Key words : Childhood, Posterior reversible encephalopathy syndrome, Seizure, Stroke

Pediatric heart transplant (PHTx) is increasingly used for the treatment of pediatric patients with end-stage heart disease. Many complications such as infections, graft vascular disease, acute graft failure, tumors, and neurologic complications are seen after heart transplant. These complications can increase mortality and morbidity rates of heart transplant recipients.

Neurologic complications in PHTx recipients have been reported to range from 23.6% to 45%, a higher rate than in adults.^1-3 Seizures, posterior reversible encephalopathy syndrome (PRES), ischemic-hemorrhagic stroke, peripheral neuropathy, transient ischemic attack, and cerebral infections are the most common neurologic complications, which are seen in the perioperative period in particular. Awareness of neurologic complications in heart transplant recipients may help to reduce mortality and morbidity risks.

In this study, the frequency, time, cause, and characteristics of neurologic complications in PHTx recipients in a single center with a large sample size were evaluated retrospectively to increase awareness of these complications in PHTx patients.

We performed a retrospective review of 37 PHTx recipients aged <18 years who received their transplant at Baskent University Hospital, Ankara, Turkey, between 2007 and 2017. This study was approved by the Baskent University Institutional Review Board (project No. KA20/232) and supported by the Baskent University Research Fund. The study protocol conforms to the ethical guidelines of the 1975 Helsinki Declaration.

Demographic and clinical factors, such as transplant age, sex, weight, body mass index (calculated as weight in kilograms divided by height in meters squared), primary heart diseases, aortic cross-clamp time, cardiopulmonary bypass time, total allograft ischemic time, and donor weight, were recorded for all heart transplant recipients. Medical records were reviewed to identify neurologic complications that were suspected in the presence of neurologic symptoms, such as seizure, headache, acute mental state change, and focal neurologic deficit. The clinical features were compared between the 2 groups, ie, PHTx recipients with and without neurologic complications.

Initial presentation symptoms and clinical findings of neurologic complications, time and duration of symptoms after transplant, physical examination findings, blood pressure, medical treatments, tacrolimus plasma levels, electrolytes and glucose plasma levels, features of neuroradiologic imaging, electroencephalography (EEG) findings, and neurologic sequelae type and severity during follow-up were recorded in recipients diagnosed with neurologic complications.

Statistical analyses were performed with the SPSS software package (version 23.0). Qualitative variables are shown as the number of cases with percentages, and quantitative variables are shown as mean values ± SD. The normality of distribution was assessed with the Shapiro-Wilk test for continuous data. Demographic and clinical parameters were compared between recipients with and without neurologic complications with the t test or the Wilcoxon rank-sum test. A value of P < .05 was accepted as statistically significant.

A total of 37 patients were evaluated. Twenty-one were female (57%), and 16 were male (43%). Transplant age ranged from 2 to 18 years (median, 13 years). The demographic and clinical data of patients with posttransplant neurologic complications are presented in Table 1. The primary diagnoses of 37 patients were dilated cardiomyopathy (DCMP) (n = 18; 48.6%), restrictive cardiomyopathy (RCMP) (n = 14; 37.8%), congenital heart disease (n = 4; 10.8%), and arrhythmogenic right ventricular dysplasia (n = 1; 2.7%).

Ten children (6 female, 4 male) showed neurologic complications after PHTx. The rate of posttransplant neurologic complications in PHTx was 27% (10/37). The median age of patients with neurologic complications was 12 years (range, 11-18 years). The primary diagnoses of these 10 recipients were DCMP (n = 7) and RCMP (n = 3). There were no significant differences between the recipients with and without neurologic complications in terms of transplant age, sex, body mass index, primary cardiac disease, total allograft ischemic time, aortic cross-clamp time, cardiopulmonary bypass time, and donor weight (P > .05).

Eight of 10 patients with neurologic complications presented with clinical signs of seizure. Two patients showed lethargic consciousness levels after the seizure. The neurologic symptoms of 2 other patients were weakness and numbness in the legs. The etiologies of the neurologic complications were PRES in 3 patients (8.1%), stroke in 2 patients (5.4%), peripheral neuropathy in 2 patients (5.4%), and hypertensive encephalopathy in 1 patient (2.7%) (Table 1). A 12-year-old female patient with DCMP developed seizure 46 days after transplant. Her blood calcineurin inhibitor (CNI) level (tacrolimus) was higher than the target level at the seizure presentation day. Therefore, she was diagnosed with drug encephalopathy related to tacrolimus. Only 1 patient with seizures had no etiology.

Eight patients showed general tonic-clonic seizures that lasted <5 minutes. The EEGs of 7 of the patients with seizures were normal; bilateral epileptic activity was seen in only 1 patient’s EEG. To treat the seizures, levetiracetam was given as monotherapy in 5 patients, and 3 patients were treated with both levetiracetam and carbamazepine. Seven patients had no sequelae or seizure recurrence during follow-up, and antiepileptic drugs were discontinued after their discharge. One female patient who had a diagnosis of stroke showed mild hemiplegia and had seizure recurrence during follow-up, and her antiepileptic treatment was continued with levetiracetam (Table 1).

