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Serial 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography was performed in identical twins with Niemann-Pick disease type C. Two such scans, performed at ages 4 and 6 years, revealed a characteristic, unique pattern of brain metabolic abnormality. Whereas the first scans indicated mild, diffuse cortical hypometabolism, most pronounced in the medial frontal cortex, the repeated scans in both twins revealed a unique pattern consisting of severe hypometabolism of the frontal cortex bilaterally, particularly involving medial and inferior frontal regions, and hypometabolism in the bilateral parietal and temporal cortex. In the parietal cortex, lateral and medial aspects were most severely affected, with some sparing of the intermediate parietal region. This progression of brain hypometabolism between two positron emission tomography studies was associated with clinical and neurologic deterioration. This distinctive brain metabolic pattern, which we have observed in no other condition, may constitute a "biomarker" to assess neurologic progression and possible treatment responses in children with Niemann-Pick disease type C, because magnetic resonance imaging findings are either normal at earlier stages or demonstrate only nonspecific changes. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a relatively noninvasive imaging test that is able to detect abnormalities in different organs based on derangements in the chemical functions and/or receptor expression at the cellular level. PET imaging of the brain has been shown to be a powerful diagnostic tool for detecting neurochemical abnormalities associated with various neurologic disorders as well as to study normal brain development. Although its use in detecting neurological abnormalities has been well described in adults and pediatrics, its application in the newborn nursery has not been explored adequately. Early detection of brain injury secondary to intrauterine and perinatal insults using PET imaging can provide new insight in prognosis and in instituting early therapy. In this review, the authors describe applications of PET imaging in the newborn nursery specifically related to the detection of metabolic changes seen in hypoxic ischemic encephalopathy, neonatal seizures, and neuroinflammation in the neonatal period. © Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]

Functional reorganization after focal brain injury can lead to altered cerebral metabolism of glucose. Sturge-Weber syndrome (SWS) with unilateral involvement is a clinical model for evaluating the effects of early focal brain injury on brain metabolism and function. In this study, 2-deoxy-2[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) was used to measure glucose metabolism in cortex and basal ganglia, both ipsilateral and contralateral to the angioma, in 17 children (eight males, nine females; age range 1y 8mo-10y 4mo; mean 5y 7mo [SD 2y 11mo]) with unilateral SWS and epilepsy. The PET findings were compared with those of a control group of 11 age-matched children (four males, seven females; age range 3y-10y 8mo; mean 6y [SD 2y 10mo]) with partial epilepsy but normal magnetic resonance imaging and PET scans. In the SWS group, visual and parietal cortex showed decreased glucose metabolism on the side of the angioma (p=0.001) but increased metabolism on the contralateral side (p=0.002). In particular, glucose metabolism was very high in contralateral visual cortex of childrenwith SWS, showing severe occipital hypometabolism on the side of the angioma. Eight children with visual field defect showed increased metabolism in the contralateral visual cortex (p=0.012). These findings indicate that early, severe unilateral cortical damage in SWS may induce increased glucose metabolism in the contralateral visual cortex, probably reflecting reorganization. [ABSTRACT FROM AUTHOR]

Buspirone is used to treat generalized anxiety disorder in children and may be useful in developmental disorders in which brain serotonin synthesis is altered. Autistic children (13 boys, 7 girls) were given a single oral dose of 2.5 mg (2-3 years) or 5.0 mg (4-6 years). Blood was collected for 8 hours, and plasma was assayed for buspirone and its metabolite 1-pyrimidinylpiperazine (1-PP). The peak concentration of buspirone averaged 1141 +/- 748 pg/mL with a time to maximum concentration of 0.8 hours. Half-life was 1.6 +/- 0.3 hours. Peak concentrations of 1-PP were 4.5-fold higher than for buspirone. Girls had higher peak concentrations (1876 vs 746 pg/mL) for buspirone and a lower peak 1-PP/buspirone concentration ratio. These results suggest that buspirone is rapidly absorbed and eliminated in young children with extensive metabolism to 1-PP. Plasma concentrations with 2.5- to 5.0-mg doses were similar to those observed in older children receiving 7.5- to 15-mg doses. [ABSTRACT FROM AUTHOR]

