Biomedical subjects

Edward J Novotny

Publications and source records attributed to Edward J Novotny.

9 recordsLinked to original sources

PubMed2005

Inherited disorders of neurotransmitters in children and adults.

Inherited disorders of neurotransmitters are a group of neurometabolic syndromes attributable to a primary disturbance of neurotransmitter metabolism or transport. This is an enlarging group of recognized disorders requiring specialized diagnostic procedures for detection. This review considers clinical disorders of biopterin, catecholamines, serotonin, glycine, pyridoxine, and GABA metabolism. Newly described syndromes such as cerebral folate deficiency and pyridoxal-5-phosphate dependency are included. The disorders of the metabolic pathways of biopterin, catecholamines, and serotonin are linked due to their common synthetic components. Glycine encephalopathy represents an enlarging phenotype related to abnormalities of the glycine degradative cleavage system. Both pyridoxine and pyridoxal-5-phosphate dependency need to be considered in refractory neonatal seizures. The most common disorder of GABA metabolism is SSADH deficiency, which has a broad phenotype of mental retardation, epilepsy, ataxia, and hyporeflexia and which invokes the combined problems of elevated brain GABA and GHB.

Adult↗

PubMed2005

Localizing value of ictal-interictal SPECT analyzed by SPM (ISAS).

PURPOSE: The goal of neuroimaging in epilepsy is to localize the region of seizure onset. Single-photon emission computed tomography with tracer injection during seizures (ictal SPECT) is a promising tool for localizing seizures. However, much uncertainty exists about how to interpret late injections, or injections done after seizure end (postictal SPECT). A widely available and objective method is needed to interpret ambiguous ictal and postictal scans, with changes in multiple brain regions. METHODS: Ictal or postictal SPECT scans were performed by using [99mTc]-labeled hexamethyl-propylene-amine-oxime (HMPAO), and images were analyzed by comparison with interictal scans for each patient. Forty-seven cases of localized epilepsy were studied. We used methods that can be implemented anywhere, based on freely downloadable software and normal SPECT databases (http://spect.yale.edu). Statistical parametric mapping (SPM) was used to localize a single region of seizure onset based on ictal (or postictal) versus interictal difference images for each patient. We refer to this method as ictal-interictal SPECT analyzed by SPM (ISAS). RESULTS: With this approach, ictal SPECT identified a single unambiguous region of seizure onset in 71% of mesial temporal and 83% of neocortical epilepsy cases, even with late injections, and the localization was correct in all (100%) cases. Postictal SPECT, conversely, with injections performed soon after seizures, was very poor at localizing a single region based on either perfusion increases or decreases, often because changes were similar in multiple brain regions. However, measuring which hemisphere overall had more decreased perfusion with postictal SPECT, lateralized seizure onset to the correct side in approximately 80% of cases. CONCLUSIONS: ISAS provides a validated and readily available method for epilepsy SPECT analysis and interpretation. The results also emphasize the need to obtain SPECT injections during seizures to achieve unambiguous localization.

Adolescent↗

PubMed2004

Positive and negative network correlations in temporal lobe epilepsy.

Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.

Adolescent↗

PubMed2003

Succinic semialdehyde dehydrogenase deficiency in children and adults.

Succinic semialdehyde dehydrogenase deficiency is a rare disorder of the degradation pathway of gamma-aminobutyric acid. The disorder is detected when 4-hydroxybutyric aciduria is present on urine organic acid analysis, and is subsequently confirmed by enzyme measurement on leucocytes. The disorder has been identified in approximately 350 individuals worldwide. We review the clinical features in 60 patients. The most common characteristics are developmental delay maximally involving expressive language, hypotonia, mental retardation, ataxia, and behavioral problems. Seizures occur in approximately half of patients, and include tonic-clonic, absence, and myoclonic seizures, including status epilepticus. Electroencephalographic findings are background slowing and generalized and focal epileptiform discharges. Magnetic resonance imaging typically reveals increased T2-weighted signal of the globus pallidus bilaterally, with variable involvement of white matter and the cerebellar dentate nucleus. Preliminary human cerebrospinal fluid measurements are consistent with neurometabolic aberrations documented in the murine animal model, with elevations in gamma-aminobutyric acid, gamma-hydroxybutyrate, and homocarnosine, and low glutamine. Succinic semialdehyde dehydrogenase deficiency may be an underrecognized neurometabolic disorder with a nonspecific and wide phenotypic spectrum, and carries implications for a comprehensive fundamental understanding of interrelations between multiple neurotransmitter systems.

