Tacrolimus-induced posterior reversible encephalopathy syndrome following liver transplantation

Abstract

In this editorial, we talk about a compelling case focusing on posterior reversible encephalopathy syndrome (PRES) as a complication in patients undergoing liver transplantation and treated with Tacrolimus. Tacrolimus (FK 506), derived from Streptomyces tsukubaensis, is a potent immunosuppressive macrolide. It inhibits T-cell transcription by binding to FK-binding protein, and is able to amplify glucocorticoid and progesterone effects. Tacrolimus effectively prevents allograft rejection in transplant patients but has adverse effects such as Tacrolimus-related PRES. PRES presents with various neurological symptoms alongside elevated blood pressure, and is primarily characterized by vasogenic edema on neuroimaging. While computed tomography detects initial lesions, magnetic resonance imaging, especially the Fluid-Attenuated Inversion Recovery sequence, is superior for diagnosing cortical and subcortical edema. Our discussion centers on the incidence of PRES in solid organ transplant recipients, which ranges between 0.5 to 5 +ACU-, with varying presentations, from seizures to visual disturbances. The case of a 66-year-old male status post liver transplantation highlights the diagnostic and management challenges associated with Tacrolimus-related PRES. Radiographically evident in the parietal and occipital lobes, PRES underlines the need for heightened vigilance among healthcare providers. This editorial emphasizes the importance of early recognition, accurate diagnosis, and effective management of PRES to optimize outcomes in liver transplant patients. The case further explores the balance between the efficacy of immunosuppression with Tacrolimus and its potential neurological risks, underlining the necessity for careful monitoring and intervention strategies in this patient population.

Key Words: Posterior reversible encephalopathy syndrome; Liver transplantation; Tacrolimus; Immunocompromised patients; Neurological complications; Solid organ transplant

Core Tip: Tacrolimus, a crucial immunosuppressant in liver transplantation, is associated with the rare but serious complication of posterior reversible encephalopathy syndrome (PRES). Although the incidence is relatively low (0.5%-5%) in solid organ transplant recipients, the presentation of PRES can vary significantly, including seizures and visual disturbances. This condition, primarily affecting the parietal and occipital lobes, underscores the need for diligent monitoring and early intervention in liver transplant patients undergoing Tacrolimus therapy. The case presented highlights the complexities in diagnosing and managing Tacrolimus-related PRES, emphasizing the critical balance between adequate immunosuppression and the risk of severe neurological adverse effects.

INTRODUCTION

Tacrolimus, also known as FK 506, is a potent macrolide antibiotic originating from Streptomyces tsukubaensis, recognized for its robust immunosuppressive capabilities[1]. Its immunosuppressive mechanisms closely mirror those of cyclosporine, a calcineurin inhibitor (CNI). Cyclosporine impedes T cell transcription of nuclear factor of activated T-cells by binding to the immunophilin FK-binding protein (FKBP). This interaction forms a complex that effectively inhibits IL-2 transcription, Calcineurin phosphatase, T-lymphocyte signal transduction, and Calcium-dependent events[2]. Tacrolimus further enhances its immunomodulatory and anti-inflammatory effects by amplifying the effectiveness of glucocorticoids and progesterone. This augmentation occurs through its binding to FKBPs within the hormone receptor complex, effectively hindering the degradation process[3].

