Elsevier

Epilepsy Research

Volume 110, February 2015, Pages 206-215
Epilepsy Research

Topography of brain glucose hypometabolism and epileptic network in glucose transporter 1 deficiency

https://doi.org/10.1016/j.eplepsyres.2014.11.007Get rights and content

Highlights

  • Generalized seizures are common in Glut1 DS, often present with absence and myoclonic seizures.

  • Milder clinical phenotypes of Glut1 DS may present without clinical seizures.

  • Visual analysis and the quantitative analysis of FDG-PET data demonstrate that the glucose hypometabolism is prominent in thalamus, cerebellum and neocortex.

  • Glucose hypometabolism in thalamus is spared in the milder clinical phenotype of Glut 1 DS.

  • In Glut1 DS, the epileptic network most likely involves thalamo neocortical connection.

Summary

Rationale

18F fluorodeoxyglucose positron emission tomography (18F FDG-PET) facilitates examination of glucose metabolism. Previously, we described regional cerebral glucose hypometabolism using 18F FDG-PET in patients with Glucose transporter 1 Deficiency Syndrome (Glut1 DS). We now expand this observation in Glut1 DS using quantitative image analysis to identify the epileptic network based on the regional distribution of glucose hypometabolism.

Methods

18F FDG-PET scans of 16 Glut1 DS patients and 7 healthy participants were examined using Statistical parametric Mapping (SPM). Summed images were preprocessed for statistical analysis using MATLAB 7.1 and SPM 2 software. Region of interest (ROI) analysis was performed to validate SPM results.

Results

Visual analysis of the 18F FDG-PET images demonstrated prominent regional glucose hypometabolism in the thalamus, neocortical regions and cerebellum bilaterally. Group comparison using SPM analysis confirmed that the regional distribution of glucose hypo-metabolism was present in thalamus, cerebellum, temporal cortex and central lobule. Two mildly affected patients without epilepsy had hypometabolism in cerebellum, inferior frontal cortex, and temporal lobe, but not thalamus. Glucose hypometabolism did not correlate with age at the time of PET imaging, head circumference, CSF glucose concentration at the time of diagnosis, RBC glucose uptake, or CNS score.

Conclusion

Quantitative analysis of 18F FDG-PET imaging in Glut1 DS patients confirmed that hypometabolism was present symmetrically in thalamus, cerebellum, frontal and temporal cortex. The hypometabolism in thalamus correlated with the clinical history of epilepsy.

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.

References (46)

  • M.B. Schapiro et al.

    Nature of mental retardation and dementia in Down syndrome: study with PET, CT, and neuropsychology

    Neurobiol. Aging

    (1992)
  • M.N. Shouse et al.

    Temporal lobe and petit mal antiepileptics differentially affect ventral lateral thalamic and motor cortex excitability patterns

    Brain Res.

    (1988)
  • O.C. Snead et al.

    Increased gamma hydroxybutyric acid receptors in thalamus of a genetic animal model of petit mal epilepsy

    Epilepsy Res.

    (1990)
  • B.E. Swartz et al.

    Rapid quantitative analysis of individual (18) FDG-PET scans

    Clin. Positron Imaging

    (1999)
  • D.M. Tucker et al.

    Discharges in ventromedial frontal cortex during absence spells

    Epilepsy Behav.

    (2007)
  • C.I. Akman et al.

    Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency

    Ann. Neurol.

    (2010)
  • C.H. Chan et al.

    Thalamic atrophy in childhood absence epilepsy

    Epilepsia

    (2006)
  • D.A. Coulter et al.

    Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: GABA current blockade

    Br. J. Pharmacol.

    (1990)
  • V. Crunelli et al.

    Childhood absence epilepsy: genes, channels, neurons and networks

    Nat. Rev. Neurosci.

    (2002)
  • M. de Curtis et al.

    Thalamic regulation of epileptic spike and wave discharges

    Funct. Neurol.

    (1994)
  • D.C. De Vivo et al.

    Glucose transporter 1 deficiency syndrome and other glycolytic defects

    J. Child Neurol.

    (2002)
  • D.C. De Vivo et al.

    Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay

    N. Engl. J. Med.

    (1991)
  • D.H. Dobrogowska et al.

    Quantitative immunocytochemical study of blood–brain barrier glucose transporter (GLUT-1) in four regions of mouse brain

    J. Histochem. Cytochem.

    (1999)
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