Cognition and behavior in children with benign epilepsy with centrotemporal spikes (BECTS).

Characteristics of cognitive deficits in benign childhood epilepsy with centrotemporal spikes (BECTS) remain unclear. The authors screened 200 BECTS children presenting for a clinical trial, finding relative weaknesses in fine motor control, visual learning, and attention in the presence of overall normal intellect, with simple partial seizures associated with more difficulty. Parental concerns for psychosomatic and learning problems were noted. Monitoring select cognitive and behavioral features in BECTS appears appropriate.

Chlorpyrifos exposure and biological monitoring among manufacturing workers.

AIM: To use biological monitoring data to evaluate the soundness of job based exposure classifications. METHODS: The authors studied 52 chlorpyrifos manufacturing workers and 60 referent workers to compare chlorpyrifos exposure estimations from job titles and work areas to urinary excretion of 3,5,6 trichloro-2-pyridinol (TCP), a metabolite of chlorpyrifos. Work history records and industrial hygiene monitoring data were used to establish cumulative interim exposure. Chlorpyrifos exposure during the study year was assessed biologically by urinary excretion of TCP. RESULTS: Exposure as measured by three urinary TCP samples was significantly higher among the chlorpyrifos workers (188 microg/l) than it was for the referent subjects (7 microg/l). Urinary TCP also correlated well with specific exposure categories of negligible (0.73-1.98 mg/m3 days), low (1.99-4.91 mg/m3 days), and moderate (4.92-15.36 mg/m3 days). The weighted Kappa coefficient was 0.80 (95% CI 0.72 to 0.87) for the mean TCP over the study period. CONCLUSIONS: The estimates of chlorpyrifos exposure based on job classifications and industrial hygiene measurements were significantly related to urinary TCP excretion, indicating that the ambient estimates are useful for providing exposure estimates among chlorpyrifos manufacturing workers.

Mechanism of activation of glucocerebrosidase by co-beta-glucosidase (glucosidase activator protein).

The nature of the stimulatory action of the protein 'coglucosidase' on glucocerebrosidase was investigated with the use of highly purified cofactor from bovine spleen, radioactive glucosyl ceramide and methylumbelliferyl-beta-glucoside. A complex between glucosidase and either substrate could not be detected under equilibrium and non-equilibrium binding conditions. Complex formation between stimulating protein and the enzyme could be shown by the binding of the enzyme to an affinity column containing coglucosidase. This binding could be blocked by adding phosphatidylserine to the enzyme. The lipid also stimulated the enzyme. Additional evidence for binding of the enzyme to the two kinds of stimulators was the finding that they protected the enzyme against inactivation by N-ethylmaleimide and chloromercuriphenylsulfonate. A role for lipids in the stimulatory action of coglucosidase was shown by extracting lipids from the enzyme; this resulted in a loss of basal enzyme activity and of sensitivity to activation by the protein. Adding back to the lipids or phosphatidylserine increased the sensitivity of the delipidated enzyme to coglucosidase. Using the crude, unextracted enzyme we could show that low concentrations of phosphatidylserine augmented the effectiveness of coglucosidase but high concentrations of the lipid blocked the effect of the protein. It is proposed that lipids, particularly acidic ones, act on solubilized glucocerebrosidase to produce an enzyme conformation which allows binding and stimulation by coglucosidase. At higher lipid concentrations, the acidic lipids bind, in competition with coglucosidase, to the latter's binding site on the enzyme.

The cohydrolases in human spleen that stimulate glucosyl ceramide beta-glucosidase.

A family of beta-glucosidase-stimulating proteins (called cohydrolase SPH-I here) was isolated from bovine, Gaucher human and control human spleens. All preparations exhibited a similar pattern of four major electrophoretic bands in polyacrylamide when stained with the cationic dye, Stains-All. The bovine bands migrated more rapidly, while the two types of human cohydrolase migrated very similarly. The two human preparations differed in several respects: the concentration was much higher in Gaucher spleen; the Gaucher factors eluted a little earlier from gel permeation and decyl agarose columns; much more of the cohydrolase was bound by a concanavalin A column; the control bands stained less intensely in gels than the Gaucher bands. Antibodies raised in rabbits to bovine cohydrolase reacted with all three preparations. All four bands from Gaucher cohydrolase showed similar ability to stimulate glucosidase and to bind the antibodies. It is evident that the cohydrolases from control and Gaucher spleens are similar in many respects, yet differ in some secondary fashion, possibly in carbohydrate content. It is suggested that Gaucher cohydrolase is formed from normal cohydrolase by the nonenzymatic action of cellular glucose over a period of many years, due to slowed catabolism of the cofactor.

