Introduction

Childhood neurodevelopment is a dynamic process in which the child learns to process complex levels of movement, thoughts, feelings, and relationships from birth to 5 years of age¹. It is difficult to separate physical factors from psychosocial factors. Neurodevelopmental evaluation aims to identify and quantify the level of maturation reached by a child compared with other children in their age group, allowing the identification of alterations and establishing an individualized profile of the strengths and weaknesses of the evaluated domains¹.

Worldwide, nearly 200 million children under 5 years of age are at risk of not achieving their full developmental potential². There are several causes, such as lack of stimulation, diseases of the central nervous system (CNS), malnutrition, and various treatments, including chemotherapy.

Cancer in children is currently a national public health problem as it is the second leading cause of death in patients under 15 years of age. In Mexico, the incidence of childhood cancer was 150.1 cases/million in 2015; approximately 20% of these cases occurred in patients under 5 years of age. The primary diagnoses at this age are leukemia, CNS tumors, lymphoma, sarcoma, kidney, and liver tumors³.

In general, patients with cancer diagnoses receive multimodal treatment with chemotherapy, radiotherapy, and surgery; the route of administration and doses depend on the specific diagnosis⁴.

Systemic and intrathecal chemotherapy leads to a wide range of cognitive symptoms, including slow information processing and difficulties with concentration, attention, and memory⁵. The etiology of cognitive impairment after chemotherapy remains unknown. However, several mechanisms have been postulated, such as direct neurotoxic effects, hormonal changes, immune dysregulation, coagulation in the small vessels of the CNS, and genetic predisposition to the development of cognitive impairment⁶. In a systematic review published in 2008, 13 articles on pediatric patients with leukemia were included in the study. Leukemia survivors showed lower fine motor skills, verbal memory, processing speed, and academic performance. However, there were no effects on visual memory and visual-motor skills⁵.

Neurocognitive difficulties as a result of chemotherapy have been documented primarily in adult survivors of childhood cancer. However, most pediatric studies have focused on children with tumors in the CNS⁷. To date, evidence of late cognitive sequelae has been found in childhood cancer survivors with brain tumors and acute lymphoblastic leukemia⁸. It has been proposed that chemotherapy can cause neurological damage through various neurobiological mechanisms, including damage to the blood–brain barrier and stimulation of a neuroinflammatory response⁵. Likewise, a high frequency of neurological alterations has been observed in leukemia survivors compared to their family controls⁹. However, there is no literature on the effect of cancer treatment (chemotherapy, radiotherapy, or surgery) on neurodevelopment in patients under 5 years of age.

This study aimed to analyze neurodevelopment using the Early Development Instrument (EDI) test in cancer patients under 5 years of age at the Instituto Nacional de Pediatría (National Institute of Pediatrics), considering their nutritional status as the initial data for this understudied problem.

Methods

A cross-sectional study was carried out in the Oncology Department of the National Institute of Pediatrics from February 2018 to March 2019. Patients > 1 month and < 5 years diagnosed with cancer outside the CNS were included. All patients were in an active phase of cancer treatment, which differed by drug and time according to the neoplasia type. Lumbar puncture was performed in patients with leukemia or lymphoma, and magnetic resonance imaging was performed in patients with solid tumors to rule out CNS involvement. The patients were divided into three groups according to their diagnosis: leukemia or lymphoma, solid tumors outside the CNS, and retinoblastoma. Patients with metastatic disease in the CNS, neurological diseases, or a history of skull trauma or CNS infections before their oncological diagnosis were excluded from the study. Patients with congenital abnormalities and severe hearing or visual problems at the time of diagnosis were also excluded from the study.

