Heart transplantation (HT) is a therapeutic option in patients with advanced and refractory heart failure. In Latin America, this procedure has been performed in more than 8,000 patients, in more than 85 institutions in 13 Latin American countries since 1968 [
Neurological complications occur between 50% and 70% of patients with HT when transient and mild effects are included. Most may occur within the first 30 days after the procedure and include cerebrovascular events, infections, seizures, encephalopathy, and neurotoxicity due to immunosuppressive medication. Neurological involvement is of particular concern because of its impact on patients’ functional prognosis and survival [
The most frequently maintained immunosuppressive agents used in heart transplants are corticosteroids, calcineurin inhibitors, and antimetabolites. Corticosteroids induce commonly acute neuropsychiatric symptoms including delirium, sleep disorders, depression, and cognitive decline. Cyclosporine and tacrolimus are both calcineurin inhibitors and can induce encephalopathy, seizures, akinetic mutism, and posterior reversible encephalopathy syndrome. Mycophenolate mofetil and azathioprine are antimetabolites. Mycophenolate mofetil does not have a significant direct neurotoxicity, but it may cause headaches on first doses. Azathioprine is rarely used for heart transplantation [
Three cases of HT patients with PRES associated with the use of tacrolimus observed at different times after the procedure are described in a cohort of 223 heart transplant patients in a Colombian hospital. Clinical and radiological information is in Table
Description of patients with PRES after heart transplant.
Case 1 | Case 2 | Case 3 | |
---|---|---|---|
Gender | Male | Male | Female |
Age (years) | 27 | 67 | 29 |
Etiology of HF | Becker muscular dystrophy | Ischemic heart disease | Chagas’ heart disease |
Onset of PRES symptoms (days) | 6 | 5 | 58 |
Symptoms | Decreased visual acuity, generalized tonic-clonic seizures, altered level of consciousness | Blurred vision generalized tonic-clonic seizures, altered level of consciousness | Blurry vision generalized tonic-clonic seizures, altered level of consciousness, severe headache |
Previous drugs | Tacrolimus MMF, methylprednisolone, TMP/SMX, acyclovir, vancomycin | Tacrolimus MMF, methylprednisolone, TMP/SMX, acyclovir, vancomycin, ceftriaxone | Tacrolimus MMF, prednisone, TMP/SMX, acyclovir, diltiazem, losartan |
Hemoglobin (mg/dl) | 9.0 | 10 | 8.5 |
Leukocytes (cel/ml) | 6,470 | 8,540 | 14,130 |
Platelets (cel/ml) | 130,000 | 140.000 | 441,000 |
Creatinine (mg/dl) | 0,9 | 0,8 | 0,88 |
Sodium (mEq/l) | 141 | 139 | 135 |
Potassium (mEq/l) | 3.9 | 4.0 | 5.97 |
Glycemia (mg/dl) | 138 | 165 | 145 |
Tacrolimus (ng/dl) | 2.6 | 8.9 | 17.4 |
Brain MR | Bilateral and symmetrical parietal and occipital cortical-subcortical hyperintensities in the FLAIR and T2 sequences (Figure | Asymmetric cortical hyperintensities in the parietal and occipital lobes (Figure | Hyperintense lesions of posterior cortical and subcortical predominance without abnormal enhancements with the contrast agent (Figure |
Management | Discontinuing tacrolimus, starting cyclosporine, levetiracetam | Discontinuing tacrolimus, starting cyclosporine, levetiracetam | Discontinuing tacrolimus, starting cyclosporine, levetiracetam |
Recurrence of symptoms at 6 months | None | None | None |
HF: heart failure; PRES: posterior reversible encephalopathy syndrome; HT: heart transplantation; MMF: mycophenolate mofetil; TMP/SMX: trimethoprim-sulfamethoxazole; NMR: nuclear magnetic resonance.
Brain MR of case 1. (a) Fluid-attenuated inversion recovery sequence showing occipital hyperintensities in occipital gyri. (b) T2-weighted sequence of the same patient showing hyperintensities in the occipital lobe.
