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Biomedical subjects

E J Novotny

Publications and source records attributed to E J Novotny.

At least 19 recordsLinked to original sources
PubMed2003

Clinical spectrum of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.

Adolescent↗
PubMed2001

Differential increase in cerebral cortical glucose oxidative metabolism during rat postnatal development is greater in vivo than in vitro.

The steady-state rate of glucose oxidation through the mitochondrial TCA cycle (V(TCA)) was measured in acid extracts of 10- and 30-day-old cerebral cortex of rats receiving [1-13C]glucose intravenously and in neocortical slices superfused in vitro with the same isotope. TCA cycle flux was determined for each age group based on metabolic modeling analysis of the isotopic turnover of cortical glutamate and lactate. The sensitivity of the calculated rates to assumed parameters in the model were also assessed. Between 10 and 30 postnatal days, V(TCA) increased by 4.3-fold (from 0.46 to 2.0 micromol g(-1) min(-1)) in the cortex in vivo, whereas only a 2-fold (from 0.17 to 0.34 micromol g(-1) min(-1)) increase was observed in neocortical slices. The much greater increase in glucose oxidative metabolism of the cortex measured in vivo over that measured in vitro as the cortex matures suggests that function-related energy demands increase during development, a process that is deficient in the slice as a result of deafferentiation and other mechanisms.

Aging↗
PubMed2001

Differentiation of glucose transport in human brain gray and white matter.

Localized 1H nuclear magnetic resonance spectroscopy has been applied to determine human brain gray matter and white matter glucose transport kinetics by measuring the steady-state glucose concentration under normoglycemia and two levels of hyperglycemia. Nuclear magnetic resonance spectroscopic measurements were simultaneously performed on three 12-mL volumes, containing predominantly gray or white matter. The exact volume compositions were determined from quantitative T1 relaxation magnetic resonance images. The absolute brain glucose concentration as a function of the plasma glucose level was fitted with two kinetic transport models, based on standard (irreversible) or reversible Michaelis-Menten kinetics. The steady-state brain glucose levels were similar for cerebral gray and white matter, although the white matter levels were consistently 15% to 20% higher. The ratio of the maximum glucose transport rate, V(max), to the cerebral metabolic utilization rate of glucose, CMR(Glc), was 3.2 +/- 0.10 and 3.9 +/- 0.15 for gray matter and white matter using the standard transport model and 1.8 +/- 0.10 and 2.2 +/- 0.12 for gray matter and white matter using the reversible transport model. The Michaelis-Menten constant K(m) was 6.2 +/- 0.85 and 7.3 +/- 1.1 mmol/L for gray matter and white matter in the standard model and 1.1 +/- 0.66 and 1.7 +/- 0.88 mmol/L in the reversible model. Taking into account the threefold lower rate of CMR(Glc) in white matter, this finding suggests that blood--brain barrier glucose transport activity is lower by a similar amount in white matter. The regulation of glucose transport activity at the blood--brain barrier may be an important mechanism for maintaining glucose homeostasis throughout the cerebral cortex.

Adult↗
PubMed2000

Brain regional development of the activity of alpha-ketoglutarate dehydrogenase complex in the rat.

This study was initiated to test the hypothesis that the development of alpha-ketoglutarate dehydrogenase complex (KGDHC) activity, like that of pyruvate dehydrogenase complex, is one of the late developers of tricarboxylic acid (TCA) cycle enzymes. The postnatal development of KGDHC in rat brain exhibits four distinct region-specific patterns. The age-dependent increases in olfactory bulb (OB) and hypothalamus (HYP) form one pattern: low in postnatal days (P) 2 and 4, KGDHC activity rose linearly to attain adult level at P30. The increases in mid-brain (MB) and striatum (ST) constitute a second pattern: being <40% of adult level at P2 and P4, KGDHC activity rose steeply between P10 and P17 and attained adult level by P30. The increases in cerebellum (CB), cerebral cortex (CC), and hippocampus (HIP) form a third pattern: being 25-30% of adult level at P2 and P4, KGDHC activity doubled between P10 and P17 and rose to adult level by P30. KGDHC activity development is unique in pons and medulla (PM): being >60% of the adult level at P2, it rose rapidly to adult level by P10. Thus, KGDHC activity develops earlier in phylogenetically older regions (PM) than in phylogenetically younger regions (CB, CC, HIP). Being lowest in activity among all TCA cycle enzymes, KGDHC activity in any region at any age will exert a limit on the maximum TCA cycle flux therein. The results may have functional and pathophysiological implications in control of brain glucose oxidative metabolism, energy metabolism, and neurotransmitter syntheses.

