Background
Hematopoietic stem cell transplantation (HSCT) is the most effective curative therapy for a variety of hematological disorders [
1]. Excitingly, the success of haploidentical HSCT (HID-HSCT) has ushered in a new era wherein “everyone has a donor” [
2]. The number of children with hematopathy who undergo HID-HSCT has increased dramatically in China, where donor sourcing has been complex because the former one-child policy resulted in sibling donors being a relative rarity [
3]. However, the success of HSCT is restricted by graft-versus-host disease (GvHD), a serious complication that affects quality of life and is the main cause of death after transplantation [
4,
5]. Prophylaxis against GvHD usually involves the administration of a calcineurin inhibitor, such as cyclosporine A (CSA) or tacrolimus, together with an immunosuppressant, such as low-dose methotrexate or mycophenolate, although alternative agents are also available [
6].
CSA is the cornerstone of GvHD prophylaxis. However, neurotoxicity is one of the most common early complications occurring with CSA usage in clinical practice because CSA has a narrow therapeutic index and large inter-individual and intra-individual variability in its pharmacokinetics [
7,
8]. Neurotoxicity occurs in 5–11% of patients receiving CSA as GvHD prophylaxis after HSCT [
9‐
13]. The presentation of CSA-related neurotoxicity includes impaired consciousness, seizures, visual disturbance, headache, involuntary movements and paresis [
9‐
14]. Magnetic resonance imaging (MRI) usually shows radiologic features of posterior reversible encephalopathy syndrome (PRES) such as focal regions of symmetric edema affecting the white mater of the parietal and occipital lobes [
15]. CSA-related neurotoxicity usually resolves completely with dose reduction or drug withdrawal, but this can have major implications on clinical outcomes, particularly in the face of ongoing GvHD. Furthermore, some CSA-related neurological lesions are irreversible and associated with the later occurrence of epilepsy and persistent abnormalities in the electroencephalogram (EEG) [
16]. However, little information is available regarding CSA-related neurotoxicity in children undergoing HID-HSCT.
In this study, we retrospectively examined the data of children who underwent HID-HSCT in order to describe the risk factors and long-term outcomes of CSA-related neurotoxicity. Our aim was to identify factors that potentially could be targeted to prevent post-transplantation CSA-related neurotoxicity or facilitate its early diagnosis and thereby improve survival outcomes and quality of life for patients following HID-HSCT.
Discussion
A notable finding of this study was that 13.7% of children who underwent HID-HSCT for hematopathy developed CSA-related neurotoxicity after a median 38 days. Furthermore, 6 of the 7 patients with CSA-related neurotoxicity had MRI features consistent with PRES, although 1 patient exhibited atypical abnormalities. Hypertension was the most common prodrome, occurring in 71% of those who developed CSA-related neurotoxicity. Importantly, hypertension during prophylaxis with CSA was more common in patients with CSA-related neurotoxicity than in those without neurotoxicity (71% vs. 11%). Our findings indicate that CSA-related neurotoxicity is not uncommon in children with hematopathy undergoing HID-HSCT. Furthermore, blood pressure should be carefully evaluated during the early post-transplantation period, since hypertension was the most common prodrome and the only factor in our analysis that differed significantly between patients with CSA-related neurotoxicity and those without.
In this case series, the incidence of CSA-related neurotoxicity was 13.7% in children with hematological malignancies or aplastic anemia treated with HID-HSCT. This incidence was higher than 4.7% reported by a previous Italian multi-center retrospective study [
20]. This might be based on the following reasons. On the one hand, the patients in the Italian study mostly had nonmalignant hematological diseases, and previous studies have suggested that the incidence of CSA-related neurotoxicity after HSCT is higher in patients with malignant disorders (9–28.8%) compared with those with nonmalignant disorders (4–11%) [
14,
21]. On the other hand, transplantation was mostly HLA-matched allo-HSCT and autologous HSCT in Zama et al. [
20], while HLA-unmatched HSCT is considered a risk factor for PRES [
22]. In addition, the incidence of CSA-related neurotoxicity may be associated with donor type. For example, Faraci et al. reported that the rate of neurological complications varied with the source of stem cells (27.1% for cells from unrelated donors, 13.9% for cells from related donors, and 2.3% for autologous cells) [
11]. Similarly, Koh et al. described neurotoxicity rates of 18.0% for unrelated donors, 11.1% for mismatched related donors and 3.3% for matched related donors [
10]. Moreover, Elgarten et al. reported no cases of calcineurin inhibitor-related neurotoxicity in pediatric patients with malignant and nonmalignant diseases who underwent HSCT with matched sibling donors [
23]. Since Zimmer et al. also found that the frequency of CSA-related neurotoxicity increased with greater HLA disparity between donor and recipient [
24], it is likely that our rate of 13.7% would be higher than that for children who receive HSCT from HLA-matched siblings.