Binding of tumor necrosis factor alpha (TNF-alpha) to high-affinity receptors on polymorphonuclear cells.

The effects of tumor necrosis factor alpha (TNF-alpha) on human polymorphonuclear (PMN) cells were investigated. We found that 125I-TNF-alpha bound specifically to high-affinity receptors on PMN cells. At 4 degrees C, the binding occurred rapidly and reached steady state after 20 min. The Scatchard plot showed a single class of high-affinity receptors with approximately 2200 receptors/cell and a dissociation constant of 2 x 10(-10) M. There was a linear relationship between TNF-alpha binding and TNF-alpha-induced PMN cell adherence. The concentration of TNF-alpha required to achieve approximately 50% of maximum binding was also approximately the concentration required to reach 50% cell adherence. Auranofin was shown to inhibit TNF-alpha-induced PMN cell adherence at a dose of 5-10 micrograms/ml. This inhibitory effect was not due to the inhibition of TNF-alpha binding to PMN cells by the drug. These observations may have clinical implications.

Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing's syndrome.

Patients with chronic hypercortisolemia due to Cushing's syndrome (CS) exhibit cognitive dysfunction. Because glucocorticoid excess is associated with hippocampal damage in animals, and the hippocampus participates in learning and memory, we explored the relationships between hippocampal formation (HF) volume, memory dysfunction, and cortisol levels in 12 patients with CS. After magnetic resonance imaging, HF volume was determined using digital sum of track ball traces of dentate gyrus, hippocampus proper and subiculum, correcting for total intracranial volume. For 27% of the patients, HF volume fell outside the 95% confidence intervals for normal subject volume given in the literature. In addition, there were significant and specific correlations between HF volume and scores for verbal paired associate learning, verbal recall, and verbal recall corrected for full-scale IQ (r = 0.57 to 0.70, p < 0.05). HF volume was negatively correlated with plasma cortisol levels (r = -0.73, p < 0.05). These studies suggest an association between reduced HF volume, memory dysfunction, and elevated cortisol in patients with CS.

Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease.

BACKGROUND: Decreased hippocampal volume is observed in patients with Cushing's syndrome and other conditions associated with elevated cortisol levels, stress, or both. Reversibility of hippocampal neuronal atrophy resulting from stress occurs in animals. Our study investigated the potential for reversibility of human hippocampal atrophy. METHODS: The study included 22 patients with Cushing's disease. Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment. RESULTS: Following treatment, hippocampal formation volume (HFV) increased by up to 10%. The mean percent change (3.2 +/- 2.5) was significantly greater (p < .04) than that of the comparison structure, caudate head volume (1.5 +/- 3.4). Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol (r = -.61, p < .01). This relationship strengthened after adjustments for age, duration of disease, and months elapsed since surgery (r = -.70, p < .001). There was no significant correlation between caudate head volume change and magnitude of cortisol decrease. CONCLUSIONS: Changes in human HFV associated with sustained hypercortisolemia are reversible, at least in part, once cortisol levels decrease. While many brain regions are likely affected by hypercortisolemia, the human hippocampus exhibits increased sensitivity to cortisol, affecting both volume loss and recovery.

The effect of diazepam sedation on cerebral glucose metabolism in Alzheimer's disease as measured using positron emission tomography.