High blood pressure values (>95th percentile) were seen in 4 patients with posttransplant neurologic complications. Two of these 4 patients with systemic hypertension were diagnosed with PRES, and 1 was diagnosed with stroke. The fourth patient presented with seizures and was evaluated and diagnosed with hypertension encephalopathy.

Three of 37 recipients (8.1%) developed PRES after PHTx. The clinical symptoms of 3 patients with PRES were seizures. Systemic hypertension was detected in the etiology of 2 patients with PRES. The levels of tacrolimus were normal in all PRES patients. No cause was found in the third patient. The time of onset of PRES was 5 days (range, 3-29 days). The median time to recovery from PRES onset was 8 days (range, 3-8 days). There were no sequelae in 3 patients with PRES during follow-up.

Two patients with a primary diagnosis of DCMP who had weakness and numbness in the legs were diagnosed with peripheral neuropathy in the early postoperative period. These 2 patients received extracorporeal membrane oxygenation (ECMO) treatment, and they both recovered within a month with physiotherapy and vitamin B complex treatment.

Brain magnetic resonance imaging was performed in 9 patients. The diagnosis of stroke was confirmed through radiologic imaging (brain computed tomography) in 1 patient under emergency con­ditions. Clinicoradiologic outcomes are presented in Table 1.

Neurologic complications are common after heart transplant and may cause serious morbidity and mortality. Although some studies in adult patients from Turkey with heart transplants have been published, to the best of our knowledge, the present study is the largest study to report a detailed experience from a single center in Turkey on neurologic complications in PHTx.^4,5 In the present study, we evaluated 37 pediatric patients with PHTx for neurologic complications. The rate of neurologic complications was 27% (10/37).

According to the literature, the time of occurrence of neurologic complications in PHTx recipients is reported mostly in the first postoperative month.^6-8 Heart transplant carries a higher risk in terms of neurologic complications than other solid-organ transplants in the perioperative period because of hemodynamic changes, bypass time, perioperative conditions, and hypertension. The median time for neurologic complications in our patients was 3 days (range, 2-46 days). Nine of the 10 patients developed neurologic complications in the first month after transplant and 5 in the first week. Only 1 patient, a girl aged 12 years with DCMP, developed neurologic complications as drug encephalopathy 46 days after transplant.

Neurologic complications after heart transplant can present with many neurologic symptoms such as seizures, changes in the level of consciousness, headache, and visual and auditory symptoms.⁹ The most common neurologic clinical condition in heart transplant recipients is seizure. Seizures are usually reported as generalized or multifocal but rarely focal. Mayer and colleagues, in a study that included 77 pediatric and 107 adult recipients, found the frequency of seizures was 12.8% in adult recipients and 31.8% in pediatric recipients.10 In the present study, the most common neurologic condition in the PHTx patients was seizure. The rate of seizure was 21% (8/37), all of which were generalized tonic-clonic seizures. Antiepileptic drugs were discontinued in 7 patients during follow-up; however, 1 patient with a diagnosis of stroke had epileptic activity on EEG, and her antiepileptic treatment was continued.

Posterior reversible encephalopathy syndrome is a clinical and radiologic syndrome characterized by various neurologic symptoms such as seizure, headache, acute mental state change, focal neurologic deficits, and typical radiologic findings.^1,11,12 The frequency of PRES after adult solid-organ transplant is approximately 0.5% to 5%, whereas the frequency of PRES after adult heart transplant has been reported to range from 0.62% to 1.2%.^9,12-15 In the literature, a few reports that discuss PRES after PHTx have been published, and the frequency of PRES in children has been reported to be higher than in adults. Lee and colleagues reported that 2 of 55 recipients developed PRES after PHTx.1 In another study, the frequency of PRES was 5.5% in PHTx recipients.⁶ In our study, 3 of 37 PHTx recipients developed PRES (8.1%).

Although the pathophysiology of PRES remains controversial, there are some theories to explain the pathophysiology and the underlying etiology. Two major theories have been proposed for the mechanism of PRES. One of the 2 theories suggests the deterioration of the cerebral autoregulation that regulates increased cerebral blood flow secondary to systemic hypertension. The other theory claims that endothelial damage and dysfunction lead to vasoconstriction and hypoperfusion by alteration of the intrinsic vascular tone.12,16 Therefore, blood-brain barrier dysfunction with cerebral vasogenic edema occurs in both hypotheses. According to previous reports in the literature, PRES is commonly reported with hypertension; however, PRES is also seen in the absence of hypertension in 20% to 40% of patients.13 Among our cases, 2 patients were hypertensive at the diagnosis of PRES and 1 patient was normotensive, which is in accordance with previous reports of normotensive posttransplant patients.^11-13

The typical radiologic findings of PRES are described as white matter lesions in the occipital and parietal lobes. For the magnetic resonance images of our patients with PRES, in the first case there was bilateral frontal, parietooccipital hyperintensity, and vasogenic edema; in the second case there was bilateral temporal, parietooccipital hyperintensity, and vasogenic edema; and in the sixth case we observed bilateral frontal, temporal, posterior parietal, occipital cortical, subcortical white matter intensity, and diffusion limitation.