Background: Enlarged deep medullary veins (EDMVs) in patients with Sturge-Weber syndrome (SWS) may provide compensatory venous drainage for brain regions affected by the leptomeningeal venous malformation (LVM). We evaluated the prevalence, extent, hemispheric differences, and clinical correlates of EDMVs in SWS., Methods: Fifty children (median age: 4.5 years) with unilateral SWS underwent brain magnetic resonance imaging prospectively including susceptibility-weighted imaging (SWI); children aged 2.5 years or older also had a formal neurocognitive evaluation. The extent of EDMVs was assessed on SWI by using an EDMV hemispheric score, which was compared between patients with right and left SWS and correlated with clinical variables., Results: EDMVs were present in 89% (24 of 27) of right and 78% (18 of 23) of left SWS brains. Extensive EDMVs (score >6) were more frequent in right (33%) than in left SWS (9%; P = 0.046) and commonly occurred in young children with right SWS. Patients with EDMV scores >4 had rare (less than monthly) seizures, whereas 35% (11 of 31) of patients with EDMV scores ≤4 had monthly or more frequent seizures (P = 0.003). In patients with right SWS and at least two LVM-affected lobes, higher EDMV scores were associated with higher intelligence quotient (P < 0.05)., Conclusions: Enlarged deep medullary veins are common in unilateral SWS, but extensive EDMVs appear to develop more commonly and earlier in right hemispheric SWS. Deep venous remodeling may be a compensatory mechanism contributing to better clinical outcomes in some patients with SWS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rationale: Posttraumatic epilepsy (PTE) is a common cause of morbidity in children after a traumatic brain injury (TBI), occurring in 10-20% of children following severe TBI. PTE is diagnosed after two or more unprovoked seizures occurring 1-week post TBI. More often, studies have focused on children with epilepsy due to severe TBI. We aim to understand the utility of head computed tomography (HCT), EEG, and the risk of developing drug-resistant epilepsy in children after mild TBI., Method: We retrospectively studied 321 children with TBI at a tertiary pediatric referral center during a 10-year period. Mild TBI was defined as loss of consciousness (LOC) or amnesia < 30 min, moderate TBI as LOC or amnesia between 30 min and 1 day, and severe TBI as LOC or amnesia > 1 day, subdural hemorrhage, or contusion. Multiple clinical variables were reviewed, including past and present antiepileptic drug(s), seizure control, and mode of injury. First and subsequent post-TBI EEGs/prolonged video-EEGs were obtained acutely, subacutely, and/or chronically (range, day 1-3 years, median 1 month). Descriptive analyses were conducted using medians and ranges for continuous data. Categorical data were reported using frequencies and percentages, while comparisons between groups were made using Fisher's exact test for small sample sizes., Results: Forty-seven children were diagnosed with posttraumatic epilepsy: eight children (17%) due to mild TBI, 39 children (83%) due to severe TBI. For the eight children with mild TBI whom all had an accidental trauma (non-inflicted), the median follow-up time was 25 months (range 1.5 months-84 months). The median age was 10 years (range 4-18 years), and the median age at the time of injury was seven years (range: 23 months-13 years). No relevant previous medical history was present for six patients (80%), and two patients' (20%) relevant previous medical histories were unknown. Seven patients (88%) had no history of seizures, and patient #6 (12%) had unknown seizure history. Six patients (75%) had normal routine EEG(s). Patient #6 (13%) had an abnormal VEEG 3 months after the initial normal routine EEG, while patient #1 (13%) had an initial prolonged EEG 8 months after TBI. Compared to the 39 patients with severe TBI, 31 (79%) of whom had abnormal EEGs (routine and/or prolonged with video), mild TBI patients were more likely to have normal EEGs, p = 0.005. Head CT scans were obtained acutely for seven patients (90%), all of which were normal. One patient only had brain magnetic resonance imaging (MRI) 8 months after the injury. Compared to the 39 patients with severe TBI, all of whom had abnormal HCTs, mild TBI patients were less likely to have abnormal HCTs, p < 0.0001. In patients with mild TBI, no patient had both abnormal EEG/VEEG and HCT, and no one was on more than one Antiepileptic drug (AED), p < 0.005. Six patients (75%) had MRIs, of which five (63%) were normal. Two patients (#1, 7) did not have MRIs, while one patient's (#4) MRI was unavailable. Five patients (63%) had a seizure <24 h post TBI, while the rest had seizures after the first week of injury., Conclusion: Children with epilepsy due to mild TBI, loss of consciousness, or amnesia < 30 min are more likely to have normal HCT and EEG and to be on 0-1 AED. Limitations of our study include the small sample size and retrospective design. The current findings add to the paucity of data in children who suffer from epilepsy due to mild TBI.