The effect of sedation induced by intravenous diazepam on cerebral glucose metabolic activity was examined with [18F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) in five patients with probable Alzheimer's disease. Each subject was studied on 2 separate days: on one occasion at rest with eyes patched and ears open, and on the second when sedated with intravenous diazepam titrated to maintain stage II sleep by clinical and EEG criteria. Similar patterns of glucose uptake were observed in both the presence and the absence of sedation, but overall glucose utilization was depressed an average of 20% and was closely correlated with the amount of diazepam administered prior to the injection of FDG. The predominant temporoparietal hypometabolism and relative sparing of frontal metabolism observed in this disease are therefore not explained by differences in anxiety or activity level in this patient group. Utilization of diazepam sedation for PET study appears to be safe and may permit the study of patients otherwise unable to cooperate with FDG-PET procedures.

The erythromycin breath test predicts the clearance of midazolam.

Midazolam, a commonly used sedative and amnestic medication, has recently been shown to be largely metabolized in the liver by a cytochrome P450, termed CYP3A4. There is at least a tenfold intersubject variability in the liver content and catalytic activity of CYP3A4, which may in part account for the known interpatient differences in the kinetics of midazolam. To test this hypothesis, we determined the intravenous midazolam kinetics of 20 medically stable, hospitalized patients, whose hepatic CYP3A4 activities were determined with use of the [14C-N-methyl]erythromycin breath test. During the kinetic study, we also performed psychometric testing designed to quantitate the level of sedation and amnesia. We found a significant positive correlation between the erythromycin breath test results and weight adjusted clearance (in milliliters per minute per kilogram) of both total midazolam (r = 0.52; p = 0.03) and unbound midazolam (r = 0.61; p < 0.01). The relatively low dose of midazolam used (0.0145 mg/kg) produced significant but transient sedation and memory impairment in some of the patients. We conclude that interpatient differences in liver CYP3A4 activity in part account for the variations in midazolam kinetics. Our observations account for reported drug interactions involving midazolam and suggest that patients with low CYP3A4 activity may be most susceptible to prolonged amnestic effects occasionally produced by this short-acting benzodiazepine.

Mild cognitive impairments predict dementia in nondemented elderly patients with memory loss.

BACKGROUND: Some elderly individuals exhibit significant memory deficits but do not have dementia because their general intellect is preserved and they have no impairments in everyday activities. These symptoms are often a precursor to Alzheimer disease (AD), but sometimes dementia does not occur, even after many years of observation. There is currently no reliable way to distinguish between these 2 possible outcomes in an individual patient. We hypothesized that clear impairments in at least 1 cognitive domain in addition to memory would help identify those who will progress to AD. OBJECTIVE: To determine whether nondemented patients with impairments in memory and other domains are more likely than those with memory impairment alone to develop AD. DESIGN AND METHODS: In a retrospective study, we evaluated 48 nondemented, nondepressed patients with clinical and psychometric evidence of memory impairment who were followed up for 2 or more years. Age-adjusted normative criteria were used to identify whether additional impairments were present in language, attention, motor visuospatial function, and verbal fluency at this initial evaluation. The presence or absence of dementia after 2 years and at the most recent neurological evaluation was compared in subjects with normal scores in all 4 of these cognitive areas apart from memory (M-) and those with impairment in 1 or more of these areas (M+). Outcomes were adjusted for age, intelligence at initial evaluation, and years of education. RESULTS: Of the 48 nondemented patients with memory loss, 17 met M- criteria, leaving 31 in the M+ group. Deficits in block design were the most frequent abnormality other than memory loss. At the 2-year follow-up, 1 M- subject (6%) had progressed to AD, whereas 15 (48%) of the M+ group had progressed to AD (P =.003). At the most recent follow-up (mean +/- SD, 4.0 +/- 2.0 years), 4 (24%) of the M- patients progressed to AD compared with 24 (77%) of the M+ patients (P<.001). CONCLUSIONS: Among nondemented elderly patients, memory loss alone rarely progresses to dementia in the subsequent 2 years. However, the risk of dementia is significantly increased among patients with clear cognitive impairments beyond memory loss. Further study is needed to determine whether patients with impairments limited to memory loss have a distinctive clinical course or pathophysiology.

Longitudinal neuropsychological and genetic linkage analysis of persons at risk for Huntington's disease.