Adult↗

PubMed2003

Magnetic resonance spectroscopy of neurotransmitters in human brain.

Magnetic resonance spectroscopy (MRS) is a noninvasive method that permits measurement of the concentration of specific biochemical compounds in the brain and other organ systems in precisely defined regions guided by MR imaging (MRI). Recently, MRS methods have been developed to measure specific neurotransmitters in the brain. More advanced MRS methods have been developed to measure the synthesis rates and turnover of specific neurotransmitters. These turnover rates can provide measures of brain metabolism similar to radioisotope techniques. Also, investigations of the relationship of brain metabolism and specific neurotransmitter systems are now possible using MRS. Here, we review the MRS techniques and studies of neurotransmitters in the human brain. A discussion of the potential use of these techniques in the context of certain pediatric neurotransmitter disorders will be presented.

Brain Chemistry↗

PubMed2003

Chronic hypoxia in development selectively alters the activities of key enzymes of glucose oxidative metabolism in brain regions.

The immature brain is more resistant to hypoxia/ischemia than the mature brain. Although chronic hypoxia can induce adaptive-changes on the developing brain, the mechanisms underlying such adaptive changes are poorly understood. To further elucidate some of the adaptive changes during postnatal hypoxia, we determined the activities of four enzymes of glucose oxidative metabolism in eight brain regions of hypoxic and normoxic rats. Litters of Sprague-Dawley rats were put into the hypoxic chamber (oxygen level maintained at 9.5%) with their dams starting on day 3 postnatal (P3). Age-matched normoxic rats were use as control animals. In P10 hypoxic rats, lactate dehydrogenase (LDH) activity in cerebral cortex, striatum, olfactory bulb, hippocampus, hypothalamus, pons and medulla, and cerebellum was significantly increased (by 100%-370%) compared to those in P10 normoxic rats. In P10 hypoxic rats, hexokinase (HK) activity in hypothalamus, hippocampus, olfactory bulb, midbrain, and cerebral cortex was significantly decreased (by 15%-30%). Neither alpha-ketoglutarate dehydrogenase complex (KGDHC, which is believed to have an important role in the regulation of the tricarboxylic acid [TCA] cycle flux) nor citrate synthase (CS) activity was significantly decreased in the eight regions of P10 hypoxic rats compared to those in P10 normoxic rats. In P30 hypoxic rats, LDH activity was only increased in striatum (by 19%), whereas HK activity was only significantly decreased (by 30%) in this region. However, KGDHC activity was significantly decreased in olfactory bulb, hippocampus, hypothalamus, cerebral cortex, and cerebellum (by 20%-40%) in P30 hypoxic rats compared to those in P30 normoxic rats. Similarly, CS activity was decreased, but only in olfactory bulb, hypothalamus, and midbrain (by 9%-21%) in P30 hypoxic rats. Our results suggest that at least some of the mechanisms underlying the hypoxia-induced changes in activities of glycolytic enzymes implicate the upregulation of HIF-1. Moreover, our observation that chronic postnatal hypoxia induces differential effects on brain glycolytic and TCA cycle enzymes may have pathophysiological implications (e.g., decreased in energy metabolism) in childhood diseases (e.g., sudden infant death syndrome) in which hypoxia plays a role.

Aging↗

PubMed2002

Aspartame: review of safety.

Over 20 years have elapsed since aspartame was approved by regulatory agencies as a sweetener and flavor enhancer. The safety of aspartame and its metabolic constituents was established through extensive toxicology studies in laboratory animals, using much greater doses than people could possibly consume. Its safety was further confirmed through studies in several human subpopulations, including healthy infants, children, adolescents, and adults; obese individuals; diabetics; lactating women; and individuals heterozygous (PKUH) for the genetic disease phenylketonuria (PKU) who have a decreased ability to metabolize the essential amino acid, phenylalanine. Several scientific issues continued to be raised after approval, largely as a concern for theoretical toxicity from its metabolic components--the amino acids, aspartate and phenylalanine, and methanol--even though dietary exposure to these components is much greater than from aspartame. Nonetheless, additional research, including evaluations of possible associations between aspartame and headaches, seizures, behavior, cognition, and mood as well as allergic-type reactions and use by potentially sensitive subpopulations, has continued after approval. These findings are reviewed here. The safety testing of aspartame has gone well beyond that required to evaluate the safety of a food additive. When all the research on aspartame, including evaluations in both the premarketing and postmarketing periods, is examined as a whole, it is clear that aspartame is safe, and there are no unresolved questions regarding its safety under conditions of intended use.