When one is interpreting clinical 18 F-FDG PET scans of the brain (excluding tumors) in children, the typical abnormality seen is hypometabolism of various brain regions. Focal areas of hypermetabolism are noted occasionally, and the usual interpretation is that the hypermetabolic region represents a seizure focus. In this review, I discuss and illustrate the multiple causes of hypermetabolism on 18 F-FDG PET studies that should not be interpreted as seizure activity, as such an interpretation could potentially be incorrect. Various conditions in which focal hypermetabolism can be encountered on 18 F-FDG PET studies include interictal hypermetabolism, Sturge-Weber syndrome, changes associated with brain plasticity after injury, Rett syndrome, hypoxic-ischemic brain injury, various inborn errors of metabolism, and autoimmune encephalitis. The radiologist or nuclear medicine physician interpreting clinical 18 F-FDG PET studies should be aware of these circumstances to accurately assess the findings., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Sturge-Weber syndrome (SWS) is a sporadic, neurocutaneous syndrome involving the skin, brain, and eyes. Because of the variability of the clinical manifestations and the lack of prospective studies, consensus recommendations for management and treatment of SWS have not been published., Objective: This article consolidates the current literature with expert opinion to make recommendations to guide the neuroimaging evaluation and the management of the neurological and ophthalmologic features of SWS., Methods: Thirteen national peer-recognized experts in neurology, radiology, and ophthalmology with experience treating patients with SWS were assembled. Key topics and questions were formulated for each group and included (1) risk stratification, (2) indications for referral, and (3) optimum treatment strategies. An extensive PubMed search was performed of English language articles published in 2008 to 2018, as well as recent studies identified by the expert panel. The panel made clinical practice recommendations., Conclusions: Children with a high-risk facial port-wine birthmark (PWB) should be referred to a pediatric neurologist and a pediatric ophthalmologist for baseline evaluation and periodic follow-up. In newborns and infants with a high-risk PWB and no history of seizures or neurological symptoms, routine screening for brain involvement is not recommended, but brain imaging can be performed in select cases. Routine follow-up neuroimaging is not recommended in children with SWS and stable neurocognitive symptoms. The treatment of ophthalmologic complications, such as glaucoma, differs based on the age and clinical presentation of the patient. These recommendations will help facilitate coordinated care for patients with SWS and may improve patient outcomes., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The understanding and management of epileptic spasms has considerably evolved since the mid 19th century. The realization that epileptic spasms can be generated from a focal brain lesion played a pivotal role in the development of neurosurgical management for intractable forms of this epilepsy. During pre-surgical planning, the addition of functional FDG PET imaging has further refined the electroencephalographic localization of epileptogenic lesions. In some cases, neurosurgical resection of a focus that is co-localized by the FDG PET scan and electroencephalography can lead to partial or complete reversal of developmental delay along with reduced seizure frequency or seizure freedom. In cases where near-complete hemispheric cortex is implicated in spasm generation, subtotal hemispherectomy has shown encouraging results. Moreover, palliative resection of the major perpetrating focus in carefully chosen patients with bilateral multifocal spasms has also led to favorable outcomes. However, in patients with tuberous sclerosis with high tuber burden, the localizing value of FDG PET imaging may be limited. In such cases, employment of AMT PET technology has become a valuable tool for localization of actively epileptogenic tubers. This article highlights the historic steps in the successful advancements of neurosurgical interventions for the treatment of intractable epileptic spasms., (Copyright © 2016. Published by Elsevier Inc.)