Animals↗
PubMed1999

Glucose transporter type 1 deficiency: a study of two cases with video-EEG.

Glucose transporter type 1 (GLUT1) deficiency is an inborn error of glucose transport. Clinical manifestations are presumed secondary to reduced glucose transport across the blood brain barrier, and include seizures, abnormal tone, developmental delay and hypoglycorrhachia. A high index of suspicion is important as GLUT1 deficiency is a potentially treatable cause of mental retardation. We studied two affected children by continuous video-EEG in order to better understand the cause of the clinical manifestations and improvement on a ketogenic diet. The EEG was characterized by generalized paroxysmal 2-2.5 Hz spike-wave discharges, although normal EEGs were also obtained. Atypical absence seizures were the most prominent clinical seizure. Epileptiform activity and clinical seizures occurred in both children while acutely ketotic and non-ketotic, but were markedly more frequent in one child when non-ketotic. Discharges were not associated with a reduction in substrate for brain metabolism in the blood at that time. Conclusion Atypical absence seizures are common in glucose transporter type 1 deficiency and should alert the clinician to the possibility of this treatable disorder when present in a young child with developmental delay. Our data suggest that the therapeutic mechanism of the ketogenic diet in this disorder is more complicated than simply delivering ketones as an alternative substrate for brain metabolism.

Child↗
PubMed1999

GABA changes with vigabatrin in the developing human brain.

PURPOSE: Changes in gamma-aminobutyric acid (GABA) physiology are important in determining seizure susceptibility in the developing nervous system. Noninvasive measurements of brain GABA in adults with epilepsy have demonstrated important relations among seizure control, brain GABA levels, and changes in brain GABA with drugs designed to alter GABA metabolism. The purpose of this study was to demonstrate the changes in GABA in the occipital lobes of children with epilepsy after treatment with vigabatrin (VGB). METHODS: Ten proton nuclear magnetic resonance spectroscopic (NMRS) studies were obtained on four subjects with epilepsy. The subjects were between ages 1 and 5 years. Occipital lobe GABA levels were measured before and after treatment with VGB. RESULTS: Brain GABA levels increased significantly in these subjects after VGB treatment (p < 0.05, paired Student's t test). In one subject, brain GABA was decreased in the region of the epileptic focus compared with the homologous region of the opposite hemisphere. A nearly fivefold increase in GABA occurred in the epileptic region after VGB treatment in this subject. CONCLUSIONS: VGB increases brain GABA levels in children with epilepsy. NMRS can be used to monitor the response of brain GABA levels to drugs known to alter GABA physiology and serve as an important tool to understand the role of GABA-mediated inhibition in pediatric epilepsies.

Adult↗
PubMed1999

Functional magnetic resonance imaging identifies abnormal visual cortical function in patients with occipital lobe epilepsy.