Affect↗

PubMed2002

Frontal lobe tumoral epilepsy: clinical, neurophysiologic features and predictors of surgical outcome.

PURPOSE: To review the clinical, neurophysiologic features and surgical outcomes in patients with frontal lobe tumors and chronic intractable seizures. METHODS: Medical records of patients with intractable epilepsy who underwent resection or stereotactic biopsy of frontal lobe tumor (confirmed by surgical pathology) seen between 1985 and 1999 at Yale University School of Medicine Epilepsy Center were reviewed for age at diagnosis, age at onset of seizures, delay between seizure onset and tumor diagnosis, types and frequencies of seizures, EEG results, use of anticonvulsants, extent of surgery, pathological diagnosis, and tumor recurrence. RESULTS: Thirty-seven patients were included. Mean age at seizure onset was 31.6 years, and at tumor diagnosis was 36.2 years. Mean duration between onset of seizures and tumor diagnosis was 6.1 years. Seventeen patients had auras. Seizure frequency averaged 7.6 seizures per week, with 58% of patients having more than one seizure type. All patients used anticonvulsants, with 90% eventually using polytherapy. All patients eventually underwent at least one surgical procedure. Only 13 (35.1%) patients were class I. Twelve (32.4%) patients were class II, seven (18.9%) class III, and five (13.5%) class IV. No statistically significant differences were seen between good and poor long-term seizure outcome in relation to specific tumor pathology, seizure types, or type of resection. CONCLUSIONS: Long-term surgical outcomes in tumoral frontal lobe epilepsy are more favorable than those in nontumoral intractable frontal lobe epilepsy (65% class I or II) and less favorable than those in other tumoral epilepsy (overall, 70% class I). Frontal location of intracranial neoplasm may predict a less favorable long-term epilepsy prognosis than tumoral epilepsy in general, an observation for which several explanations are proposed.

Adolescent↗

PubMedDate not supplied

Reference values for long echo time MR spectroscopy in healthy adults.

BACKGROUND AND PURPOSE: There is a lack of information with regard to normal metabolic ratios acquired with MR spectroscopy utilizing a long echo time technique. Our purpose was to measure metabolic ratios in healthy adults to determine whether the metabolites varied across brain regions and by sex. METHODS: Single voxel proton spectra were acquired with an echo time of 135 milliseconds in 10 brain regions of 72 healthy subjects ranging in age from 20 to 44 years. Six gray matter sites in the cerebrum included four cortical areas in the frontal, parietal, temporal, and occipital lobes, and two deep nuclear sites in the basal ganglia and the thalamus. Two subcortical white matter regions were in the parietal and the frontal lobes. Two posterior fossa sites included the pons and the cerebellum. All 10 brain regions were not studied in each subject. For each spectrum, the metabolites n-acetylaspartate (NAA), creatine (Cr), and choline (Ch) were identified and ratios of NAA/Cr and Ch/Cr calculated for each brain region. A multifactorial analysis of variance was performed with the two metabolic ratios as dependent variables and with brain region and sex as independent variables. Post hoc statistical analysis consisted of the Scheffé F statistic for significant difference between pairs of brain regions for both metabolic ratios. RESULTS: There was significant regional variation for both the NAA/Cr ratio (P < .0001) and the Ch/Cr ratio (P < .0001). The NAA/Cr ratio was consistent within cortical gray and white matter but differed between cortical gray (smaller ratio) and white matter (larger ratio). The Ch/Cr ratio was variable in the gray matter, differed between some but not all gray and white matter regions, but was consistent within subcortical white matter regions. There was no difference between men and women for either metabolic ratio. CONCLUSION: There was variation of the NAA/Cr ratio and the Ch/Cr ratio across brain regions, but no sex differences were found. These findings provide the requisite normative values to use single voxel, long-echo-time MR spectroscopy in adult patients with neurologic disorders.

Adult↗