Cognitive changes 5 years after coronary artery bypass grafting: is there evidence of late decline?

OBJECTIVE: To determine the long-term (preoperative to 5 years postoperative) and late (1-5 years postoperative) changes in cognitive test performance in patients after coronary artery bypass grafting. SETTING: The departments of surgery and neurology at The Johns Hopkins University School of Medicine, Baltimore, Md. PATIENTS: A group of 102 patients who completed preoperative and follow-up cognitive testing up to 5 years after coronary artery bypass grafting. MAIN OUTCOME MEASURES: A battery of neuropsychological tests, assessing 8 cognitive domains (attention, language, verbal and visual memory, visuoconstruction, executive function, and psychomotor and motor speed), was administered preoperatively and at 1 month, 1 year, and 5 years postoperatively. RESULTS: Significant changes in neuropsychological test scores from baseline to 5 years were observed in only 3 of the 8 domains: there were declines in visuoconstruction and psychomotor speed and an improvement in executive function. When the period from baseline to 5 years was divided into 2 intervals, we found that cognitive test scores generally improved from baseline to 1 year. By contrast, between 1 and 5 years, there was significant decline in all cognitive domains except for attention and executive function. Some potential explanatory covariates (demographic, medical history, and surgery variables) were associated with changes from baseline to 5 years in some cognitive domains, but few covariates were statistically significant in more than 1 cognitive domain. CONCLUSIONS: The change in cognitive test performance between baseline and 5 years is likely related to several factors, including low baseline performance and practice effects. The significant decline in performance between 1 and 5 years, however, raises the possibility that a late cognitive decline may be occurring in this population. Additional studies, with the use of a nonsurgical control group, are needed to determine if the observed cognitive decline is related to bypass surgery itself, normal aging in a population with cardiovascular risk factors, or some combination of these and other factors.

Determinants of cognitive change after coronary artery bypass surgery: a multifactorial problem.

BACKGROUND: Several studies have investigated predictors of cognitive decline after coronary artery bypass grafting (CABG), but there is little consensus as to which specific factors are predictive of poor cognitive outcomes. METHODS: We evaluated 127 patients undergoing CABG with standardized neuropsychological tests preoperatively, at 1 month and at 1 year. The outcome measure was a continuous variable reflecting change in z-scores for eight cognitive domains over time for individual patients. Univariate analyses were performed to evaluate the association between the demographic, operative, and postoperative factors and the cognitive outcome variables. Factors that were significant were included in a multiple linear regression analysis. RESULTS: Among the medical history variables, diabetes was associated with change in executive functions and psychomotor speed. Some of the operative variables were associated with short-term changes, but none with the 1-year outcomes. For example, the surgeon's rating of degree of difficulty in selecting a cross-clamp site was associated with change in attention. Higher mean pump rate during the procedure was associated with improved performance on tests of language. The cognitive domains associated with medical variables were different from those associated with surgical variables, and the associations observed at 1-year were different from those seen at 1-month. CONCLUSIONS: Change in cognition after CABG is associated with both medical and surgical variables. The specifics of these associations depend on the choice of time points after surgery. This suggests that there are multiple etiologies for these changes, with nonspecific effects of anesthesia and prolonged surgery interacting with the more specific effects of the surgical procedure itself.

Relation between CT scan findings and human sense of smell.

Symptom questionnaires were obtained from 106 patients immediately before nasal and sinus computed tomography scans at the Johns Hopkins Outpatient Center. Their scans were analyzed by two otolaryngologists and three neuroradiologists by using a semiobjective rating system of the size and opacity of 36 anatomic areas. Patients estimated their own left and right sense of smell as excellent, diminished, or absent. Results of the data are as follows: (1) There is no correlation between smell ability and size of the nasal and sinus structures. This indicates that there is no gross effect of the bulging of sinuses into the nasal airway; (2) As a rule, opacity of only left-sided anatomic structures was correlated with both left and right sense of smell (p < 0.01). This suggests that our subjects were using their left smell receptors preferentially, to the exclusion of and in place of the right smell receptors; and (3) Total, not partial, opacity of the left olfactory cleft, frontal recess, or ethmoidal infundibulum was correlated with decreased sense of smell. This suggests that these anterior structures in the region of the olfactory cleft do affect airflow, but complete obstruction of these spaces is needed. Possible explanations for the effect of opacified sinuses on the sense of smell include (1) The presence of fluid or thickened mucosa in the sinuses may interfere with perceived olfactory ability by changing nasal airflow patterns or odorant access to receptors; (2) There may be olfactory receptors inside the sinuses; and (3) There may be a relation between the trigeminal receptors in the sinuses and the olfactory system.