PURPOSE: To determine whether functional magnetic resonance imaging (fMRI) can reliably identify lateralized cortical dysfunction in patients with suspected occipital lobe epilepsy. METHODS: We compared visual cortical function of 10 patients with intractable occipital lobe epilepsy with nine control subjects' fMRI. Visual stimulation by using an alternating checkerboard pattern results in transient increases in the intensity of the proton magnetic resonance signal of water in the occipital lobes during echo-planar imaging. We used these stimulus-dependent changes in signal intensity to construct functional activation maps, which we registered onto anatomic images. RESULTS: After full-field stimulation, none of the patients with occipital lobe epilepsy had normal activation patterns, whereas eight of the nine control subjects had normal patterns (p = 0.001). Abnormalities consisted of either a markedly asymmetric activation pattern in six of 10 patients (p = 0.04), or a complete absence of activation in four of 10 patients (p = 0.05). The abnormal side of activation was concordant with the side of seizure onset in all six patients with asymmetric activation maps. Half-field stimulation produced less reliable results. Although more patients had abnormal activation maps than did controls with half-field stimulation (p = 0.04), the abnormal side was discordant with the side of seizure onset in three of the five patients who had markedly asymmetric activation patterns. CONCLUSIONS: These results suggest that fMRI with full-field stimulation is a reliable, noninvasive method for identifying areas of abnormal visual cortical function ipsilateral to the epileptogenic region in patients with occipital lobe epilepsy.

Adolescent↗
PubMed1998

In vivo lactate and beta-hydroxybutyrate editing using a pure-phase refocusing pulse train.

A refocusing pulse train consisting of a semiselective refocusing pulse and a selective inversion pulse to obtain a pure-phase refocusing at the frequency of maximal excitation of the semiselective refocusing pulse is proposed and applied to in vivo lactate and beta-hydroxybutyrate editing using difference spectroscopy. It is shown, using both rotation matrix theory and phantom experiments, that the soft inversion pulse has to be halved to flank the semiselective pulse to obtain perfect refocusing and cancellation of interfering resonances. The editing method is used to obtain lactate and beta-hydroxybutyrate spectra from the occipital cortex of juvenile epilepsy patients before and after ketogenic diet treatment.

3-Hydroxybutyric Acid↗
PubMed1998

The role of clinical neurophysiology in the management of epilepsy.

Clinical neurophysiologic studies have an important role in the diagnosis and management of the patient with epilepsy. Epilepsy is a clinical diagnosis and the EEG is an important adjunct used to differentiate epileptic seizures from nonepileptic events, refine the diagnosis of epilepsy into specific seizure types and epileptic syndromes, and provide a measure of brain function. The value of the EEG is highly dependent on the clinical context in which it is being applied. In some epilepsies the interictal EEG may be diagnostic whereas in others an ictal recording may be necessary to obtain a specific diagnosis. Both the interictal and ictal EEG characteristics vary with specific seizure types and epilepsies and are described in detail in this review. The usefulness of the EEG in the management of epilepsy and in aiding in the decision to discontinue antiepileptic therapy is also discussed.

Anticonvulsants↗
PubMed1996

1H NMR studies of glucose transport in the human brain.

The difference between 1H nuclear magnetic resonance (NMR) spectra obtained from the human brain during euglycemia and during hyperglycemia is depicted as well-resolved glucose peaks. The time course of these brain glucose changes during a rapid increase in plasma glucose was measured in four healthy subjects, aged 18-22 years, in five studies. Results demonstrated a significant lag in the rise of glucose with respect to plasma glucose. The fit of the integrated symmetric Michaelis-Menten model to the time course of relative glucose signals yielded an estimated plasma glucose concentration for half maximal transport, Kt, of 4.8 +/- 2.4 mM (mean +/- SD), a maximal transport rate, Tmax, of 0.80 +/- 0.45 micromol g-1 min-1, and a cerebral metabolic glucose consumption rate (CMR)glc of 0.32 +/- 0.16 micromol g-1 min-1. Assuming cerebral glucose concentration to be 1.0 micromol/g at euglycemia as measured by 13CMR, the fit of the same model to the time course of brain glucose concentrations resulted in Kt = 3.9 +/- 0.82 mM, Tmax = 1.16 +/- 0.29 micromol g-1 min-1, and CMRglc = 0.35 +/- 0.10 micromol g-1 min-1. In both cases, the resulting time course equaled that predicted from the determination of the steady-state glucose concentration by 13C NMR spectroscopy within the experimental scatter. The agreement between the two methods of determining transport kinetics suggests that glucose is distributed throughout the entire aqueous phase of the human brain, implying substantial intracellular concentration.

