Faculty Bibliography

In this review, we discuss molecular brain imaging studies using positron emission tomography (PET) with 2-deoxy-2(¹⁸F)fluoro-d-glucose (FDG) in human newborns and infants, and illustrate how this technology can be applied to probe the neuropathophysiology of neonatal neurologic disorders. PET studies have been difficult to perform in sick babies because of patient transportation issues and suboptimal spatial resolution. With approval from the FDA and the institutional review board, we modified and installed the Focus 220 animal microPET scanner (Concorde Microsystems, Knoxville, TN) directly in our neonatal intensive care unit in Children's Hospital of Michigan and verified the high spatial resolution (<2 mm full-width-at-half-maximum) of this microPET. The neonatal pattern of glucose metabolism is very consistent, with the highest degree of activity in primary sensory and motor cortex, medial temporal region, thalamus, brain stem, and cerebellar vermis. Prior studies have shown that increases of glucose utilization are seen by 2 to 3 months in the parietal, temporal, cingulate, and primary visual cortex; basal ganglia; and cerebellar hemispheres. Between 6 and 8 months, lateral and inferior frontal cortex becomes more functionally active and, eventually, between 8 and 12 months, the dorsal and medial frontal regions also show a maturational increase. These findings are consistent with the physical, behavioral, and cognitive maturation of the infant. At birth, metabolic rates of glucose utilization in cortex are about 30% lower than in adults but rapidly rise such that, by 3 years, the cerebral cortical rates exceed adult rates by more than 2-fold. At around puberty, the rates for cerebral cortex begin to decline and gradually reach adult values by 16-18 years. These nonlinear changes of glucose utilization indirectly reflect programed periods of synaptic proliferation and pruning in the brain. Positron emission tomographic (PET) imaging of GABA_A receptors (using ¹¹C-flumazenil) in newborns also show a pattern very different from adults, with high binding in amygdala-hippocampus, sensory-motor cortex, thalamus, brain stem, and basal ganglia, in that order. We speculate that the early development of amygdala/hippocampus prepares the baby for bonding, attachment, and memory, and the deprivation of such experiences during a sensitive period results in malfunction of these networks and psychopathology, as has been shown in studies on severely socioemotionally deprived children. Recently developed hybrid PET/magnetic resonance (MR) scanners allow the simultaneous acquisition of PET and MR data sets with advanced applications. These devices are particularly advantageous for scanning babies and infants because of the high spatial resolution, automated coregistration of anatomical and functional images and, in the case of need for sedation, maximal data acquired in 1 session.

Three children with drug-refractory epilepsy, normal magnetic resonance image (MRI), and a heterozygous SCN1A variant underwent 2-deoxy-2-[¹⁸F]fluoro-d-glucose positron emission tomography (FDG-PET) scanning between age 6 months and 1 year and then at age 3 years 6 months to 5 years 5 months. Regional FDG uptake values were compared to those measured in age- and gender-matched pseudo-controls. At baseline, the brain glucose metabolic pattern in the SCN1A group was similar to that of the pseudo-controls. At follow-up, robust decreases of normalized FDG uptake was found in bilateral frontal, parietal and temporal cortex, with milder decreases in occipital cortex. Children with epilepsy and an SCN1A variant have a normal pattern of cerebral glucose metabolism at around 1 year of age but develop bilateral cortical glucose hypometabolism by age 4 years, with maximal decreases in frontal, parietal, and temporal cortex. This metabolic pattern may be characteristic of epilepsy associated with SCN1A variants and may serve as a biomarker to monitor disease progression and response to treatments.

OBJECTIVE:We analyzed long-term changes of lobar glucose metabolic abnormalities in relation to clinical seizure variables and development in a large group of children with medically refractory epilepsy. METHODS:F)-fluoro-D-glucose-PET at baseline and follow-up was correlated with epilepsy variables and developmental outcome. RESULTS:On the initial PET scan, 24 children had unilateral and 13 had bilateral glucose hypometabolism, whereas 4 children had normal scans. On the follow-up scan, 63% of the children showed an interval expansion of the hypometabolic region, and this progression was associated with persistent seizures. In contrast, 27% showed less extensive glucose hypometabolism at follow-up; most of these subjects manifested a major interval decrease in seizure frequency. Delayed development was observed in 21 children (51%) at baseline and 28 (68%) at follow-up. The extent of glucose hypometabolism at baseline correlated with developmental levels at the time of both baseline (r = .31, P = .05) and follow-up scans (r = .27, P = .09). SIGNIFICANCE:In this PET study of unoperated children with focal epilepsy, the lobar pattern of glucose hypometabolism changed over time in 90% of the cases. The results support the notion of an expansion of metabolic dysfunction in children with persistent frequent seizures and its association with developmental delay, and support that optimized medical treatment to control seizures may contribute to better neurocognitive outcome if no surgery can be offered.