Notably, Tacrolimus has demonstrated remarkable success in preventing allograft rejection, especially in patients unresponsive to cyclosporine, thereby catalyzing a paradigm shift in the landscape of solid organ transplant management. It is crucial to note that the drug displays a substantial pharmacokinetic and pharmacodynamic variability. Following oral administration, the drug undergoes rapid absorption and exhibits extensive binding to erythrocytes in the blood, leading to significantly higher concentrations in blood compared to plasma (estimated to be 20:1). In the plasma, 99% of the drug is bound to proteins[4]. Tacrolimus undergoes systemic metabolism primarily in the liver, predominantly mediated by cytochrome P450 3A4 (CYP3A4) and CYP3A5 enzyme system. However, there is also evidence of pre-systemic gastrointestinal metabolism occurring in the intestinal wall via CYP3A4 and CYP3A5, contributing to a decrease in the oral bioavailability of tacrolimus. Additionally, it serves as a substrate for the efflux transporter P-glycoprotein, influencing gastrointestinal absorption and cellular distribution. The variability in pharmacokinetics has been attributed to polymorphisms of CYP3A5 enzymes, P-glycoprotein, and other factors like age, race, gender, hepatic dysfunction, organ transplanted and time post transplantation[5,6]. The primary pathway for eliminating tacrolimus metabolites is through biliary excretion, with a minor portion excreted in the urine[7]. Tacrolimus exhibits a terminal elimination half-life of approximately 12 h, encompassing a range from 3.5 to 40.5 h[8]. The clinical application of tacrolimus is not without potential drawbacks. The principal adverse effects associated with tacrolimus include neurotoxicity, nephrotoxicity, alterations in glucose metabolism, heightened susceptibility to infections or malignancies, and the infrequent yet severe complication known as Tacrolimus-related posterior reversible encephalopathy syndrome (PRES)[1,9-11].

PRES encompasses a range of neuroradiological symptoms initially described in 1996 by Hinchey and colleagues[12]. Its presentation includes headaches, visual disturbances, altered consciousness, seizures, and focal neurological deficits, and is often accompanied by elevated blood pressure, leading to hypertensive emergencies in many cases. The term PRES was coined after studying the neuroradiological manifestations in the posterior occipital circulation in a case of vasogenic edema. It can affect individuals from as young as two years old to older individuals[13], with a female predominance[14]. While its name suggests reversible etiology, that may not always be true. It has a strong association with hypertensive states; however, a broad spectrum of diseases can lead to PRES, namely preeclampsia, post-stem cell transplantation, autoimmune disorder, and use of cytotoxic medications, among others[15].

The incidence of PRES following solid organ transplantation is reported to range from 0.5%-5%[16], contingent on the specific organ transplanted. While hypertension is a prevalent condition in this population and may lead to the development of PRES, other contributing factors include the administration of immunosuppressive medications like CNI and long-term corticosteroids, use of antibiotics, reperfusion injury post-surgery, and so on. CNI, such as Tacrolimus, is commonly used post-transplant to avoid rejection and help sustain graft function. Elevated levels of circulating CNI have been linked with the development of PRES. The most common presenting symptoms in such patients include seizures followed by encephalopathy and headaches. However, the duration of occurrence of PRES varies based on the solid organ transplanted. In the case of liver transplants, it could manifest as early as 2 months post-transplant[17].

CNI most commonly causes PRES in post-transplant patients. However, the exact pathophysiology behind the same has yet to be elucidated entirely. CNI, particularly Tacrolimus, disrupts the cell membrane, leading to increased cytoplasmic calcium influx and apoptosis of the brain's capillary endothelium. This leads to damage to the blood-brain barrier and downregulation of P-glycoprotein, essential for membrane integrity. These mechanisms have been postulated in the development of PRES secondary to CNI use[18,19].

Vasogenic edema of the subcortical white matter, rather than cytotoxic edema, primarily influences the neuroimaging features of Tacrolimus-associated PRES. However, cases of both coexisting types indicating irreversible damage have been reported[20,21]. Primarily, there is symmetric involvement of the parietal and posterior areas of cerebral circulation with occasional involvement of the frontal lobe[22].