OBJECTIVE: To determine (1) whether the neuropsychological profiles of healthy individuals at risk (AR) for Huntington's disease who were positive (AR/+) or negative (AR/-) for the Huntington's disease genetic marker differed from those of symptomatic patients with Huntington's disease and normal control individuals and (2) whether the neuropsychological performance of the two AR groups differed from each other on three assessments during a 4-year span. DESIGN: Case-control, double-blind study, with AR status determined by genetic linkage analysis (G8 probe), in addition to examination of trinucleotide repeats for most AR subjects. SETTING: The Neuropsychology Program in the Department of Psychiatry and the Department of Neurology at the University of Michigan Medical Center, Ann Arbor, a tertiary care center. PARTICIPANTS: Eight subjects matched as closely as possible for age, gender, and education in each of the following groups: AR/+, AR/-, normal control, and Huntington's disease. MEASURES: A battery of neuropsychological tasks, including measures of intelligence, memory, problem solving, and motor ability. RESULTS: Although both AR groups demonstrated variability on select intellectual subtests relative to normal subjects, they did not differ from each other on the three assessments during a 4-year span. Patients with Huntington's disease performed more poorly than the other groups across a range of neuropsychological measures. CONCLUSIONS: These results do not support previous evaluations concluding that AR/+ individuals demonstrate cognitive impairments as compared with AR/- individuals. Findings in earlier studies without genetic linkage analysis of lower performance of AR individuals, including children, as compared with normal controls may relate to extraneous environmental and familial issues that interfere with intellectual development.

Normal caudate glucose metabolism in persons at risk for Huntington's disease.

Glucose metabolism was examined by positron emission tomographic scanning with F-2-fluoro-2-deoxy-D-glucose in 29 persons at risk for Huntington's disease (HD), 28 age-matched controls, nine patients with stage I, and eight patients with stage II symptomatic HD. Absolute caudate metabolic rates and normalized indexes of caudate metabolism for at-risk persons were normal compared with controls. No at-risk person had caudate indexes outside two SDs of the controls' mean. Caudate metabolism in the earliest HD cases was significantly reduced compared with controls and at-risk persons, but within the 99% confidence levels of both groups. Stage II patients had caudate measures that were significantly depressed compared with those of stage I HD patients. Measurement of caudate glucose hypometabolism is unlikely to be sufficiently sensitive to serve as a presymptomatic marker of heterozygote status, although it will provide a sensitive marker for progressive caudate dysfunction in HD.

Neuropsychological changes in olivopontocerebellar atrophy.

We used standardized neuropsychological measures of intellectual, cognitive, psychomotor, and emotional functioning to compare 39 patients with olivopontocerebellar atrophy and 25 normal controls of similar age. The patients reflected greater depression, anxiety, and subjective emotional discomfort than did the control subjects. While 4 of the patients had below-normal IQ scores (Wechsler Adult Intelligence Scale [WAIS-R] Full-Scale IQ [FSIQ] less than 80), their clinical histories suggested lifelong functioning at such levels. As a group, the patients were not abnormal in general intellectual functioning and related cognitive abilities (WAIS-R FSIQ, mean [+/- SD], 93.46 +/- 13.19; Wechsler Memory Scale mental quotient, 108.95 +/- 17.43). These scores were lower than those of the normal controls (WAIS-R FSIQ, 113.72 +/- 12.68; mental quotient, 127.80 +/- 12.40); however, the controls were a highly educated group with intelligence levels that were higher than those of the average population. Moreover, when education and motor dysfunction were statistically covaried, no significant differences between the patients and the normal controls were apparent on the cognitive and intellectual tasks. Further analysis of specific memory performance in a subgroup of patients and controls matched for age, sex, and education yielded findings that were comparable with the overall group analysis. We conclude that motor dysfunction and depressed mood could leave patients with olivopontocerebellar atrophy appearing to be impaired in memory, even demented, when they are not.

Perceptual analysis of speech disorders in progressive supranuclear palsy.