The selective effectiveness of adrenocorticotropic hormone (ACTH) in treating infantile spasms suggests an underlying neuroinflammation. Because neuroinflammation is mediated by activated microglia, which express translocator protein (TSPO), we imaged neuroinflammation in children with infantile spasms using positron emission tomography (PET) with 11 C-PK11195 (PK), which selectively binds to TSPO. Children were studied prospectively before and following treatment with Acthar Gel (repository corticotropin injection). We hypothesized that PK-PET would show neuroinflammation (increased PET uptake) in cortical and/or subcortical structures before treatment, and that this inflammation will be abolished/reduced following Acthar Gel treatment. Eight children with infantile spasms (5 males; mean age 1.8±1.1, range 0.9-4.1 years) were recruited. After clinical and video electroencephalograph (EEG) evaluation and dynamic PK-PET scan, children underwent treatment with Acthar Gel over 4 weeks, followed by repeat clinical evaluation/video-EEG 2 weeks after initiation of treatment and repeat PK-PET 2 weeks after treatment completion. Visual and quantitative analysis of PK-PET scans were performed. We calculated regional binding potential (measure of receptor-ligand binding) using a reference tissue model. Focal areas of increased PK-binding were found in the pretreatment PK-PET in 5 children. Following treatment, these increases were either reduced or normalized and were associated with cessation (n=4) or significant reduction (n=1) of spasms and complete disappearance of hypsarrhythmia. One child showed increased binding potential in basal ganglia and thalamus, despite normalization of cortical binding potential; however, these increases were likely associated with death-related causes. This study suggests Acthar Gel-responsive neuroinflammatory changes in children with infantile spasms, supporting a potential role of neuroinflammation in the pathogenesis of infantile spasms.

Automated production of an fluorine-18 labeled tryptophan analogue, 1-(2-[ 18 F]fluoroethyl)-l-tryptophan (1-L-[ 18 F]FETrp) in a current Good Manufacturing Practice facility was achieved. 1-L-[ 18 F]FETrp was produced by a one-pot, two-step strategy with an overall synthesis time of approximately 100 min, a radiochemical yield of 20 ± 5% (decay corrected), radiochemical purity and enantiomeric excess over 90%, and a molar activity of 103 ± 15 GBq/μmol at the end of synthesis (EOS). The dose mass of 1-L-FETrp in four consecutive batches was less than 5 μg. The radiopharmaceutical product met all quality control criteria for clinical use., Competing Interests: Declaration of competing interest The authors have declared that they have no conflict of interest relevant to this article., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Neuroinflammation and toll-like receptors (TLR) of the innate immune system have been implicated in epilepsy. We previously reported high levels of microRNAs miR-142-3p and miR-223-3p in epileptogenic brain tissue resected for the treatment of intractable epilepsy in children with tuberous sclerosis complex (TSC). As miR-142-3p has recently been reported to be a ligand and activator of TLR7, a detector of exogenous and endogenous single-stranded RNA, we evaluated TLR7 expression and downstream IL23A activation in surgically resected TSC brain tissue., Methods: Gene expression analysis was performed on cortical tissue obtained from surgery of TSC children with pharmacoresistent epilepsy. Expression of TLRs 2, 4 and 7 was measured using NanoString nCounter assays. Real-time quantitative PCR was used to confirm TLR7 expression and compare TLR7 activation, indicated by IL-23A levels, to levels of miR-142-3p. Protein markers characteristic for TLR7 activation were assessed using data from our existing quantitative proteomics dataset of TSC tissue. Capillary electrophoresis Western blots were used to confirm TLR7 protein expression in a subset of samples., Results: TLR7 transcript expression was present in all TSC specimens. The signaling competent form of TLR7 protein was detected in the membrane fraction of each sample tested. Downstream activation of TLR7 was found in epileptogenic lesions having elevated neuroinflammation indicated by clinical neuroimaging. TLR7 activity was significantly associated with tissue levels of miR-142-3p., Conclusion: TLR7 activation by microRNAs may contribute to the neuroinflammatory cascade in epilepsy in TSC. Further characterization of this mechanism may enable the combined of use of neuroimaging and TLR7 inhibitors in a personalized approach towards the treatment of intractable epilepsy.