BACKGROUND:Sturge-Weber syndrome is a neurocutaneous disorder associated with port-wine birthmark, leptomeningeal capillary malformations, and glaucoma. It is associated with an unpredictable clinical course. Because of its rarity and complexity, many physicians are unaware of the disease and its complications. A major focus moving ahead will be to turn knowledge gaps and unmet needs into new research directions. METHODS:On October 1-3, 2017, the Sturge-Weber Foundation assembled clinicians from the Clinical Care Network with patients from the Patient Engagement Network of the Sturge-Weber Foundation to identify our current state of knowledge, knowledge gaps, and unmet needs. RESULTS:One clear unmet need is a need for consensus guidelines on care and surveillance. It was strongly recommended that patients be followed by multidisciplinary clinical teams with life-long follow-up for children and adults to monitor disease progression in the skin, eye, and brain. Standardized neuroimaging modalities at specified time points are needed together with a stronger clinicopathologic understanding. Uniform tissue banking and clinical data acquisition strategies are needed with cross-center, longitudinal studies that will set the stage for new clinical trials. A better understanding of the pathogenic roles of cerebral calcifications and stroke-like symptoms is a clear unmet need with potentially devastating consequences. CONCLUSIONS:Biomarkers capable of predicting disease progression will be needed to advance new therapeutic strategies. Importantly, how to deal with the emotional and psychological effects of Sturge-Weber syndrome and its impact on quality of life is a clear unmet need.

To evaluate metabolic changes in the ipsi- and contralateral hemisphere in children showing a cognitive profile consistent with early reorganization of cognitive function, we evaluated the regional glucose uptake, interhemispheric metabolic connectivity, and cognitive function in children with unilateral SWS. Interictal 2-deoxy-2[¹⁸ F]fluoro-D-glucose (FDG)-PET scans of 27 children with unilateral SWS and mild epilepsy and 27 age-matched control (non-SWS children with epilepsy and normal FDG-PET) were compared using statistical parametric mapping (SPM). Regional FDG-PET abnormalities calculated as SPM(t) scores in the SWS group were correlated with cognitive function (IQ) in left- and right-hemispheric subgroups. Interhemispheric metabolic connectivity between homotopic cortical regions was also calculated. Verbal IQ was substantially (≥10 points difference) higher than non-verbal IQ in 61% of the right- and 71% of the left-hemispheric SWS group. FDG SPM(t) scores in the affected hemisphere showed strong positive correlations with IQ in the left-hemispheric, but not in right-hemispheric SWS group in several frontal, parietal, and temporal cortical regions. Significant positive interhemispheric metabolic connectivity, present in controls, was diminished in the SWS group. In addition, the left-hemispheric SWS group showed inverse metabolic interhemispheric correlations in specific parietal, temporal, and occipital regions. FDG SPM(t) scores in the same regions of the right (unaffected) hemisphere showed inverse correlations with IQ. These findings suggest that left-hemispheric lesions in SWS often result in early reorganization of verbal functions while interfering with ("crowding") their non-verbal cognitive abilities. These cognitive changes are associated with specific metabolic abnormalities in the contralateral hemisphere not directly affected by SWS.

PURPOSE:Most children with Sturge-Weber syndrome (SWS) develop seizures that may contribute to neurocognitive status. In this study, we tested the hypothesis that very early seizure onset has a particularly detrimental effect on the cognitive and/or motor outcomes of children with unilateral SWS. We also tested whether side of SWS brain involvement modulates the effect of seizure variables on the pattern of cognitive abnormalities. METHODS:Thirty-four children (22 girls; mean age 6.1years) with unilateral SWS and history of epilepsy in a longitudinal cohort underwent neurological and cognitive evaluations. Global intelligent quotient (GIQ), verbal intelligent quotient (VIQ), nonverbal intelligent quotient (IQ), and motor function were correlated with epilepsy variables, side and extent of brain involvement on magnetic resonance imaging (MRI). RESULTS:Mean age at seizure onset was 1.3years (0.1-6years) and mean IQ at follow-up was 86 (45-118). Age at seizure onset showed a logarithmic association with IQ, with maximum impact of seizures starting before age 1year, both in uni- and multivariate regression analyses. In the left SWS group (N=20), age at seizure onset was a strong predictor of nonverbal IQ (p=0.001); while early seizure onset in the right-hemispheric group had a more global effect on cognitive functions (p=0.02). High seizure frequency and long epilepsy duration also contributed to poor outcome IQ independently in multivariate correlations. Children with motor involvement started to have seizures at/before 7months of age, while frontal lobe involvement was the strongest predictor of motor deficit in a multivariate analysis (p=0.017). CONCLUSION:These findings suggest that seizure onset prior to age 1year has a profound effect on severity of cognitive and motor dysfunction in children with SWS; however, the effect of seizures on the type of cognitive deficit is influenced by laterality of brain involvement.