The occurrence times of PRES after adult heart transplant were reported frequently in the first week, but it can be seen as late as 6 to 21 months after heart transplant.^1,6,12,17 However, according to case reports and a retrospective study, the occurrence time of PRES after PHTx was reported usually in the early period.^1,6,11,16 The occurrence times of PRES in our 3 recipients after PHTx were days 3, 5, and 29 and in the early period, similar to previous publications. The median time to recovery from PRES onset was 8 days (range, 3-8 days), consistent with other publications.¹⁴

Systemic hypertension has been reported in the etiology of neurologic complications, especially PRES.¹⁷ Systemic hypertension causes cerebral vasodilatation and capillary leakage as a result of transient disruption of cerebral autoregulation. This causes fluid extravasation and vasogenic cerebral edema.¹⁸ Our 4 recipients had elevated blood pressure (>95th percentile); 2 of 4 patients with systemic hypertension were diagnosed with PRES, 1 patient was diagnosed with stroke, and 1 patient with systemic hypertension presented with seizures only. The most common cause of PRES has been reported as systemic hypertension. In the literature, systemic hypertension has been found in 75% to 85% of patients with PRES.^14,19 Careful blood pressure monitoring in PHTx patients during the follow-up period, especially in the early postoperative period, is very important, and this may help to avoid complications.

Calcineurin inhibitors, including tacrolimus, which are used as immunosuppressive agents, have been reported to cause neurotoxicity in heart transplant recipients.¹⁸ The major manifestations of neurotoxicity with CNIs are PRES, encephalopathy, akinetic mutism, peripheral neurotoxicity, and seizures. Serum levels of tacrolimus are often within the therapeutic range in CNI-associated neurotoxicity, and CNI levels may not be necessarily above the upper limit of therapeutic levels in CNI-associated neurotoxicity cases. Replacement of tacrolimus with other CNIs or other immunosuppressive agents or reduction of the tacrolimus dose are the most common primary approaches in the literature.^3,18 The serum level of tacrolimus was found to be high in 1 of our patients with seizures. The tacrolimus dose was reduced in our patient who had high tacrolimus levels after the seizures; this patient had no recurrence of seizures during follow-up.

Stroke is an important cerebrovascular event that increases short- and long-term mortality after heart transplant. Generally, ischemic stroke is more common in the early posttransplant period and is associated with hypertension, arrhythmia, renal dysfunction, and infection. Morgan and colleagues found a 3% rate of stroke after PHTx. They evaluated congenital heart disease and the use of mechanical support devices such as ECMO and ventricular assist devices as an independent risk factor in the development of stroke.²⁰ Furthermore, Jarquin-Valdivia and colleagues found significantly more common transplant-associated ischemic stroke in patients with DCMP and suggested that manipulation and excision of the diseased heart might be the cause of intraoperative stroke.²¹ Stroke was seen in 2 of our patients (5.4%). The primary diagnoses of these patients were DCMP and RCMP. Stroke was not seen in 2 of our patients who were treated with ECMO, but peripheral neuropathy was observed.

Peripheral neuropathy is generally seen after cardiac surgery and may be caused by procedure, traction, and the duration of the procedures. In addition, as shown in a case report, tacrolimus may also cause peripheral neuropathy.²² Peripheral neuropathy does not cause mortality but prolongs hospital stay and may deteriorate quality of life in transplant patients. Peripheral neuropathy may occur with pain, weakness, altered sensation, or autonomic symptoms. Our 2 patients with primary diagnoses of DCMP who had weakness and numbness in the legs received a diagnosis of peripheral neuropathy in the early postoperative period. Unlike our other patients, these 2 patients had received ECMO treatment, and they both recovered within a month with physiotherapy and vitamin B complex treatment. Careful patient follow-up during and after the transplant period may help to prevent peripheral neuropathy complications.

Neurologic complications may be seen in PHTx recipients and may cause serious mortality and morbidity. To the best of our knowledge, the present study is the largest study to present a detailed experience from a single center in Turkey on neurologic complications in PHTx. The rate of neurologic complications was 27% (10/37). Although seizures, PRES, and peripheral neuropathy are reversible and well-managed sequelae do not remain, stroke is an important cause of mortality and morbidity. Careful follow-up of PHTx patients and detection and early treatment of neurologic findings may contribute to lower rates of sequelae. Multicenter research with large populations would be valuable to provide a more detailed assessment of neurologic complications in PHTx patients.

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