Application of molecular neuroimaging using positron emission tomographic techniques to assess pediatric neurodegenerative disorders has been limited, unlike in adults where positron emission tomography has contributed to clinical diagnosis, monitoring of neurodegenerative disease progression, and assessment of novel therapeutic approaches. Yet, there is a huge unexplored potential of molecular imaging to improve our understanding of the pathophysiology of neurodegenerative disorders in children and provide radiological biomarkers that can be applied clinically. The obstacles in performing PET scans on children include sedation, radiation exposure, and access but, as will be illustrated, these barriers can be easily overcome. This review summarizes findings from PET studies that have been performed over the past three decades on children with various neurodegenerative disorders, including the neuronal ceroid lipofuscinoses, juvenile Huntington disease, Wilson disease, Niemann-Pick disease type C, Dravet syndrome, dystonia, mitochondrial disorders, inborn errors of metabolism, lysosomal storage diseases, dysmyelinating disorders, Rett syndrome, neurotransmitter disorders, glucose transporter Glut 1 deficiency, and Lesch-Nyhan disease. Because positron emission tomographic scans have often been clinically useful and have contributed to the management of these disorders, we suggest that the time has come for glucose metabolism positron emission tomographic scans to be reimbursed by insurance carriers for children with neurodegenerative disorders, and not restricted only to epilepsy surgery evaluation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: We aimed to identify the current status and major unmet needs in the management of neurological complications in Sturge-Weber syndrome., Methods: An expert panel consisting of neurologists convened during the Sturge-Weber Foundation Clinical Care Network conference in September 2018. Literature regarding current treatment strategies for neurological complications was reviewed., Results: Although strong evidence-based standards are lacking, the implementation of consensus-based standards of care and outcome measures to be shared across all Sturge-Weber Foundation Clinical Care Network Centers are needed. Each patient with Sturge-Weber syndrome should have an individualized seizure action plan. There is a need to determine the appropriate abortive and preventive treatment of migraine headaches in Sturge-Weber syndrome. Likewise, a better understanding and better diagnostic modalities and treatments are needed for stroke-like episodes. As behavioral problems are common, the appropriate screening tools for mental illnesses and the timing for screening should be established. Brain magnetic resonance imaging (MRI) preferably done after age one year is the primary imaging modality of choice to establish the diagnosis, although advances in MRI techniques can improve presymptomatic diagnosis to identify patients eligible for preventive drug trials., Conclusion: We identified the unmet needs in the management of neurological complications in Sturge-Weber syndrome. We define a minimum standard brain MRI protocol to be used by Sturge-Weber syndrome centers. Future multicenter clinical trials on specific treatments of Sturge-Weber syndrome-associated neurological complications are needed. An improved national clinical database is critically needed to understand its natural course, and for retrospective and prospective measures of treatment efficacy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate microsurgical trans-sylvian trans-ventricular anatomical hemispherectomy with regard to seizure outcome, risk of hydrocephalus, blood loss, and risk of chronic hemosiderosis in patients with intractable seizures selected for surgery using current preoperative assessment techniques., Methods: Out of 86 patients who underwent hemispherectomy between February 2000 and April 2019, by a single surgeon, at a tertiary care referral center, 77 patients (ages 0.2-20 years; 40 females) who had an anatomical hemispherectomy were analyzed. Five of these were 'palliative' surgeries. One-stage anatomical hemispherectomy was performed in 55 children, two-stage anatomical hemispherectomy after extraoperative intracranial monitoring in 16, and six hemispherectomies were done following failed previous resection. Mean follow-up duration was 5.7 years (range 1-16.84 years). Forty-six patients had postoperative MRI scans., Results: Ninety percent of children with non-palliative hemispherectomy achieved ILAE Class-1 outcome. Twenty-seven patients were no longer taking anticonvulsant medications. Surgical failures (n = 4) included one patient with previous meningoencephalitis, one with anti-GAD antibody encephalitis, one with idiopathic neonatal thalamic hemorrhage, and one with extensive tuberous sclerosis. There were no failures among patients with malformations of cortical development. Estimated average blood loss during surgery was 387 ml. Ten (21%) children developed hydrocephalus and required a shunt following one-stage hemispherectomy, whereas 10 (50%) patients developed hydrocephalus among those who had extraoperative intracranial monitoring. Only 20% of the shunts malfunctioned in the first year. Early malfunctions were related to the valve and later to fracture disconnection of the shunt. One patent had a traumatic subdural hematoma. None of the patients developed clinical signs of chronic 'superficial cerebral hemosiderosis' nor was there evidence of radiologically persistent chronic hemosiderosis in patients who had postoperative MRI imaging., Conclusion: Surgical results of anatomical hemispherectomy are excellent in carefully selected cases. Post-operative complications of hydrocephalus and intraoperative blood loss are comparable to those reported for hemispheric disconnective surgery (hemispherotomy). The rate of shunt malfunction was less than that reported for patients with hydrocephalus of other etiologies Absence of chronic 'superficial hemosiderosis', even on long-term follow-up, suggests that anatomical hemispherectomy should be revisited as a viable option in patients with intractable seizures and altered anatomy such as in malformations of cortical development, a group that has a reported high rate of seizure recurrence related to incomplete disconnection following hemispheric disconnective surgery.

