Deep Venous Remodeling in Unilateral Sturge-Weber Syndrome: Robust Hemispheric Differences and Clinical Correlates.

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.

Epilepsy Due to Mild TBI in Children: An Experience at a Tertiary Referral Center.

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.

Consensus Statement for the Management and Treatment of Sturge-Weber Syndrome: Neurology, Neuroimaging, and Ophthalmology Recommendations.

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.

Hypermetabolism on Pediatric PET Scans of Brain Glucose Metabolism: What Does It Signify?

When one is interpreting clinical 18F-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 18F-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 18F-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 18F-FDG PET studies should be aware of these circumstances to accurately assess the findings.

Evolution of Surgical Management for Intractable Epileptic Spasms.

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.

Neuroinflammation in Children With Infantile Spasms: A Prospective Study Before and After Treatment With Acthar Gel (Repository Corticotropin Injection).

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 11C-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 1-(2-[18F]fluoroethyl)-l-tryptophan for imaging of tryptophan metabolism.

Automated production of an fluorine-18 labeled tryptophan analogue, 1-(2-[18F]fluoroethyl)-l-tryptophan (1-L-[18F]FETrp) in a current Good Manufacturing Practice facility was achieved. 1-L-[18F]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.

The SOFIA Study: Negative Multi-center Study of Low Dose Fluoxetine on Repetitive Behaviors in Children and Adolescents with Autistic Disorder.

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that reduces obsessive-compulsive symptoms. There is limited evidence supporting its efficacy for repetitive behaviors (RRBs) in autistic spectrum disorder (ASD). We conducted a randomized controlled trial (RCT) of fluoxetine in 158 individuals with ASD (5-17 years). Following 14 treatment weeks (mean dose 11.8 mg/day), no significant differences were noted on the Children's Yale-Brown Obsessive Compulsive Scale; the proportion of responders was similar (fluoxetine: 36%; placebo: 41%). There were similar rates of AEs (e.g., insomnia, diarrhea, vomiting); high rates of activation were reported in both groups (fluoxetine: 42%; placebo: 45%). Overly cautious dosing/duration may have prevented attainment of a therapeutic level. Results are consistent with other SSRI RCTs treating RRBs in ASD.Trial Registration: clinicaltrials.gov Identifier: NCT00515320.

TLR7 activation in epilepsy of tuberous sclerosis complex.

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.

Positron Emission Tomography in Pediatric Neurodegenerative Disorders.

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.

Neurological Complications of Sturge-Weber Syndrome: Current Status and Unmet Needs.

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.

Anatomical hemispherectomy revisited-outcome, blood loss, hydrocephalus, and absence of chronic hemosiderosis.

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.

Automated production of a N-methyl-D-aspartate receptor radioligand [18F]GE179 for clinical use.

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. [18F]GE179 is a promising PET probe for imaging functional NMDA receptor alterations (activated or 'open' channel) with a high binding affinity (Kd = 2.4 nM). Here, we report the production of the NMDA receptor radioligand [18F]GE179 in a current Good Manufacturing Practice (cGMP) facility through a one-pot two-step strategy. [18F]GE179 was produced in approximately 110 min with a radiochemical yield of 12 ±â€¯6% (n = 4, decay corrected), radiochemical purity >95%, molar activity of 146 ±â€¯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.

Objective PET study of glucose metabolism asymmetries in children with epilepsy: Implications for normal brain development.

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.

Linking spherical mean diffusion weighted signal with intra-axonal volume fraction.

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/mm2) to derive the intra-axonal volume fraction (Vin) from the calculated FOD. Recently, the spherical mean technique (SMT) was developed to fit Vin 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 Vin systematically. At high b-values (b ≥ 3000 s/mm2), S¯ is linearly related to Vin, and S¯ provides similar contrast with Vin in white matter. At low b-values (b ~ 1000 s/mm2), the linear relation between S¯ and Vin is sensitive to the variations of intrinsic diffusivity. These results demonstrate that S¯ measured with the typical b-value of 1000 s/mm2 is not an indicator of Vin, and previous DTI studies acquired with b = 1000 s/mm2 cannot be re-analyzed to provide Vin-weighted contrast.

Evolution of Brain Glucose Metabolic Abnormalities in Children With Epilepsy and SCN1A Gene Variants.

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.

Minimal number of gradient directions for robust measurement of spherical mean diffusion weighted signal.

PURPOSE: Determination of the minimum number of gradient directions (Nmin) 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 Nmin. At high SNRs, Nmin increases with increasing b-value to achieve sufficient sampling. Simulations showed that Nmin is linearly dependent on the b-value. At low SNRs, Nmin 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 Nmin is affected by b-value and SNR, we recommend using 10 × b / b1 (b1 = 1 ms/µm2) uniformly distributed gradient directions for typical human diffusion studies with SNR ~ 20 for robust spherical mean signal measurement.

Imaging Brain Metabolism in the Newborn.

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 GABAA 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.

Evolution of lobar abnormalities of cerebral glucose metabolism in 41 children with drug-resistant epilepsy.

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.