Cognitive outcome after coronary artery bypass: a one-year prospective study.

BACKGROUND: Cognitive deficits have been reported in patients after coronary artery bypass grafting, but the incidence of these deficits varies widely. We studied prospectively the incidence of cognitive change and whether the changes persisted over time. METHODS: Cognitive testing was done preoperatively and 1 month and 1 year postoperatively in 127 patients undergoing coronary artery bypass grafting. Tests were grouped into eight cognitive domains. A change of 0.5 standard deviation or more at 1 month and 1 year from patient's preoperative Z score was the outcome measure. RESULTS: We identified four main outcomes for each cognitive domain: no decline; decline and improvement; persistent decline; and late decline. Only 12% of patients showed no decline across all domains tested; 82% to 90% of patients had no decline in visual memory, psychomotor speed, motor speed, and executive function; 21% and 26% had decline and improvement in verbal memory and language; approximately 10% had persistent decline in the domains of verbal memory, visual memory, attention, and visuoconstruction; and 24% had late decline (between 1 month and 1 year) in visuoconstruction. CONCLUSIONS: This study establishes that the incidence of cognitive decline varies according to the cognitive domain studied and that some patients have persistent and late cognitive changes in specific domains after coronary artery bypass grafting.

Predictors of stroke risk in coronary artery bypass patients.

BACKGROUND: Stroke occurs after coronary artery bypass grafting with an incidence ranging between 0.8% and 5.2%. To identify factors associated with stroke, we prospectively examined a study cohort and tested findings in an independent validation sample. METHODS: The study cohort comprised 456 patients undergoing coronary artery bypass grafting only, and the validation sample comprised 1,298 patients. Stroke was detected postoperatively by the study team and confirmed by neurologic consultation and computed tomographic scanning. RESULTS: Five factors taken together were correlated with stroke: previous stroke, presence of carotid bruit, history of hypertension, increasing age, and history of diabetes mellitus. The only significant intraoperative factor was cardiopulmonary bypass time. Probabilities were calculated, and patients were placed into low, medium, and high stroke-risk groups. In the validation sample, this model was able to rank the majority of patients with stroke into the high-risk group. CONCLUSIONS: These five factors taken together can identify the risk of stroke in patients having coronary artery bypass grafting. Recognition of the high-risk group will aid studies on the mechanism and prevention of stroke by modification of surgical procedures or pharmacologic intervention.

Crohn's disease: concordance for site and clinical type in affected family members--potential hereditary influences.

BACKGROUND & AIMS: The association of genetic influences between bowel location and clinical type of Crohn's disease may provide more information on the genetic heterogeneity of inflammatory bowel disease. The aim of this study was to analyze familial occurrences of Crohn's disease for concordance for site and type. METHODS: Of 554 consecutive patients, 95 (17%) had a family history of Crohn's disease. Sixty families were analyzed for concordance for site and clinical type and by a series of conditional logistic regression models to test the significance of concordance within families. RESULTS: Eighty-six percent of families were concordant in at least 2 members for the site of Crohn's disease, and 82% were concordant for clinical type. Pairing family members together, concordance greater than expected in an unrelated population was observed. Using a conditional logistic regression model, a statistically significant role for concordance in predicting site and type of Crohn's disease in other affected family members was found. CONCLUSIONS: Greater-than-expected concordance for site and clinical type of Crohn's disease within individual families is compatible with a concept of multiple, distinct forms of Crohn's disease, which, although possibly influenced by environment, seem more likely to be separate inheritable forms or phenotypes.

The treatment of attention-deficit hyperactivity disorder in Tourette's syndrome: a double-blind placebo-controlled study with clonidine and desipramine.