N-Methyl-d-aspartate (NMDA) receptors are ligand and voltage-gated heteromeric ion channel receptors. Excessive activation of NMDA receptors is implicated in many neurological and psychiatric disorders, including ischemic stroke, neuropathic pain, epilepsy, drug addition, Alzheimer's disease, and schizophrenia. [ 18 F]GE179 is a promising PET probe for imaging functional NMDA receptor alterations (activated or 'open' channel) with a high binding affinity (K d  = 2.4 nM). Here, we report the production of the NMDA receptor radioligand [ 18 F]GE179 in a current Good Manufacturing Practice (cGMP) facility through a one-pot two-step strategy. [ 18 F]GE179 was produced in approximately 110 min with a radiochemical yield of 12 ± 6% (n = 4, decay corrected), radiochemical purity >95%, molar activity of 146 ± 32 GBq/μmol (at the end of synthesis), an average mass of GE179 at 2.2 μg/batch, and total impurities less than 0.5 μg/batch (n = 4). The radiopharmaceutical dose meets all quality control (QC) criteria for human use, and is suitable for clinical PET studies of activated NMDA receptor ion channels., (Copyright © 2019. Published by Elsevier Ltd.)

Diffusion MRI has been widely used to assess brain tissue microstructure. However, the conventional diffusion tensor imaging (DTI) is inadequate for characterizing fiber direction or fiber density in voxels with crossing fibers in brain white matter. The constrained spherical deconvolution (CSD) technique has been proposed to measure the complex fiber orientation distribution (FOD) using a single high b-value (b ≥ 3000 s/mm 2 ) to derive the intra-axonal volume fraction (V in ) from the calculated FOD. Recently, the spherical mean technique (SMT) was developed to fit V in directly from a multi-compartment model with multi-shell b-values. Although different numbers of b-values are needed in the two techniques, both methods have been suggested to be related to the spherical mean diffusion weighted signal (S¯). The current study compared the two techniques on the same high-quality Human Connectome Project diffusion data and investigated the relation between S¯ and V in systematically. At high b-values (b ≥ 3000 s/mm 2 ), S¯ is linearly related to V in , and S¯ provides similar contrast with V in in white matter. At low b-values (b ~ 1000 s/mm 2 ), the linear relation between S¯ and V in is sensitive to the variations of intrinsic diffusivity. These results demonstrate that S¯ measured with the typical b-value of 1000 s/mm 2 is not an indicator of V in , and previous DTI studies acquired with b = 1000 s/mm 2 cannot be re-analyzed to provide V in -weighted contrast., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Clinical interpretation of cerebral positron emission tomography with 2-deoxy-2[F-18]fluoro-d-glucose (FDG-PET) images often relies on evaluation of regional asymmetries. This study was designed to establish age-related variations in regional cortical glucose metabolism asymmetries in the developing human brain. FDG-PET scans of 58 children (age: 1-18 years) were selected from a large single-center pediatric PET database. All children had a history of epilepsy, normal MRI, and normal pattern of glucose metabolism on visual evaluation. PET images were analyzed objectively by statistical parametric mapping with the use of age-specific FDG-PET templates. Regional FDG uptake was measured in 35 cortical regions in both hemispheres using an automated anatomical labeling atlas, and left/right ratios were correlated with age, gender, and epilepsy variables. Cortical glucose metabolism was mostly symmetric in young children and became increasingly asymmetric in older subjects. Specifically, several frontal cortical regions showed an age-related increase of left > right asymmetries (mean: up to 10%), while right > left asymmetries emerged in posterior cortex (including portions of the occipital, parietal, and temporal lobe) in older children (up to 9%). Similar trends were seen in a subgroup of 39 children with known right-handedness. Age-related correlations of regional metabolic asymmetries showed no robust gender differences and were not affected by epilepsy variables. These data demonstrate a region-specific emergence of cortical metabolic asymmetries between age 1-18 years, with left > right asymmetry in frontal and right > left asymmetry in posterior regions. The findings can facilitate correct interpretation of cortical regional asymmetries on pediatric FDG-PET images across a wide age range., (© 2018 Wiley Periodicals, Inc.)