Computed tomography (CT) is the initial method for detecting hypodense lesions in posterior encephalopathy. However, magnetic resonance imaging (MRI), especially the Fluid-Attenuated Inversion Recovery (FLAIR) sequence, is a superior diagnostic tool, demonstrating higher sensitivity in detecting cortical and subcortical edema with more pronounced hyperintense signal changes than conventional sequences[10]. Recent advancements in imaging technologies, namely magnetic spectrography, susceptibility-weighted imaging, and positron emission tomography (PET), have significantly contributed to diagnosing more complex cases[23,24]. Additionally, there is compelling data for the utility of fluorodeoxyglucose (FDG)-PET scan in the diagnosis of PRES, especially as it aids in differentiating it from low-grade tumors. In PRES, the affected areas exhibit decreased FDG uptake, indicating reduced metabolism (associated with increased cerebral circulation). In contrast, brain tumors typically display increased FDG uptake attributable to their elevated metabolic rate[23,25]. This sophisticated imaging tool plays a crucial role in diagnostics, as both PRES and malignancy are potential complications observed in solid-organ transplant patients undergoing immunosuppressive therapy[26].

A 66-year-old male with a pertinent history of orthotopic liver transplantation (OLT) for hepatocellular carcinoma, Immunocompromised on chronic immunosuppression, end-stage renal disease (ESRD) on hemodialysis presented to the emergency department (ED) via emergency medical services after sustaining a mechanical fall.

Collateral information obtained from the patient’s spouse reports worsening mental status and gait instability over the last month before the presentation. The patient was reported to have hit his head from the fall but did not lose consciousness. The spouse also reported a tremor-like movement of his right lower extremity following the fall, but she denies observing whole-body tonic-clonic activity. There was no tongue biting, bowel incontinence, or urinary incontinence (however, the patient is anuric at baseline, given ESRD status).

In the ED, the patient was found to be hemodynamically stable. Given the patient’s altered state with a Glasgow coma scale score of 10, a full neurological exam could not be performed, but he was observed to have right-hand high-amplitude intention tremors. His labs were pertinent for hyperglycemia, normocytic anemia, mild thrombocytopenia, mild hyponatremia, and elevated creatinine, consistent with his ESRD (Table 1). CT head was done and did not show any evidence of acute territorial infarct, intracranial hemorrhage or mass effect. There were nonspecific areas of white matter hypodensity and generalized parenchymal volume loss, otherwise, it was generally unremarkable.

Table 1 Relevant laboratory data.

Variable	Results on arrival	Reference range
White blood cell count (k/uL)	6.45	4.50-11.00
Red blood cell count (M/uL)	3.21	4.40-5.90 (male); 3.80-5.20 (female)
Hemoglobin (g/dL)	8.4	13.0-18.0 (male); 12.0-16.0 (female)
Hematocrit (%)	24.7	40.0-52.0 (male); 35.0-47.0 (female)
MCV (fL)	82.3	80.0-100.0
Platelet count (k/uL)	131	150-440
ESR (mm/h)	16	< 20
CRP (mg/L)	2.1	< 5.0
Sodium (mEq/L)	132	136-145
Potassium (mEq/L)	4.4	3.4-4.4
Chloride (mEq/L)	89	98-107
Bicarbonate (mEq/L)	33	22-29
BUN (mg/dL)	33	8-26
Creatinine (mg/dL)	6.63	0.72-1.25
Ammonia (umol/L)	12	18-72
Hemoglobin A1C (%)	11.4	4.3-5.7
Tacrolimus level (ng/mL)	20.6 (on admission)	3-5 (goal therapeutic trough level in the late post-transplant phase)

BUN: Blood urea nitrogen; MCV: Mean corpuscular volume; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein.

Further workup for acute toxic metabolic encephalopathy with liver function tests, thyroid function tests, venous blood gas, ammonia levels, and blood culture was within normal limits. The patient was subsequently admitted to the Internal Medicine service for further evaluation of his encephalopathy. A review of his home medication list included amlodipine 10 mg daily, Carvedilol 6.25 mg twice daily, hydralazine 10 mg three times daily, losartan 100 mg daily, paroxetine 20 mg every morning, basal insulin degludec 15 units daily, Insulin lispro 7 units three times daily after meals, entecavir 0.5 mg every Monday, levetiracetam 500 mg twice daily, tacrolimus 4 mg every morning and 3 mg at night. His blood toxicology report was generally unremarkable. He had mildly elevated troponins which peaked at 0.05, however he denied any chest pain or dyspnea and electrocardiography did not show any ischemic changes.