OBJECTIVES: Because psychostimulants can exacerbate preexisting motor/phonic tics in individuals with Tourette's syndrome (TS), a clinical trial was performed to examine the ability of clonidine and desipramine to modify attention-deficit hyperactivity disorder (ADHD) behaviors in children with TS + ADHD. METHODS: A double-blind, placebo-controlled protocol was used in which each subject served as his or her own control and received, in a randomly assigned fashion, 6-week medication cycles with clonidine (0.05 mg four times daily), desipramine (25 mg four times daily), and placebo. RESULTS: Thirty-seven children with TS+ADHD between the ages 7 to 13 years and of normal intellect were recruited, and 34 (31 males, 3 females) completed the entire protocol. Outcome measures for ADHD included Parent and Teacher Child Behavior Checklists (CBCL), continuous performance tests, and neuropsychologic tests of executive function. Several markers for ADHD were shown to improve significantly (P < .05) after treatment with desipramine (parent linear analogue rating, parent CBCL "hyperactivity" subscale, and teacher CBCL subscales "nervous/overactive," "anxious," and "unpopular"). Improvement with desipramine was always superior to that noted with clonidine. Clinical improvement did not correlate with drug blood levels. On measures of tic severity, neither drug made tics worse. Desipramine showed a statistically significant improvement on a global linear analogue scale, but not on the Hopkins Motor/Vocal Tic Severity Scale, the Tourette Syndrome Severity Scale, or the Yale Global Tic Severity Scale. Clonidine did not significantly alter tic severity on any measure. CONCLUSION: The results of this study suggest that desipramine may be a useful alternative for the treatment of symptoms of ADHD in children with TS.

Inter- and intraexaminer reliability of nerve conduction measurements in patients with diabetic neuropathy.

We determined the inter- and intraexaminer reliability of nerve conduction measurements in six patients with diabetic peripheral neuropathy. Each patient was examined by six electromyographers on two separate occasions at least 1 week apart. We obtained attributes of nerve conduction at each examination and analyzed the data by analysis of variance. Intraexaminer reliability was high for 11 of 12 measurements, and interexaminer reliability was high for eight of twelve. Three of the four measurements that varied between examiners were either sensory or motor amplitudes, attributes frequently used to measure disease progression or to assess the result of therapeutic intervention. Our results suggest that longitudinal nerve conduction measurements used to assess worsening or improvement over time should optimally be performed by a single examiner to minimize the degree of variability associated with different examiners.

Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation.

Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, recent studies have suggested an autoimmune mechanism of pathogenesis. Previous trials of immunosuppressive treatment have yielded inconclusive results. Our study was designed to determine whether more powerful and prolonged immunosuppression, produced by total lymphoid irradiation (TLI), would alter the course of ALS. In a double-blind, randomized, placebo-controlled study, 30 patients with classic ALS were treated with TLI, and 31 were given sham radiation. Quantitative measurements of muscle strength, functional motor activity, and humoral and cellular immune status were followed for 2 years, or until death or respirator dependence. Motor function in the TLI-treated and control groups showed no significant differences throughout the study. Overall survival was not significantly different in the TLI-treated and control groups. TLI effectively suppressed cellular and humoral immune function throughout the 2-year study period. Analysis of the relationship between immunosuppression and motor functions showed no consistent effect of treatment. We conclude that powerful and prolonged immunosuppression produced by TLI did not benefit patients with ALS. This fails to support the concept of an autoimmune mechanism of pathogenesis of ALS.

Determinants of children's health care use: an investigation of psychosocial factors.

Factors related to the amount of health care used by 5- to 11-year-old children in a health maintenance organization (HMO) were investigated using a comprehensive multivariate model that assessed the contribution of child health need, mental health, and social functioning; maternal mental health, social support and health care utilization; and family functioning and life events. Mothers reported on the 450 participating children. Health care visits for a two-year retrospective period were obtained from the computerized encounter system. Child health need and maternal patterns of health care use were powerful predictors of the overall amount of health care used, and these factors discriminated high users from low users of care. Family conflict was associated with a higher volume of care, while children's depressive symptoms and non-white race were related to lower use. Maternal social support, mental health, and life events were not predictive of use in either full multivariate model. Enabling factors were held relatively constant by participation of all families in a prepaid HMO. The multiple regression model explained 33% of the variance in use, slightly more than in previous studies of children's health care use. When included in a comprehensive analysis, child and family psychosocial characteristics help to explain children's health care use beyond what is possible using simple health and illness variables. The implications of these findings in the development of further research and to the practice of routine pediatric care are discussed.

Efficacy of the ketogenic diet for intractable seizure disorders: review of 58 cases.