Tuberous sclerosis complex (TSC) is characterized by hamartomatous lesions in various organs and arises due to mutations in the TSC1 or TSC2 genes. TSC mutations lead to a range of neurological manifestations including epilepsy, cognitive impairment, autism spectrum disorders (ASD), and brain lesions that include cortical tubers. There is evidence that seizures arise at or near cortical tubers, but it is unknown why some tubers are epileptogenic while others are not. We have previously reported increased tryptophan metabolism measured with α[¹¹C]-methyl-l-tryptophan (AMT) positron emission tomography (PET) in epileptogenic tubers in approximately two-thirds of patients with tuberous sclerosis and intractable epilepsy. However, the underlying mechanisms leading to seizure onset in TSC remain poorly characterized. MicroRNAs are enriched in the brain and play important roles in neurodevelopment and brain function. Recent reports have shown aberrant microRNA expression in epilepsy and TSC. In this study, we performed microRNA expression profiling in brain specimens obtained from TSC patients undergoing epilepsy surgery for intractable epilepsy. Typically, in these resections several non-seizure onset tubers are resected together with the seizure-onset tubers because of their proximity. We directly compared seizure onset tubers, with and without increased tryptophan metabolism measured with PET, and non-onset tubers to assess the role of microRNAs in epileptogenesis associated with these lesions. Whether a particular tuber was epileptogenic or non-epileptogenic was determined with intracranial electrocorticography, and tryptophan metabolism was measured with AMT PET. We identified a set of five microRNAs (miR-142-3p, 142-5p, 223-3p, 200b-3p and 32-5p) that collectively distinguish among the three primary groups of tubers: non-onset/AMT-cold (NC), onset/AMT-cold (OC), and onset/AMT-hot (OH). These microRNAs were significantly upregulated in OH tubers compared to the other two groups, and microRNA expression was most significantly associated with AMT-PET uptake. The microRNAs target a group of genes enriched for synaptic signaling and epilepsy risk, including SLC12A5, SYT1, GRIN2A, GRIN2B, KCNB1, SCN2A, TSC1, and MEF2C. We confirmed the interaction between miR-32-5p and SLC12A5 using a luciferase reporter assay. Our findings provide a new avenue for subsequent mechanistic studies of tuber epileptogenesis in TSC.

AIM:To evaluate clinical and metabolic correlates of cerebral calcifications in children with Sturge-Weber syndrome (SWS). METHOD:Fifteen children (11 females, four males; age range 7mo-9y, mean 4y 1mo) with unilateral SWS underwent baseline and follow-up magnetic resonance imaging (MRI) with susceptibility weighted imaging (SWI), glucose metabolism positron emission tomography (PET), and neurocognitive assessment (mean follow-up 1y 8mo). Calcified brain volumes measured on SWI were correlated with areas of abnormal glucose metabolism, seizure variables, and cognitive function (IQ). RESULTS:=-0.53, p=0.042). INTERPRETATION:Brain calcifications are common and progress faster in children with SWS with early epilepsy onset, and are associated with a variable degree of hypometabolism, which is typically more extensive than the calcified area. Higher calcified brain volumes may indicate a risk for poorer neurocognitive outcome.

To determine the spatial relationship between 2-deoxy-2[¹⁸ F]fluoro-D-glucose (FDG) metabolic and intracranial electrophysiological abnormalities in children undergoing two-stage epilepsy surgery, statistical parametric mapping (SPM) was used to correlate hypo- and hypermetabolic cortical regions with ictal and interictal electrocorticography (ECoG) changes mapped onto the brain surface. Preoperative FDG-PET scans of 37 children with intractable epilepsy (31 with non-localizing MRI) were compared with age-matched pseudo-normal pediatric control PET data. Hypo-/hypermetabolic maps were transformed to 3D-MRI brain surface to compare the locations of metabolic changes with electrode coordinates of the ECoG-defined seizure onset zone (SOZ) and interictal spiking. While hypometabolic clusters showed a good agreement with the SOZ on the lobar level (sensitivity/specificity = 0.74/0.64), detailed surface-distance analysis demonstrated that large portions of ECoG-defined SOZ and interictal spiking area were located at least 3 cm beyond hypometabolic regions with the same statistical threshold (sensitivity/specificity = 0.18-0.25/0.94-0.90 for overlap 3-cm distance); for a lower threshold, sensitivity for SOZ at 3 cm increased to 0.39 with a modest compromise of specificity. Performance of FDG-PET SPM was slightly better in children with smaller as compared with widespread SOZ. The results demonstrate that SPM utilizing age-matched pseudocontrols can reliably detect the lobe of seizure onset. However, the spatial mismatch between metabolic and EEG epileptiform abnormalities indicates that a more complete SOZ detection could be achieved by extending intracranial electrode coverage at least 3 cm beyond the metabolic abnormality. Considering that the extent of feasible electrode coverage is limited, localization information from other modalities is particularly important to optimize grid coverage in cases of large hypometabolic cortex. Hum Brain Mapp 38:3098-3112, 2017. © 2017 Wiley Periodicals, Inc.