Of note, patient underwent OLT in May 2013 for hepatocellular carcinoma secondary to underlying chronic hepatitis C and alcoholic cirrhosis. He was placed on chronic immunosuppression with tacrolimus monotherapy with a goal trough level of 3-5 ng/mL in the late post-transplant phase. His post-transplant course was complicated by ESRD, likely related to multiple risk factors and comorbidities including tacrolimus toxicity, Hypertension and uncontrolled diabetes. A random tacrolimus trough level done on day 1 of admission was found to be 20.6 ng/mL. Nephrology, neurology and transplant hepatology were consulted and his tacrolimus was temporarily held due to suspicion of Tacrolimus neurotoxicity.

MRI of the brain was done which showed bilateral cortical and subcortical hyperintense lesions (arrows) involving occipital lobes and parietal lobes on Axial FLAIR sequence imaging (Figure 1).

Figure 1 Magnetic resonance imaging of the brain (Axial Fluid-Attenuated Inversion Recovery sequence imaging) showing bilateral cortical and subcortical hyperintense lesions (arrows) involving occipital lobes and parietal lobes. A: Hyperintense lesions in the parietooccipital sulcus (white arrow); B: Hyperintense lesions at the transverse occipital fasciculi (white arrow).

His workup excluded seizures and any infectious or metabolic causes. Given his markedly elevated tacrolimus trough levels, clinical presentation and impressive MRI findings, PRES secondary to tacrolimus toxicity was the most probable diagnosis. Patient’s mental status returned to baseline, and his tacrolimus twice daily (4 mg in the morning and 3 mg at night) was resumed prior to discharge, with follow-up with a transplant hepatology clinic set up to review alternatives for immunosuppressive regimen.

MECHANISMS OF PRES DUE TO TACROLIMUS

The use of tacrolimus in solid-organ transplant patients has been associated with various complications, including a rare but critical neurological disorder known as PRES[9-11]. Tacrolimus related PRES can present with a wide range of clinical symptoms, including tremors, headaches, seizures, gait instability and incoordination, altered mental status, visual disturbances, nausea and vomiting. The most common presentation is usually seizures and altered mental status[27]. Due to its nonspecific symptoms, PRES should always be considered in the appropriate patient subset as early recognition and timely intervention are crucial for reversing PRES and preventing long-term clinical sequelae.

Various theories aim to elucidate the pathophysiology of PRES, yet its exact cause remains elusive, and no single mechanism explains the development of PRES in all cases. The association between severe hypertension and PRES is well established in the extant literature[12,28]. The suggested mechanism posits that a rapid surge in blood pressure triggers the acute disruption of the blood-brain barrier, causing the failure of cerebral autoregulation. Consequently, cerebral arterioles dilate, resulting in the interstitial extravasation of serum protein and fluid, ultimately leading to vasogenic edema. Given that autoregulatory mechanisms rely on the neurogenic response, areas with poorer innervation in the posterior circulation become more susceptible to heightened blood pressure. The less adaptive mechanism in the posterior circulation of the brain for dealing with increasing pressures and preventing blood-brain barrier disruption when compared to the anterior circulation makes it more prone to vasogenic edema[29-32], hence the name ‘Posterior’ reversible encephalopathy syndrome.

While hypertension remains a prevalent theory, it is contested because PRES has also been observed in normotensive patients and our patient is a prime example. Similarly, a retrospective study by Liman et al[33] also revealed that 50% of PRES patients did not exhibit severe hypertension before presentation. This disparity in blood pressure findings in patients found to have PRES suggests that there are probably other factors at play in how PRES develops and which patients are prone to having PRES. Another postulated mechanism is through direct cytotoxicity by exogenous toxins. These toxigenic substances cause direct endothelial damage, leading to blood-brain barrier disruption. This is likely the mechanism through which tacrolimus causes PRES[34,35].

