Diabetic ketoacidosis (DKA), a serious but common complication of type 1 diabetes, is linked to lower IQ scores and worse memory in children with type 1 diabetes, according to a study led by UC Davis Health researchers.
The study published Sept. 22 in Diabetes Care is also the first large-scale work to differentiate between DKA’s impact on children with a new diagnosis and children with a previous diagnosis of type 1 diabetes.
With DKA, blood sugar gets very high as acidic substances called ketones build up to dangerous levels in the body.
Early signs of DKA include excessive thirst, frequent urination, and nausea, abdominal pain, weakness and confusion.
“We assessed the neurocognitive effects of DKA in children with known type 1diabetes as well as in those who were just diagnosed with it,” said Simona Ghetti, professor of psychology at UC Davis and the lead author on the study.
“Our study uncovered that even one severe episode of DKA in children newly diagnosed with type 1 diabetes is linked to cognitive problems; and among children with a previous diagnosis, repeated DKA exposure predicted lower cognitive performance after accounting for glycemic control.”
The study included 376 children with type 1 diabetes and no DKA history and 758 children with type 1 diabetes and a history of DKA. These children, ages 6-18 years, were participating in a DKA clinical trial at the Pediatric Emergency Care Applied Research Network (PECARN) sites led by two of the study’s co-authors, Nathan Kuppermann and Nicole Glaser.
One severe DKA episode can hurt memory and IQ
The study found that among children newly diagnosed with type 1 diabetes, those who experienced moderate and severe DKA had lower long-term memory compared to children with diabetes and no exposure to DKA. Greater severity of DKA was also associated with lower IQ in these children.
Children with a previous diagnosis showed lower performance compared with children with new onset in measures of memory and IQ, suggesting that cognitive deficits may worsen over time.
The study’s large sample allowed the researchers to capture complex associations of DKA severity, socioeconomic status and glycemic control among previously diagnosed patients.
These associations revealed that patients with repeated DKA exposure and poorly controlled type 1 diabetes are at substantial risk of cognitive deficits.
“The results from the study emphasize the importance of prevention of DKA in children with known type 1 diabetes and of timely diagnosis during new onset before the development of DKA,” said Glaser, professor of pediatrics at UC Davis Health and senior author of the study. “There is an opportunity to prevent DKA with proper management of the glucose level in the blood.”
Diabetic ketoacidosis (DKA) is the most common acute cause of morbidity and mortality in youth with type 1 diabetes. An episode of DKA (1,2) has acute structural effects on the brain, such as clinical and subclinical cerebral edema (3), at the time of diagnosis as well as MRI-associated volume and diffusion tensor imaging (DTI) changes 3 months after diagnosis (4). A history of DKA has been associated with long-term adverse cognitive effects (4–8).
Subtle learning and emotional problems and poor concentration have been reported by parents and providers in children after an episode of DKA, and evidence suggests long-lasting decreases in memory function in school-aged children (ages 7–16 years) years after a DKA episode (5).
However, few studies have examined the effects of a DKA episode on cognitive and brain development from a longitudinal perspective, especially in young children with type 1 diabetes (9). The goal of this study was to determine how the severity of a DKA episode is associated with longitudinal memory and brain changes in young children (4–10 years) with type 1 diabetes.
Multiple studies have reported cognitive differences in children with type 1 diabetes, particularly in those diagnosed before age 5 years (17,18); however, the mechanisms for these differences are unknown.
Because the incidence of severe DKA is higher in children younger than 5 years (19) the severity of DKA at diagnosis may be a contributing factor. Few pediatric studies have examined the effect of DKA on the brain and cognitive performance (5,7,9,20), and these studies defined DKA as pH <7.3 or bicarbonate <15 mmol/L. To our knowledge, our study is the first to report that history of DKA, modulated by severity, results in longitudinal changes in brain imaging and cognitive outcomes in young children.
Compared with the none/mild group, the moderate/severe DKA group had increased growth of total and regional GMV and WMV over the 18-month period of the study and lower performance in Full Scale IQ and CPT2 test results (Detectability and Commissions) at the 18-month assessment of this study.
Because brain growth rate varies with age (21) and participants with moderate/severe DKA had higher hyperglycemic indices, analyses were also conducted with subgroups that were matched for age at baseline enrollment and glycemic HbA1c exposure.
For these matched subgroups, the growth differences in total and regional GMV and WMV as well as the performance differences in cognitive scores at follow-up became more prominent relative to the overall sample, despite smaller sample size.
These structural and cognitive results for the matched subgroups suggest that DKA severity, rather than onset age or 18-month HbA1c exposure, contributes to the observed group differences. In addition, our results indicate that the effects of a moderate/severe episode of DKA are still observable at least 4 years after the occurrence of the metabolic disturbance.
There are limited studies of DKA and its effect on pediatric brain development and cognitive function. The structural brain imaging results of our study are consistent with those previously published (9); namely, there is a different pattern of brain growth, presumably from the time of the DKA episode, in those who experience moderate/severe DKA compared with those who do not.
However, the authors found the effects of DKA on brain volume and diffusivity were largely dissipated by 6 months after the DKA event (9), when their study ended.
Although our study scanned the children more than 6 months after the DKA episode and the follow-up scan was 18 months from the baseline scan, we found that children who experienced moderate/severe DKA had an increased growth pattern in both total and regional GMV and WMV compared with those who experienced none/mild DKA.