Purpose: Determination of the minimum number of gradient directions (N min ) for robust measurement of spherical mean diffusion weighted signal (S¯)., Methods: Computer simulations were employed to characterize the relative standard deviation (RSD) of the measured spherical mean signal as a function of the number of gradient directions (N). The effects of diffusion weighting b-value and signal-to-noise ratio (SNR) were investigated. Multi-shell high angular resolution Human Connectome Project diffusion data were analyzed to support the simulation results., Results: RSD decreases with increasing N, and the minimum number of N needed for RSD ≤ 5% is referred to as N min . At high SNRs, N min increases with increasing b-value to achieve sufficient sampling. Simulations showed that N min is linearly dependent on the b-value. At low SNRs, N min increases with increasing b-value to reduce the noise. RSD can be estimated as σS¯N, where σ = 1/SNR is the noise level. The experimental results were in good agreement with the simulation results. The spherical mean signal can be measured accurately with a subset of gradient directions., Conclusion: As N min is affected by b-value and SNR, we recommend using 10 × b / b 1 (b 1  = 1 ms/μm 2 ) uniformly distributed gradient directions for typical human diffusion studies with SNR ~ 20 for robust spherical mean signal measurement., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Three children with drug-refractory epilepsy, normal magnetic resonance image (MRI), and a heterozygous SCN1A variant underwent 2-deoxy-2-[ 18 F]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.

In this review, we discuss molecular brain imaging studies using positron emission tomography (PET) with 2-deoxy-2( 18 F)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 11 C-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.

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: Forty-one children (25 males) with drug-resistant epilepsy had a baseline positron emission tomography (PET) scan at a median age of 4.7 years; the scans were repeated after a median of 4.3 years. Children with progressive neurological disorders or space-occupying lesion-related epilepsy and those who had undergone epilepsy surgery were excluded. The number of affected lobes on 2-deoxy-2( 18 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., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (© 2017 Wiley Periodicals, Inc.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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[ 11 C]-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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of Interest: The authors report no conflict of interest.

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: Ten children had brain calcification at baseline and 11 at follow-up. Mean calcified brain volume increased from 1.69 to 2.47cm 3 (p=0.003) in these children; the rate of interval calcified volume increase was associated with early onset of epilepsy (Spearman's rho [r s ]=-0.63, p=0.036). Calcified brain regions showed a variable degree of glucose hypometabolism with the metabolic abnormalities often extending to non-calcified cerebral lobes. Larger calcified brain volumes at baseline were associated with longer duration of epilepsy (r s =0.69, p=0.004) and lower outcome IQ (r s =-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., (© 2017 Mac Keith Press.)

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., (© 2017 Wiley Periodicals, Inc.)

Corpus callosotomy is a palliative procedure performed to reduce the severity of drug-resistant epilepsy. The authors assessed its efficacy on different seizure types in 20 subjects (age range 5-19 years); 8 with active vagus nerve stimulator. Fifteen had complete callosotomy, 3 had anterior 2/3, and 2 had anterior 2/3 followed later by complete callosotomy. Ten had endoscopic approach. In all, 65% had ≥ 50% reduction of generalized seizures leading to falls (atonic, tonic, myoclonic); 35% became seizure-free (follow-up period: 6 months to 9 years; mean 3 years). Seizure outcome distribution was better for generalized than for partial seizures ( P = .003). Endoscopic approach was as effective as transcranial approach. Seven subjects who failed vagus nerve stimulator therapy responded with ≥50% seizure reduction. Corpus callosotomy is an effective treatment for intractable generalized epilepsy leading to falls with significant seizure reduction or even elimination of seizures, in the majority of children.