We used oral motor examinations and quantitative perceptual speech analysis to study deviant speech dimensions in 44 patients with progressive supranuclear palsy (PSP). All patients had dysarthria with variable degrees of spasticity, hypokinesia, and ataxia; 28 patients had all three of these components, and 16 patients had only two components. Twenty-two patients (50%) had predominantly spastic components, 15 (34%) had predominantly hypokinetic components, six (14%) had predominantly ataxic components, and in one (2%) the spastic, hypokinetic, and ataxic components were equal. Stuttering occurred in nine patients (20%) and palilalia in five (11%). The finding of a mixed dysarthria with a combination of spastic, hypokinetic, and ataxic components might assist in diagnosis and is consistent with the widespread neuropathologic changes found in PSP.

Personality of patients with pseudoseizures.

We studied personality features of 19 patients with pseudoseizures (PS) only. Scores on a personality inventory (MMPI) were compared with those of adults with generalized seizures and correlated to cognitive measures (Halstead-Reitan). Mean MMPI scores did not differ significantly, and no profile distinguished PS and epilepsy patients. MMPI abnormalities of PS patients were diverse and seldom characteristic of hysteria. Eight PS patients had cognitive impairment, two without MMPI evidence of personality disorder. These findings suggest that the etiology of pseudoseizures is multifactorial, involving different psychopathologies and sometimes cerebral dysfunction.

Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP despite effects on sleep.

Postmortem studies of patients with progressive supranuclear palsy (PSP) have demonstrated loss of cholinergic neurons in the striatum, nucleus basalis of Meynert, and the pedunculopontine nucleus. These findings suggest that cholinergic drugs might be an effective treatment for this disease. We studied the efficacy of RS-86, a direct cholinergic agonist, upon motor abilities, eye movements, and psychometric performance in 10 patients with PSP during a 9-week placebo-controlled, double-blinded, crossover trial. Glycopyrrolate, a peripheral anticholinergic drug, was given throughout the trial to minimize cholinergic side effects. We used changes in rapid eye movement (REM) sleep to assess the degree of cholinergic activation achieved by treatment. Despite the enhancement of cholinergic activity in the CNS as indicated by increases in REM sleep latency and REM sleep time, RS-86 did not improve motor signs, eye movements, or cognition. Pharmacologic replacement of the cholinergic deficits in PSP does not result in significant clinical benefit.

Improvement in neuropsychological performance in patients with refractory seizures after intensive diagnostic and therapeutic intervention.

Tests of cognitive, perceptual, motor, and memory function were administered to patients with refractory seizures before and after intensive treatment on a specialized epilepsy unit. Improved test performance related to withdrawal of barbiturates and an overall reduction in the number of antiepileptic drugs but not with reduction of seizure frequency.

The utility and generality of Mini-Mental State Examination scores in Alzheimer's disease.

The present study sought to evaluate the validity and generality of the Mini-Mental State Examination (MMSE) and its subsection scores. We gave the MMSE and other neuropsychological tests to 51 patients with probable Alzheimer's disease. On the basis of correlational and factor analyses, overall performance on the MMSE proved to have good concurrent validity with other comprehensive neuropsychological assessment instruments. However, the MMSE subsections should not be viewed as highly specific measures of cognition or memory.

Patients with pseudoseizures: intellectual and cognitive performance.

We compared cognitive and intellectual performance of patients with pseudoseizures (pseudoseizure-only group), pseudoseizures and epilepsy (mixed seizure group), and generalized epileptic seizures (generalized seizure group). The pseudoseizure-only group performed significantly better on all measures except those of simple motor function. There were no significant differences between those with mixed and generalized seizures. Therefore, cognitive and intellectual performances of patients with pseudoseizures are influenced by the presence or absence of concomitant epilepsy, and suggest that it is necessary to distinguish patients with and without epilepsy in studies of pseudoseizures.

Pilot study of fluzinamide (N-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) in refractory partial seizures.

We conducted a pilot study of fluzinamide in 15 adults with refractory partial seizures. After a baseline period, fluzinamide was added to the existing regimen of phenytoin and carbamazepine and increased to maximum tolerated dose. Common side effects included dizziness, diplopia, ataxia, headache, nausea, and rash, resulting in patient withdrawal in six cases. Seizures became less frequent in four of the nine patients who completed the 8-week trial.