CNI, notably tacrolimus, disrupt the cell membrane, triggering an increase in cytoplasmic calcium influx and the apoptosis of the brain's capillary endothelium. This process results in damage to the blood-brain barrier, downregulation of P-glycoprotein, a loss of membrane integrity and ultimately vasogenic edema. However, as previously highlighted, there is evidence to suggest that beyond vasogenic edema, there is sometimes concurrent cytotoxic edema especially if left untreated suggesting progression to irreversible damage[20,21,36]. In such instances, utilizing diffusion-weighted MRI and assessing the apparent diffusion coefficient can be beneficial for distinguishing between conditions[36]. Brain MRI stands out as the most sensitive diagnostic tool, revealing predominantly posterior subcortical white matter and gray matter lesions consistent with PRES, while excluding differential diagnoses, such as infective encephalitis, sinus thrombosis, and cerebral ischemia.

Interestingly, while our patient was found to have supratherapeutic tacrolimus trough levels (20.6 ng/mL), numerous studies have shown that elevated tacrolimus levels beyond the therapeutic range are not necessary to trigger neurological complications or a PRES event[37-39]. Therefore, the serum drug level is not a sensitive diagnostic indicator for neurotoxicity induced by tacrolimus. There are suggestions that the cerebrospinal fluid (CSF) level could offer better utility than the serum level, hypothesizing that the drug may accumulate in the central nervous system after crossing the blood–brain barrier, resulting in a CSF level that significantly surpasses the corresponding serum tacrolimus levels[40]. However, there is currently limited data on this, necessitating further research into this claim.

In our case, the diagnosis of Tacrolimus-associated PRES was established based on the following criteria: The emergence of new-onset neurological symptoms, including altered mental status, headaches, and newly developed tremors; confirmed compliance with tacrolimus, indicated by elevated drug levels in our patient; distinctive brain MRI findings revealing posterior vasogenic edema; and a comprehensive workup ruling out infectious, metabolic, structural, and other medications that could potentially account for the patient's symptoms.

CLINICAL IMPLICATIONS

The management of PRES primarily adopts a symptomatic approach, with a key emphasis on regulating blood pressure. Additionally, when feasible, discontinuation of the causative drug is recommended. In cases where immediate cessation is impractical, considering dose reduction becomes a viable alternative. For individuals presenting with seizures, the administration of anti-seizure medications (ASMs) may be necessary. A standard practice involves tapering ASMs as symptoms alleviate, and MRI findings show resolution, a trend observed in the majority of patients.

Our diagnostic approach was further substantiated when the patient's symptoms exhibited resolution after tacrolimus was withheld for several days. This underscores the pivotal role of identifying and addressing the causative agent in PRES management, highlighting the potential reversibility of symptoms upon intervention. These observations contribute valuable insights to the broader understanding of PRES and its therapeutic strategies.

CONCLUSION

Tacrolimus-related PRES represents a significant and potentially severe complication in transplant patients undergoing immunosuppressive therapy with Tacrolimus. This neurological disorder manifests with cognitive and neuropsychiatric symptoms, presenting complex challenges for both patients and healthcare providers. Achieving a delicate balance between maintaining sufficient immunosuppression and averting neurotoxicity is pivotal for successful management. Timely recognition and intervention are of utmost importance, necessitating healthcare teams to remain vigilant in identifying subtle signs indicative of Tacrolimus-related PRES. Swift adjustments to Tacrolimus doses or consideration of alternative immunosuppressive regimens may be essential to mitigate the progression of this condition. Ongoing research plays a crucial role in deepening our understanding of the pathophysiological mechanisms involved and identifying predisposing risk factors associated with Tacrolimus-related PRES. Despite the inherent challenges posed by this condition, healthcare providers can effectively manage and reduce the impact of Tacrolimus-related PRES. By adopting a proactive approach, healthcare teams contribute to improved outcomes and enhanced quality of life for transplant recipients. This comprehensive perspective underscores the importance of continued research and clinical vigilance in refining our strategies for the prevention, recognition, and management of Tacrolimus-related PRES in the context of immunosuppressive therapy.