The parents of the patients were invited to participate in the study after providing written informed consent. The Research Ethics Committee of the National Institute of Pediatrics approved the study (No. 015/2018). Three researchers performed the EDI test. Standardization was carried out by an expert on the test who conducted exercises to apply the EDI test and repeated these exercises 2 months later (Kappa = 0.94 for its performance). The test manual, single answer sheet, and necessary materials were used. All patients were evaluated in the outpatient clinic or the oncology service. As part of their initial evaluation, patients underwent a nutritional assessment by a nutritionist at the time of their diagnosis, which included weight and height measurements; these were compared with the World Health Organization (WHO) weight indicators for age, weight-for-height, and height-for-age. The WHO weight-for-height and height-for-age z-score criteria were used to classify malnutrition: a height-for-age z-score < -2 indicated chronic malnutrition and a weight-for-height z-score < -2 indicated acute malnutrition. Patients who were assessed as having developmental delay, according to the neurodevelopmental evaluation, were sent for evaluation by a pediatric neurologist. Descriptive statistics were used for statistical analyses, including means and standard deviations for continuous quantitative variables and frequencies and proportions for qualitative variables. The odds ratio (OR), Mantel–Haenszel test, χ² test, and analysis of variance were used to compare the two groups. In addition, multiple logistic regression analysis was performed, with the OR and 95% confidence interval obtained to determine association. The analysis was performed with STATA 18.1.

Results

Forty-five patients were enrolled in the study, of whom 25 (55.5%) were male. The mean age was 26.8 (4-59) months. Regarding the oncological diagnosis, 17 (37.7%) patients had leukemia or lymphoma, 7 (15.5%) retinoblastoma, and 21 (46.6%) solid tumors outside the CNS (Table 3). In the evaluation of their nutritional status carried out at the time of diagnosis, we found that 48.8% had some degree of chronic malnutrition, and 39.8% had acute malnutrition (p = 0.37). There were no differences in nutritional stage, oncological diagnosis, or neurodevelopmental delay when considering weight. In patients with leukemia, there was a relation between low height (chronic malnutrition) and lag in neurodevelopment, with an OR of 0.66 (0.04–9.4) and p = 0.04 (Tables 4 and 5).

According to the age group, the following were included: 11 (24.4%) patients from group 14, 5 (11.1%) from group 13, 10 (22.2%) from group 12, 9 (20%) from group 11, 7 (15.5%) from group 10, and 1 (2.2%) each from groups 9, 7, and 4.

In all, 31% of patients had some biological risk factor, which was more common in patients with solid tumors (n = 9). Thirteen (28.8%) patients presented with alarm signals, of whom 9 (52%) were in the leukemia and lymphoma group (p = 0.002). Three patients (6.6%) from the retinoblastoma group presented abnormal findings in the neurologic assessment at the time of the test (p = 0.002).

Regarding the areas of development, for gross motor skills, 31 (68.8%) patients had normal development (gray), and 35 patients (77.7%) had normal fine motor development. In the language area, 33 patients (73.3%) had normal neurodevelopment; in the social area, 41 patients (91.1%) were reported as gray; and in the cognitive area, 13 patients (26%) were found as gray (only 19 patients were evaluated by their age group). It was observed that 95% of patients with solid tumors had normal fine motor development (gray) compared to 58% of patients with leukemia or lymphoma and 85% of patients with retinoblastoma (p = 0.42). In this same area, 28% of patients with retinoblastoma and 23% of patients with leukemia or lymphomas had a risk of developmental delay (black) compared to 0% of patients with solid tumors (p = 0.025) (Table 6). The final test results showed that 19 (42.2%) patients had normal neurodevelopment, 7 (15.5%) had a lag in neurodevelopment, and 19 (42.2%) had a risk of delayed development. Regarding developmental delay, 52% of patients in the leukemia and lymphoma group, 71% in the retinoblastoma group, and 23% in the solid tumor group presented developmental delay (p = 0.06); (Fig. 1).

Figure 1 Global result of the early development instrument test in cancer patients under 5 years of age at the National Institute of Pediatrics 2018-2019. 