Metabolic disturbances associated with DKA may cause acute ischemia/reperfusion of the brain (20,22) or increase in the release of inflammatory factors and cytokines (3,23–25). These physiological changes could, in turn, have lasting effects on brain growth in young children during a critical time of neurodevelopment.
As well, the finding of increased brain growth rate in the group with moderate/severe DKA history might represent neurodevelopmental compensation in those who experienced more neural insult. We do not know whether the differential pattern of brain growth associated with DKA observed here will be sustained, and thus, additional longitudinal follow-up is needed.
We found lower attention performance (i.e., CPT2 scores) in those who experienced moderate/severe DKA compared with the none/mild group, supporting previously published findings that those who experienced an episode of DKA may show cognitive deficits (7,9). Cameron et al. (9) reported lower attention performance scores in those with DKA (defined as venous pH <7.3 or bicarbonate <15 mmol/L) versus control subjects over 6 months.
It is possible that those subjects with moderate/severe DKA in the Cameron et al. (9) study may have also had the lower attention scores. Interestingly, adults up to 5 years out from a moderate/severe traumatic brain injury (14) have lower performance on the same CPT2 subtests of Detectability and Commission as did our participants who experienced moderate/severe DKA. Therefore, deficits in attention may not become detectable until some time after an insult to the developing or mature brain.
Hippocampus structure and function have been related to spatial processing (26) and working memory (27). Our report of lower scores for the Dot Location task in those with moderate/severe DKA history at baseline and at 18 months support previous pediatric studies (5,7) that have found lower spatial processing performance in children with DKA. Interestingly, animal (rat) models of DKA also demonstrate a deficit in object location (28).
As shown by Glaser et al. (20) and Hoffman et al. (29), the hippocampus is particularly vulnerable to ischemic/reperfusion of the brain. Recent immunohistochemistry findings show the presence of neuroinflammatory markers in the hippocampus of individuals who died of DKA with and without cerebral edema (29).
Therefore, it is notable that we found the moderate/severe group had lower memory performance scores compared with the none/mild group. However, the clinical significance of our memory performance scores requires further investigation because we did not find significant differences in GMV growth rate in the hippocampus.
The relationship between lower memory performance, particularly in spatial memory, and hippocampal growth may become evident over time in young children who experience DKA.
Finally, unlike other studies of children with a history of DKA, we found that those with a history of moderate/severe DKA had lower average Full Scale IQ scores compared with the none/mild group 18 months after baseline.
The observed 6-point difference in the Full Scale IQ score may not substantially alter functional outcome in the moderate/severe group. However, the effect size for this between-group difference is ∼0.5 (Cohen d) suggesting the two groups are at least moderately different.
Similar to our findings, in a meta-analysis of type 1 diabetes–associated cognitive decline, Tonoli et al. (30) reported decreased executive function performance, Full Scale IQ, and motor speed in children and reduced executive function, Full Scale IQ, motor speed, memory, and spatial memory in adults. Because more significant IQ differences may emerge later in our clinical group, it will be important to continue to monitor these participants with repeated imaging and cognitive testing.
Our study is limited by the relatively small sample size in the moderate/severe DKA group, which may have limited our ability to correlate structural and cognitive changes and to calculate sex or race effects. In addition, we did not perform these studies at the time of diagnosis to assess the acute effect of DKA.
Although the between-group differences seen in cognitive performance are statistically significant, the clinical significance is unknown at this time. We used whole-brain VBM analysis, which may be less sensitive to differences in smaller subcortical structures such as the hippocampus. However, the longitudinal nature of the neuroimaging observations and limited cognitive results support the findings and strongly indicate that further follow-up is still necessary.
Although there have been limited longitudinal studies in children after DKA, to our knowledge, this is the first to specifically examine the after effects of moderate/severe DKA in young children and its effect on brain development and cognitive function longitudinally.
Our data indicate that even a single episode of moderate/severe DKA in very young children with type 1 diabetes can potentially have long-term effects. Our results suggest that history of DKA and its severity should be included in the analysis of future studies in pediatric type 1 diabetes brain and neuropsychological studies.
Recognition of the immediate and longitudinal effect of a history of DKA on the brain further supports the development of programs to screen family members when there is an increased risk of type 1 diabetes to increase awareness of symptoms of type 1 diabetes, reduce the occurrence of DKA at diagnosis, and develop a closed-loop control or islet replacement to prevent further episodes of DKA after diagnosis.
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385695/
Funding: This study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01HD062417). It was also supported by the Health Resources and Services Administration, Maternal and Child Health Bureau, and Emergency Medical Services for Children (U03MC00008, U03MC00001, U03MC00003, U03MC00006, U03MC00007, U03MC22684 and U03MC22685).
The coauthors on this study are Nathan Kuppermann, Arleta Rewers, Sage R. Myers, Jeff E. Schunk, Michael J. Stoner, Aris Garro, Kimberly S. Quayle, Kathleen M. Brown, Jennifer L. Trainor, Leah Tzimenatos, Andrew D. DePiero, Julie K. McManemy, Lise E. Nigrovic, Maria Y. Kwok, Clinton S. Perry III, Cody S. Olsen, T. Charles Casper and Nicole S. Glaser for the PECARN DKA FLUID Study Group.