Background: Agenesis of the corpus callosum can occur in individuals with epilepsy, either in isolation or as part of various neurological conditions, such as Aicardi syndrome. In this study, we evaluated the clinical and neuroradiological differences between children with nonsyndromic agenesis of the corpus callosum and those with Aicardi syndrome., Methods: We evaluated 31 children with epilepsy and agenesis of the corpus callosum (11 males, 20 females), 14 of whom had Aicardi syndrome (all females). We compared their clinical evaluations, radiological and electrophysiological findings, treatments, and their outcome., Results: Median age at seizure onset was lower in the Aicardi syndrome group compared with nonsyndromic agenesis of the corpus callosum (two versus five months, P = 0.006). The developmental impairment in terms of verbalization and ambulation was significantly worse in patients with Aicardi syndrome. The severity of magnetic resonance imaging (MRI) and glucose metabolism positron emission tomography (PET) involvement was more extensive in children with Aicardi syndrome than in nonsyndromic agenesis of the corpus callosum. In both groups, the PET scan showed a much more extensive area of involvement than suggested by the MRI scan. Four children underwent epilepsy surgery with significant improvement, but were not seizure free. Outcome was worse in those with PET showing abnormalities in the nonsurgical hemisphere despite normal appearance on MRI. All children who did not undergo surgery also continued to have seizures at last follow-up., Conclusions: Children with Aicardi syndrome have earlier seizure onset, worse developmental outcome, and larger areas of brain abnormalities on neuroimaging compared with nonsyndromic agenesis of the corpus callosum patients. PET reveals larger area of abnormalities, compared with MRI. Although epilepsy surgery in agenesis of the corpus callosum may offer some palliative benefit in seizure frequency, none of our patients became seizure free., (Copyright © 2017 Elsevier Inc. All rights reserved.)

PET and SPECT can play an important role in the evaluation of various epileptic syndromes, particularly those with unknown causes, by revealing various underlying abnormalities that may not be fully appreciated from MR imaging studies. In some cases, PET and SPECT provide crucial data that guide surgical resections of the epileptogenic zone for medically refractory epilepsy. In other cases, these neuroimaging modalities preclude a surgical option and can guide genetic studies. Longitudinal PET and SPECT studies may increase our understanding of the etiopathogenesis of epilepsy syndromes and provide a clearer picture of the natural history of neurologic progression., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Epilepsy is one of the most common yet diverse neurologic disorders, affecting almost 1%-2% of the population. Presently, radionuclide imaging such as PET and SPECT is not used in the primary diagnosis or evaluation of recent-onset epilepsy. However, it can play a unique and important role in certain specific situations, such as in noninvasive presurgical localization of epileptogenic brain regions in intractable-seizure patients being considered for epilepsy surgery. Radionuclide imaging can be particularly useful if MR imaging is either negative for lesions or shows several lesions of which only 1 or 2 are suspected to be epileptogenic and if electroencephalogram changes are equivocal or discordant with the structural imaging. Similarly, PET and SPECT can also be useful for evaluating the functional integrity of the rest of the brain and may provide useful information on the possible pathogenesis of the neurocognitive and behavioral abnormalities frequently observed in these patients., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

To recognize epileptic spasms (ES) as a seizure type after traumatic brain injury (TBI), accidental or non-accidental, in infants and children. In the process, we aim to gain some insight into the mechanisms of epileptogenesis in ES. A retrospective electronic chart review was performed at the Children's Hospital of Michigan from 2002 to 2012. Electronic charts of 321 patients were reviewed for evidence of post-traumatic epilepsy. Various clinical variables were collected including age at TBI, mechanism of trauma, severity of brain injury, electroencephalography/neuroimaging data, and seizure semiology. Six (12.8%) of the 47 patients diagnosed with post-traumatic epilepsy (PTE) had ES. Epileptic spasms occurred between two months to two years after TBI. All patients with ES had multiple irritative zones, manifesting as multifocal epileptiform discharges, unilateral or bilateral. Cognitive delay and epileptic encephalopathy were seen in all six patients, five of whom were free of spasms after treatment with vigabatrin or adrenocorticotropic hormone. The risk of PTE is 47/321(14.6%) and the specific risk of ES after TBI is 6/321 (1.8%). The risk of ES appears to be high if the age at which severe TBI occurred was during infancy. Non-accidental head trauma is a risk factor of epileptic spasms. While posttraumatic epilepsy (not ES) may start 10 years after the head injury, ES starts within two years, according to our small cohort. The pathophysiology of ES is unknown, however, our data support a combination of previously proposed models in which the primary dysfunction is a focal or diffuse cortical abnormality, coupled with its abnormal interaction with the subcortical structures and brainstem at a critical maturation stage.