Adolescent↗
PubMed1996

Predictors of intractable epilepsy in childhood: a case-control study.

Little is known about what factors predict intractable epilepsy at the time of initial diagnosis. We performed a case-control study to identify early predictors of medically intractable epilepsy in children. Cases were children who had an average of one seizure or more a month over a 2-year period and who, during that time, had failed trials of at least three different antiepileptic drugs (AEDs). Controls were children who had epilepsy, who had been seizure-free for > or = 2 years, and who had never, before becoming seizure-free, met the definition for intractable epilepsy. Strong univariate associations were noted between intractability and several factors: infantile spasms (IS) remote symptomatic epilepsy, a history of status epilepticus (SE) before the diagnosis of epilepsy, neonatal seizures, and microcephaly. Cases were significantly younger than controls at onset (1.8 vs. 5.8 years); this was not due solely to cases with onset during the first year of life but was an association apparent throughout the age range studied. With multiple logistic regression, independent predictors of intractability were IS, odds ratio (OR) = 10.42, p = 0.03; age at onset with a decreasing risk with increasing age, OR = 0.77 per year, p less than 0.0001; remote symptomatic epilepsy, OR = 2.24, p = 0.04; and SE, OR = 3.30, p = 0.04. These findings complement those of recent cohort studies of remission of epilepsy and provide useful leads for future prospective studies of intractable epilepsy.

Adolescent↗
PubMed1995

Overview--the role of NMR spectroscopy in epilepsy.

Nuclear magnetic resonance (NMR) spectroscopy permits noninvasive, serial measurements of several metabolites with important neurobiologic roles in localized brain regions in vivo. Over the last decade, this technique has been applied to investigations of both animals and humans with epilepsy. Several nuclei that include specific proton, phosphorus, and carbon isotopes provide NMR signals that measure specific compounds in vivo. This paper reviews the studies that have used these multinuclear NMR techniques to investigate the role of these methods in the diagnosis and pathogenesis of epilepsy.

Animals↗
PubMed1995

Simultaneous determination of the rates of the TCA cycle, glucose utilization, alpha-ketoglutarate/glutamate exchange, and glutamine synthesis in human brain by NMR.

13C isotopic tracer data previously obtained by 13C nuclear magnetic resonance in the human brain in vivo were analyzed using a mathematical model to determine metabolic rates in a region of the human neocortex. The tricarboxylic acid (TCA) cycle rate was 0.73 +/- 0.19 mumol min-1 g-1 (mean +/- SD; n = 4). The standard deviation reflects primarily intersubject variation, since individual uncertainties were low. The rate of alpha-ketoglutarate/glutamate exchange was 57 +/- 26 mumol min-1 g-1 (n = 3), which is much greater than the TCA cycle rate; the high rate indicates that alpha-ketoglutarate and glutamate are in rapid exchange and can be treated as a single combined kinetic pool. The rate of synthesis of glutamine from glutamate was 0.47 mumol min-1 g-1 (n = 4), with 95% confidence limits of 0.139 and 3.094 mumol min-1 g-1; individual uncertainties were biased heavily toward high synthesis rates. From the TCA cycle rate the brain oxygen consumption was estimated to be 2.14 +/- 0.48 mumol min-1 g-1 (5.07 +/- 1.14 ml 100 g-1 min-1; n = 4), and the rate of brain glucose consumption was calculated to be 0.37 +/- 0.08 mumol min-1 g-1 (n = 4). The sensitivity of the model to the assumptions made was evaluated, and the calculated values were found to be unchanged as long as the assumptions remained near reported physiological values.

Brain↗
PubMed1995

In vivo measurement of phenylalanine in human brain by proton nuclear magnetic resonance spectroscopy.

