Topography of brain glucose hypometabolism and epileptic network in glucose transporter 1 deficiency
Graphical abstract
Introduction
Glucose transporter 1 deficiency syndrome (Glut1DS) is a genetically determined developmental encephalopathy resulting from insufficient transport of glucose into the brain (De Vivo et al., 1991). Cardinal clinical features include infantile-onset seizures, acquired microcephaly, ataxia, dysarthria, dystonia, intellectual disability, and motor retardation (Pearson et al., 2013). The majority of Glut1 DS patients present with seizures in infancy. However, seizure onset beyond the first year of life has been also described in the number of studies with normal intelligence and alteration in SLC2A1 gene (Suls, Pong). In contrast to the earlier definition of Glut1 DS, majority of these children with late seizure onset did not have the cardinal features of the syndrome that have lead to the expansion of the clinical spectrum.
Absence seizures and generalized tonic clonic seizures are the most common seizure type in this syndrome (Leary et al., 2003). Despite the progress in clinical spectrum, diagnosis and recognition of the syndrome even in the individuals with milder phenotype; the pathophysiology underlying the epileptogenesis remains obscure.
Brain glucose metabolism in this clinical condition has been studied using 18F-FDG-PET brain imaging. Qualitative analysis based on the visual interpretation of 18F-FDG-PET data revealed a global decrease in glucose metabolism (Pascual et al., 2002). Regional hypometabolism was also noted in thalamus, cerebellum and neocortical regions.
Visual interpretation of 18F-FDG-PET is the most traditional method for qualitative analysis. Introduction of quantitative methods to analyze 18F-FDG-PET data has refined this information and provided a more precise topographical understanding of the regional vulnerability and severity of the metabolic insult in various neurological disorders and in focal epilepsy (Cummings et al., 1995, Duncan et al., 1997, Engel, 1984, McMurtray et al., 2008, Rintahaka et al., 1993, Schapiro et al., 1992). Quantitative analysis of imaging data can be achieved by Statistical Parametric Mapping (SPM), an effective, objective, and reliable method that supplements visual interpretation (Salek-Haddadi et al., 2003, Swartz et al., 1999). This quantitative method provides a voxel based analysis of metabolic activity that permits whole brain global analysis.
We hypothesized that the degree of glucose hypometabolism would vary from one region to another based on the clinical phenotype, and the regional distribution of glucose uptake would correlate with the clinical features. In this study, we searched for a correlation between the epilepsy history and regional vulnerabilities to glucose hypometabolism in an effort to map the epileptic network in Glut1DS.
Section snippets
Participants
Clinical features of this patient cohort were reported in our earlier study (Pascual et al., 2002). Sixteen patients diagnosed with Glut1 DS underwent 18F-FDG-PET imaging. The study was approved by the Institutional Review Board of Columbia University. Informed consent was obtained from patients and their parents.
Mean age at the time of the imaging was 12.4 ± 9.9 years (range: 1.3–39). Except for two patients, cerebrospinal fluid (CSF) glucose concentration was less than 40 mg/dl. One patient was
Clinical features
Clinical features and pathogenic mutations are shown in Table 1 and Fig. 2. Severity of the clinical phenotypes as determined by the CNS scores ranged from severe (3 patients), moderate (3 patients), mild (9 patients) to minimal (1 patient).
All but two patients (Table 1) had a history of seizures (87%). Seizures were reported as the initial clinical manifestation, leading to the diagnosis in 8 patients (50%). Absence and myoclonic seizures were the most common seizure types. Epilepsy duration
Discussion
In this study, we examined the relationship between the classical clinical phenotype of Glut1 DS and the regional brain glucose metabolism. Voxel based analysis of 18F-FDG-PET imaging documented significant glucose hypometabolism in neocortex, thalamus and cerebellum in Glut1 DS patients. Furthermore, inter-regional hypometabolic differences correlated with the clinical history of epilepsy. In contrast, we found no correlation between glucose hypometabolism and CSF glucose concentration, head
Conclusion
Brain glucose metabolism of Glut1 DS patients is compromised globally, and is particularly pronounced in the thalamocortical network and cerebellum. Distinctive brain regional abnormalities, as visualized by PET imaging, are uniquely correlated with the clinical diagnosis of Glut1 Deficiency. The regional differences and the glucose hypometabolic topography permit us to map the affected brain network and anticipate the pathophysiology of epileptogenesis in this syndrome; namely, infantile-onset
Acknowledgements
This work was supported in part by the Colleen Giblin Charitable Foundation, Will Foundation, Milestones for Children and the United States Public Health Service [NS37949-01; RR00645 to DCD]. We remain indebted to the patients and their families for their continuing involvement and support of these investigations. Authors also thank Dr. Orhan Akman for his help in creating Fig. 2.
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