Multiple logistic regression analysis was performed, and it was observed that patients who presented alarm signals at the time of the evaluation had severe chronic malnutrition (OR: 13.8, 95% CI: 1.42-131.1; p = 0.022) and a diagnosis of leukemia or lymphoma (OR: 10.87, 95% CI: 1.94-60.95; p = 0.007).

Discussion

Pediatric cancer survivors have long-term sequelae that can affect their quality of life and prevent their full development. A study published by Tuhan in 2018 evaluated 68 surviving patients of acute lymphoblastic leukemia in childhood, who was compared with their siblings as a control group. It was observed that 82.4% had an alteration in neurocognitive functions detected by physical examination, magnetic resonance imaging, or neurocognitive tests compared to 29% in the control group (p < 0.001). The evaluations included intellect, attention, memory, judgment, learning skills, and execution, as well as structural or functional alterations. These patients had received treatment with intrathecal chemotherapy, systemic chemotherapy, and sometimes radiation therapy to the CNS⁹. They were found to have alterations in intellectual functioning, particularly in non-verbal intelligence, mathematical achievement, visual-motor integration, processing speed, attention, and executive functioning. Likewise, retrospective reports in childhood cancer survivors suggest that diagnosis at a younger age increases the risk of neurocognitive deficits. However, despite this information, there are no published studies evaluating neurodevelopment in cancer patients under 5 years of age during their treatment. Instead, most studies have been conducted on patients already in surveillance and considered survivors.

The current study found that 42.2% of children had a risk of delay, and 15.5% had a lag in neurodevelopment. In previous reports in a healthy Mexican population, a frequency of 20% neurodevelopmental lag and 4% risk of neurodevelopmental delay have been reported, indicating that this type of is more frequent in patients during cancer treatment. The areas of most frequent alterations were fine motor, gross motor, and language. Notably, developmental delay was observed more frequently in patients diagnosed with leukemia and lymphoma compared to solid tumors and retinoblastoma. In 2018, a study was published on 235 leukemia patients undergoing treatment with systemic and intrathecal chemotherapy. The study focused on analyzing biomarkers of myelin degradation in cerebrospinal fluid (such as myelin basic protein [MBP], nerve growth factor [NGF], and glial fibrillary acidic protein [GFAP]), as well as neuroinflammation by chitotriosidase. The results showed elevated levels of MBP and GFAP after the consolidation treatment. The number of intrathecal therapies was positively correlated with the elevation of NGF level (r = 0.19, p = 0.005). It was concluded that neuronal damage was associated with intrathecal therapy¹⁴. Therefore, we consider that the administration of both systemic and intrathecal treatment with chemotherapy led to the observed neurodevelopmental alterations in our patients. However, we did not analyze or demonstrate an association in this study.

There appears to be a connection between delayed development in leukemia patients and short stature. This may be linked to inadequate growth and brain development, as indicated by multiple studies. We suggest conducting additional research into brain development, growth, and developmental delays (using the EDI test). Moreover, it may be possible to establish a connection with abnormal data when the EDI test is conducted.

A significant limitation of this study was that the patients were evaluated while undergoing active cancer treatment. Consequently, it remains uncertain whether the patients exhibited neurodevelopmental delays or impairments before their cancer diagnosis or the administration of chemotherapy. Although patients with primary tumors or metastases in the CNS were excluded from the study, neurological examination at the time of evaluation revealed alterations in three patients. Despite this limitation, this study is the first to assess neurodevelopment in a population of Mexican patients with an oncological diagnosis. At present, we are evaluating patients at the time of diagnosis, before they receive chemotherapy treatment, to determine if any observed neurodevelopmental alterations are secondary to the neoplasm itself, despite its location outside the CNS, or if they are attributable to the effects of cancer treatment on the brain.

Conclusions

Neurodevelopmental delays and impairments are common among cancer patients under the age of 5. Various factors can influence child development, including nutrition, biological risk factors, and the malignancy itself. The impact of oncologic therapy on neurodevelopment extends beyond the scope of this study. Therefore, further research is necessary to evaluate the effects of these treatments on this population.