Several factors may be associated with a higher incidence of CSA-related neurotoxicity in pediatric patients who undergo HID-HSCT. First, patients with GvHD above grade II may be at an increased risk of neurotoxicity [
25]. Second, CSA-related neurotoxicity is more likely to occur in patients undergoing HSCT from unrelated or unmatched donors [
26], which in part may be due to differences in GvHD incidence and severity. Third, the use of intravenous busulfan in the preparative regimen can induce seizures, and this may play a role in the subsequent appearance of CSA-related neurotoxicity [
14]. Fourth, younger children (< 6 years of age) tend to suffer more severe seizures in the acute stage than older patients and are relatively more likely to develop epilepsy and neurotoxicity disorders in the future [
19]. The vertebrobasilar circulation in children has reduced adrenergic innervation [
27], and is less tolerant to changes in arterial blood pressure [
28]. Therefore, young children may be particularly susceptible to CSA-related neurotoxicity. Fifth, there is evidence that hypertension may be associated with CSA-related neurotoxicity. For example, hypertension has been reported as a prodrome to CSA-related neurotoxicity in 83% [
14] and 46% [
29] of patients, which is broadly comparable to our finding that 71% of patients exhibited hypertension as a prodrome. Furthermore, hypertension after CSA treatment was the only factor in our analysis associated with an increased risk of CSA-related neurotoxicity.
Neuroimaging now plays a central role in the diagnosis and long-term follow-up of CSA-related neurotoxicity. CT is typically the first tool used to investigate patients with acute neurological disorders, but this imaging technique identifies lesions in only about 50% of PRES cases [
30]. Since children receiving transplants can present with a wide spectrum of acute neurologic complications, MRI-based evaluation is essential for the accurate diagnosis of PRES. DWI and ADC maps can help to distinguish vasogenic edema from cytotoxic edema [
31]. Vasogenic edema typically presents as hyperintensity on ADC and isointensity or hypointensity on DWI, while cytotoxic edema usually manifests as hypointensity on ADC and hyperintensity on DWI [
32]. Although CSA-related neurotoxic events are typically thought to be confined to fluid extravasation, more severe endothelial damage has been reported, including erythrocyte extravasation with parenchymal hemorrhage [
33]. Cerebral hemorrhage is associated with PRES in 5–19% of cases [
34], which might explain the focal hemorrhages observed in the MRI scans of patient #4 in our study.
The clinical and imaging manifestations of PRES are reversible in the majority of patients (70%) provided CSA is promptly reduced in dosage or withdrawn, but a delay in the diagnosis and treatment of PRES can result in irreversible neurological damage [
33]. Karia et al. reported a strong association between MRI severity and clinical outcome [
35]. Furthermore, children with persistent EEG or imaging abnormalities have been reported to be at higher risk of seizure recurrence following CSA-related neurotoxicity [
36]. Cerebral hyperperfusion due to hypertension and aggravation of vascular endothelial injury may be important mechanisms by which CSA increases the permeability of the blood-brain barrier [
37]. Irrespective of the underlying pathology, MRI and electroencephalography can be extremely useful for the detection of lesions due to CSA-related neurotoxicity and the long-term follow-up of patients with persistent abnormalities. In the present study, three patients with persistent EEG or imaging abnormalities had neurological sequelae. However, two patients subsequently recovered, and the symptoms in the other patient were controlled after standardized treatment.
In the case of severe hypertension during the acute phase of neurotoxicity, arterial blood pressure should be reduced by ∼25% within the first hour (after the exclusion of cerebral infarction) and then more slowly [
38]. CSA should be discontinued following the occurrence of neurotoxicity, and tacrolimus is the most commonly used alternative agent in the event of CSA-related neurotoxicity [
13,
34,
39]. Although tacrolimus is also associated with neurotoxicity [
13,
39], it did not produce neurological adverse effects in this series of patients. Anti-convulsive therapy should be administered as early as possible to control ongoing seizures. Prolonged prophylactic treatment with anti-epileptic drugs is unnecessary in patients with occasional or provoked seizures due to CSA-related neurotoxicity, but such drugs should be considered in cases with later development of secondary epilepsy [
34]. In the present study, 1 of the 7 patients with CSA-related neurotoxicity (14%) required long-term anti-convulsive therapy.
The 5-year OS rate for the pediatric patients who developed CSA-related neurotoxicity after HID-HSCT was not significantly different to that for the patients who did not exhibit neurotoxicity. This is a promising finding, as it suggests that appropriate detection and intervention can ameliorate the long-term consequences of these relatively common adverse events.
This study has some limitations. First, this was a retrospective analysis, so the results are prone to information bias and selection bias. In addition, the rate of hypertension could be underestimated in control patients. Second, this was a single-center study, so the generalizability of the findings is not known. Third, the sample size was small, so the study may have been underpowered to detect some real differences between groups. Fourth, unknown confounding factors may have influenced the analysis. Fifth, CSA-related neurotoxicity was diagnosed on the basis of clinical and radiological findings, but it is possible that some mild cases may have been missed, leading to an underestimation of the incidence.
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