Disorders of the CNS are the major causes of morbidity and mortality observed in untreated subjects with phenylketonuria (PKU). A method to measure cerebral concentrations of phenylalanine (Phe) in vivo would greatly enhance the ability to investigate both the pathophysiology and the efficacy of therapy of this aminoacidopathy. Twelve image-guided localized proton nuclear magnetic resonance spectroscopic studies were performed in seven subjects with PKU using pulse sequences optimized to detect the aromatic protons of Phe. Ten control studies were also performed using a 2.1-Tesla Bruker Biospec spectrometer. Plasma Phe was measured at the time of the spectroscopic examination in the PKU patients. A Phe signal was observed in all 12 studies performed on the group with PKU, and in five studies cerebral Phe concentrations were measured to be 480 to 780 mumol/g. Plasma Phe concentrations were 0.7 to 3.3 mM (10.8 to 54.8 mg/dL) in the subjects with PKU. Human cerebral Phe concentrations can be measured noninvasively using proton nuclear magnetic resonance spectroscopy. A simultaneous measure of Phe and several other cerebral metabolites is obtained with this innovative technology. Adaptations of this technique can be used to investigate PKU and other neurometabolic disorders with modifications of current clinical magnetic resonance imaging systems.

Adolescent↗
PubMed1994

Aspartame has no effect on seizures or epileptiform discharges in epileptic children.

The effects of aspartame (L-aspartyl-L-phenylalanine methyl ester; APM) on the neurological status of children with well-documented seizures were examined in a randomized, double-blind, placebo-controlled, crossover study. We report on 10 children (5 boys, 5 girls, ages 5-13 yr) who were tested for 2 weeks each on APM and placebo (single morning dose, 34 mg/kg). Seven children had generalized convulsions with 4 also having absence episodes. One child had absence seizures and 2 had complex partial seizures only. On each arm of the study, children were admitted to the hospital for a standard 21-lead electroencephalogram (EEG), continuous 24-hour cassette EEG, and determination of biochemical variables in plasma and urine. Subjects completed the Subjects Treatment Emergent Symptoms Scale (STESS) and parents the Conners Behavior Rating Scale. There were no significant differences between APM and placebo in the standard EEG or 24-hour EEG. No differences were noted for the STESS or the Conners ratings, and no differences were noted for any of the biochemical measures (except for expected increases in phenylalanine and tyrosine after APM). Our findings indicate that, in this group of vulnerable children, APM does not provoke seizures.

Adolescent↗
PubMed1994

Localized 13C NMR spectroscopy in the human brain of amino acid labeling from D-[1-13C]glucose.

Cerebral metabolism of D[1-13C]glucose was studied with localized 13C NMR spectroscopy during intravenous infusion of enriched [1-13C]glucose in four healthy subjects. The use of three-dimensional localization resulted in the complete elimination of triacylglycerol resonance that originated in scalp and subcutaneous fat. The sensitivity and resolution were sufficient to allow 4 min of time-resolved observation of label incorporation into the C3 and C4 resonances of glutamate and C4 of glutamine, as well as C3 of aspartate with lower time resolution. [4-13C]Glutamate labeled rapidly reaching close to maximum labeling at 60 min. The label flow into [3-13C]glutamate clearly lagged behind that of [4-13C]-glutamate and peaked at t = 110-140 min. Multiplets due to homonuclear 13C-13C coupling between the C3 and C4 peaks of the glutamate molecule were observed in vivo. Isotopomer analysis of spectra acquired between 120 and 180 min yielded a 13C isotopic fraction at C4 glutamate of 27 +/- 2% (n = 4), which was slightly less than one-half the enrichment of the C1 position of plasma glucose (63 +/- 1%), p < 0.05. By comparison with an external standard the total amount of [4-13C]glutamate was directly quantified to be 2.4 +/- 0.1 mumol/ml-brain. Together with the isotopomer data this gave a calculated brain glutamate concentration of 9.1 +/- 0.7 mumol/ml, which agrees with previous estimates of total brain glutamate concentrations. The agreement suggests that essentially all of the brain glutamate is derived from glucose in health human brain.

Adult↗