Brain MR of case 2. (a) Fluid-attenuated inversion recovery sequence showing extensive bilateral asymmetrical occipital hyperintensities in the occipital lobe and (b) its representation on T2-weighted sequence.
Brain MR of case 3. (a) Fluid-attenuated inversion recovery sequence showing occipitoparietal hyperintensities and (b) its representation in T2-weighted sequence.
PRES was initially described in 1996 [
Reported cases compared with reported cases in Literature.
Ref | Sex | Age (years) | Days post-HT | Tacrolimus | Steroids | MMF | Sequelae |
---|---|---|---|---|---|---|---|
Reported cases | |||||||
— | M | 27 | 6 | Yes | Yes | Yes | No |
— | M | 67 | 5 | Yes | Yes | Yes | No |
— | F | 29 | 58 | Yes | Yes | Yes | No |
Cases in literature | |||||||
1 | F | 68 | 14 | Yes | No | Yes | No |
1 | M | 19 | 44 | Yes | No | Yes | No |
2 | F | 26 | 7 | Yes | Yes | Yes | No |
2 | M | 33 | 15 | Yes | Yes | Yes | No |
3 | M | 52 | 8 | Yes | Yes | Yes | Yes |
4 | M | 37 | 16 | Yes | Yes | Yes | No |
5 | F | 32 | 5 | Yes | Yes | Yes | No |
6 | F | 30 | 45 | No | Yes | Yes | No |
7 | F | 22 | 5 | Yes | No | Yes | No |
8 | M | 10 | 10 | Yes | Yes | Yes | No |
9 | F | 54 | 14 | Yes | No | Yes | No |
10 | M | 18 | 150 | Yes | Yes | Yes | No |
11 | F | 20 | 60 | Yes | Yes | Yes | No |
12 | M | 10 | 4 | Yes | Yes | Yes | No |
13 | M | 12 | 4 | Yes | Yes | Yes | No |
Ref: reference; HT: heart transplantation; MMF: mycophenolate mofetil.
PRES is characterized by an alteration of the level of consciousness, seizures, headache, visual disturbances, neurological deficit, and status epilepticus. Fugate and Rabinstein [
Brain resonance usually reports bilateral and asymmetric hyperintensities in T2-FLAIR sequences of the occipital and parietal regions, but transient lesions can also be found in the anterior region, cerebellum, centrum semiovale, pons, and hippocampus. Also, coexistent ischemic lesions can be present [
Histopathological findings of cellular edema, disruption of the blood-brain barrier, and, in some cases, necrosis are also observed [
The onset of symptoms usually occurs during the first month posttransplantation and rarely after the first year despite the chronic use of CI and dose titration during follow-up. The immediate postsurgical period and the following 30 days are critical, since the patient has been suffering from a chronic and debilitating disease with a significant compromise of the functional reserve and subsequently undergoes a major surgery with varying degrees of hemodynamic compromise, tissue hypoperfusion, and administration of immunosuppressive drugs. The reason for the greater incidence of PRES within the first 30 days is not known, but it may be favored by all the factors mentioned above [
The harmful effects of CI on the endothelium do not seem to be dose-dependent, since many reported cases show normal serum tacrolimus levels at the time of PRES diagnosis (Table
Despite the lack of a general guideline, switching from tacrolimus to cyclosporine is a common measure in the cases published to date. Cyclosporine is effective in preventing organ rejection but has also a risk of causing PRES and other types of neurotoxicity [
Neurological complications as PRES in HT patients can occur early after the procedure. Early diagnosis and treatment reduce the risk of more serious outcomes and associated mortality. CI-associated PRES in HT patients is a neurological complication that should be suspected when early “typical manifestations” of an altered level of consciousness, visual disturbances, and seizures appear. The timely diagnosis and treatment of events, change of immunosuppressive therapy to cyclosporine, and multidisciplinary follow-up could reduce the incidence of sequelae.
Calcineurin inhibitors
Heart failure
Heart transplantation
Mycophenolate mofetil
Nuclear magnetic resonance
Posterior reversible encephalopathy syndrome
Trimethoprim-sulfamethoxazol.
No data were used to support this study.
The authors of this manuscript have no conflicts of interest to disclose.