The findings indicate that not only did participants show significantly lower intellectual ability overall compared to the normal population, but twice as many patients as expected evidenced IQ delays of one or more standard deviations. Twenty-six percent of our sample had mild to moderate cognitive delay (WPPSI-III FSIQ between 71–85) and 4% had serious delay (FSIQ ≤ 70). The observed intellectual deficits would be expected to hinder academic performance as well as independent functioning long-term. Reading and math scores were significantly below test norms, and comparison of IQ and academic achievement revealed that even at this early age, 25% of patients had profiles suggesting reading and/or math LD. In addition, nearly 19% of patients in the higher IQ group and 43–50% of those with IQ <86 had clinically relevant EF deficits that were apparent in the classroom. The high prevalence of academic delays and EF deficits in the sample is all the more striking given participants were just starting school.
The rate of LD in this sample is much higher than CDC reports in the general population (7%), but consistent with previous, smaller reports of cognitive outcomes in pediatric LT recipients (12
). Although the patients demonstrated adequate mastery of simple school readiness concepts such as recognition of colors, numbers, and shapes as measured by the BBCS-R and single word vocabulary on the WPPSI-III GLC, the downward shift of IQ, the discordance between IQ and academic achievement, and the prevalence of EF deficits suggest this group is already significantly delayed in early academic skill building and cognitive development. An established diagnosis of learning disability or mental retardation was only reported for 5 and 3 percent of the group, respectively; however, 31% had received special education support during the previous 12 months. This suggests learning problems had already been recognized by the school system in many cases.
This study provides the first evidence for EF deficits in pediatric LT patients with deficits reported by multiple informants (parents and teachers). Executive skills are vital to the learning process. Teacher report on the BRIEF highlighted the most dramatic concerns. This suggests teachers’ input, which is often overlooked in neuropsychological research due to logistical challenges in obtaining it, is critical in defining the scope of the problem. The reason for elevated concerns among teachers as compared to parents is unclear. This finding may reflect the young age of participants, with about 2/3 in kindergarten. At this early elementary level, EF demands are likely to be greater in the classroom than at home (e.g., limited homework requirements). Problems with EF can have a significant impact on academic functioning in later childhood and on job performance and independent living skills in adulthood. In children with various neurological insults (TBI, cancer treatment), EF deficits often emerge as a function of age, in a pattern labeled “growth into deficits” (35
). In this scenario, a neurological insult adversely impacts EF, but the deficit does not become apparent until the demands are sufficiently high, increasing as the child ages.
Several single center studies have suggested developmental delay is prevalent in children who have survived LT, especially among patients with advanced liver disease early in infancy (13
). This multi-site design allowed us to determine the prevalence of cognitive delay in a large patient group that we believe is representative of the general population of children who receive LT at this age across North America. The distribution of parental education in our group was similar to or higher than that of the WPPSI-III standardization sample (26
) with 70% of our sample completing at least some college or beyond compared to 60% in the WPPSI-III standardization sample. This suggests the IQ deficits found cannot be attributed to lower socioeconomic status. Cognitive testing was performed at least two years after LT to minimize the impact of incomplete rehabilitation following the procedure and patients with uncontrolled seizures or current evidence of hepatic encephalopathy were excluded. Language factors were controlled by limiting participants to those who were fluent in English and had passed a hearing screen. Another important methodological advantage of the current study was the use of a small age range allowing use of a consistent test battery for all patients, which resulted in less variability in time since transplant, era of transplant and age at transplant. Our findings confirm developmental delay is a common problem for patients that receive LT in early childhood even in contemporary experience.
This cohort was selected to include patients who had all received LT prior to five years of age, with 57 (40%) being transplanted prior to 12 months of age. Hepatic encephalopathy, chronic malnutrition and other aspects of advanced liver failure are hypothesized to have a greater impact on the developing brain of an infant as compared to an older child. This report provides strong evidence that children who have received LT in infancy and early childhood are at high risk for cognitive delays and learning problems, well after the initial post-transplant period. Deficits in these areas, first recognized in pediatric LT patients more than twenty years ago, persist as important limitations to optimal long-term outcomes. These findings suggest early screening for cognitive delay at or before the age of school entry can help identify the sub-population of patients that will require educational interventions and special support services. Such services are most effective when delivered early in a child’s school experience, when there is more potential for neural plasticity (37
). Considering the large percentage of LT patients with adverse cognitive outcomes, it would be reasonable to support policies that fund intervention services at an even younger age, similar to the approach that has been taken for pre-term infants (39
We accurately predicted less than 60% of eligible patients would participate and thus chose to recruit patients from a large number of centers in order to yield the projected sample size. Despite the relatively low recruitment rate, comparisons suggest our sample was not biased by important demographic or medical factors, or by center-specific recruitment practices and logistics. Although parents of LT recipients expressed sincere interest in issues surrounding school performance, many chose not to participate, citing problems related to travel, time off from work and school absence as a deterrent. Nevertheless, comparison between participants and non-participants did not suggest bias on the basis of demographic factors, and our sample appears to be similar to the full SPLIT cohort and the IQ standardization sample in important respects. Comparison of special education resource utilization of this sample with the full SPLIT cohort reveals 31% of these participants versus 34% of the full SPLIT cohort (ages 6–11 years) were receiving special educational support (IEP). (18
) Likewise 36% of the participants had a history of evaluation for an Individualized Educational Plan (IEP) versus 35% of patients 6–11 years of age in the overall SPLIT cohort. Thus, it would seem that this patient group does not have an over-representation of LT recipients with academic problems.
This report includes the preliminary findings of a longitudinal study that will include testing at a second time point (two years later) to help establish whether deficits observed at this early age are static or progressive. Also, future multi-variant modeling of risk factors may help determine if pre or post transplant variables have the largest impact. Since one fourth of the sample missed more than 10 school days in the prior 12 months, it will be important to consider the potential contribution of missed school days to cognitive and academic outcomes. Confirming the prevalence of neurocognitive deficits in older recipients and determining predictors of these functional outcomes will be key in driving modifications in medical care and public policy to optimize post-LT quality of life.
In summary, we report the results of the first multi-center study to examine neurocognitive functioning in children following LT. Early school-age children who had received LT prior to 5 years of age displayed twice the rate of intellectual delay and three times the rate of learning disability compared to the general population. Classroom performance suggested EF deficits are prevalent even at this early age. Analyses are in progress in this longitudinal study to assess the developmental course of these delays over time and to identify risk factors that predict adverse cognitive and academic outcomes.