Itraconazole is reported to increase tacrolimus serum concentrations.27 This is believed to be due to inhibition of cytochrome P450 enzymes (Cyp3A4 and Cyp3A5) and P-glycoprotein influx and efflux transport proteins that are responsible for the metabolism and transport elimination of tacrolimus.28 29 Therefore, the daily dose of our patient (1.5 mg oral daily at the moment) is low compared with patients who are not on ‘azoles’; however, the levels are in the target therapeutic range for immunosuppression.
Besides the ‘azole’ therapy, additional considerations that led to the dosage of tacrolimus, included his prednisone and azithromycin use, which have been implicated in drug interactions with tacrolimus, as well as his Epstein-Barr virus and cytomegalovirus status.30 31 Close monitoring to maintain therapeutic doses in goal trough range is associated with lower incidences of rejection and higher graft survival, and therefore used as guidance for consistent exposure to tacrolimus. Reported doses in rodent studies, both systemically and locally administered to the nerve, differ.8 9 14 However, due to the large translational gap, no conclusions could be drawn and clinical trials are necessary to evaluate tacrolimus doses with neuroregenerative effects. The neuroregenerative effects of tacrolimus are proven to be dose dependent, with doses that are commonly sub-immunosuppressive.10 In these ranges, there is evidence for a bimodal (double peak) dose response due to two binding domains of FKBP-52. Whether the total tacrolimus exposure, duration in a specific range of exposure, or the lack of supra-therapeutic exposure is the most contributing factor to potential neuroregenerative effects has yet to be elucidated.
To date, very few clinical studies have specifically explored the neuroregenerative effect of tacrolimus. Besides the two papers that subjectively report sensory recovery after hand transplantation while being treated with tacrolimus,15 16 only one pilot study has focused on the neuroprotective outcomes.32 In this Phase II clinical trial, Phan and Schuind32 did not succeed to demonstrate any evidence that tacrolimus enhances nerve regeneration, possible explained by a number of problems including the higher tacrolimus doses and delay in commencing treatment. Tacrolimus treatment in a certain dose range has neuroregenerative properties, which are being explored recently, in addition to its immunosuppressive role.10 The exact dose is worthwhile to evaluate further in basic science models with translation to humans in the near future. To date, this case report is very unique and objectively demonstrates recovery after clinically unrecoverable lower trunk BPI, most likely as a result of tacrolimus.
In conclusion, tacrolimus is commonly used as immunosuppressive therapy after SOT to prevent allograft rejection. While the neurotoxic effects are more emphasised, recent insights show that tacrolimus may also have neuroprotective properties. Here, we report a case that showed remarkable gain of hand function after BPI while being treated with tacrolimus as part of his immunosuppression protocol for his bilateral lung transplantation. Grip strength has shown recovery which is unusual in patients with similar lower trunk BPI. His clinical scenario is unusual in the sense that a sternotomy induced BPI occurred while being on immunosuppressive medications and that he required lower doses of tacrolimus secondary to the interactions with other prescribed drugs. His recovery is the first to be reporting such an unusual recovery after BPI, most likely as a result of the low dose of tacrolimus treatment.
Learning points
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This case reports an unusual recovery after brachial plexus injury, most likely as a result of the low dose of tacrolimus treatment.
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Tacrolimus in a certain low range of dose has neuroregenerative properties, besides its immunosuppressive effects.
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The mechanism of action of tacrolimus is suggested to be mediated by binding to FK506-binding protein-52, resulting in a bimodal dose response.
Footnotes
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Contributors TMS: collected data and wrote manuscript. CJA: provided pharmacological input and critically reviewed manuscript. RJS: cared for study patient and critically reviewed manuscript. AYS: provided idea, collected data, cared for study patient and critically reviewed manuscript.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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