The ketogenic diet was developed in the 1920s as a treatment for intractable childhood seizures when few antiepileptic drugs (AEDs) were available. There are still children whose seizures are refractory even to modern therapy, but use of the ketogenic diet appears to be waning. At Johns Hopkins, we continue to believe that the diet is very effective and well accepted by patients and families. To reevaluate our opinion of the efficacy and acceptability of this form of therapy in patients cared for in the 1980s with the newer AEDs, we analyzed the records of 58 consecutive patients who had been started on the diet. Before using the diet, 80% of the patients had multiple seizure types and 88% were treated with multiple AEDs; these children were among our most intractable patients. Despite this, seizure control improved in 67% of patients with the ketogenic diet, and actuarial analysis indicated that 75% of these improved patients continued the diet for at least 18 months. Sixty-four percent had AEDs reduced, 36% became more alert, and 23% had improved behavior. The improvement in these patients with intractable seizures and the length of time that families maintained the regimen indicate that the ketogenic diet continues to have a very useful therapeutic role in selected patients and their families.

Nerve conduction studies in amyotrophic lateral sclerosis.

Nerve conduction studies (NCS) are an integral part of the evaluation of amyotrophic lateral sclerosis (ALS) patients and are useful in distinguishing ALS from disorders that mimic it. The question often arises whether in the presence of severe atrophy and reduction of the compound muscle action potential amplitude, abnormal conduction velocity (CV), distal latency (DL), or F-wave latency (F) exceeds what can be expected from ALS alone. To determine the limits of abnormality in classic ALS, we prospectively evaluated NCS data from 61 patients who met a strict clinical definition of ALS. We related CV, DL, and F to distal evoked amplitude (AMP) in peroneal (n = 63 observations), median (n = 50), and ulnar (n = 52) nerves. In nerves with reduced AMP, CV rarely fell to less than 80% of the lower limit of normal, and DL and F rarely exceeded 1.25 times the upper limit of normal. Utilizing the entire data set and regression analyses, 95% confidence limits for expected values for CV, F, and DL as a function of AMP were calculated. These limits thus derived suggest criteria for NCS abnormalities in ALS and may be useful in differentiating ALS from other illnesses.

Inter- and intra-examiner reliability of nerve conduction measurements in normal subjects.

Nerve conduction studies are widely employed in evaluating patients with peripheral nerve disease and are often used serially to measure disease progression or to assess a therapeutic intervention. We determined the inter- and intra-examiner reliability of electrophysiological data by performing serial nerve conduction studies on 7 normal subjects. A high degree of intra-examiner reliability was present, but significant inter-examiner differences were found. Our results suggest that if nerve conduction studies are to be used longitudinally, they should optimally be performed by a single examiner to minimize the degree of variability associated with different examiners.

Role of therapeutic plasmapheresis in the acute Guillain-Barré syndrome.

Plasmapheresis modifies the course of the acute Guillain-Barré syndrome (GBS) in terms of time-related parameters such as time on a respirator or time to achieve a specific area of improvement at specific times after onset of the illness such as at 1 month and at 6 months. Certain factors are associated with poorer outcomes in acute GBS. These include amplitude of compound muscle axon potentials on stimulating distally, time of onset of disease of 7 days or less, need for ventilatory support, and older age. Plasmapheresis, the only variable that the physician can influence, has a beneficial effect over and above all these factors.

Plasmapheresis and Guillain-Barré syndrome: analysis of prognostic factors and the effect of plasmapheresis.

The time course of recovery in the Guillain-Barré syndrome is known to vary widely, but factors associated with differences have not been previously defined. In this study we used multivariate analysis to identify such factors and to determine whether the presence or absence of specific factors would influence treatment decisions, particularly the use of plasmapheresis. Data from 245 patients randomized into conventional and plasmapheresis arms were used to assess the time to walk independently (Grade 2), the time to improve one grade, and the percentage improved at 4 weeks. Individually, many factors were associated with outcome. In the multivariate analysis, four factors correlate with poorer outcomes: mean amplitude of compound muscle action potential on stimulating distally of 20% of normal or less, older age, time from onset of disease of 7 days or less, and need for ventilatory support. The most powerful predictor of outcome was the abnormal mean amplitude of compound muscle action potential on stimulating distally. Plasmapheresis, the only variable the physician can influence, has a beneficial effect over and above any or all of these factors. The plasmapheresis patients on continuous flow machines had better outcomes than those on intermittent flow machines. From these data, tables of expected outcome probabilities have been developed.

Motor conduction studies in Guillain-Barré syndrome: description and prognostic value.

The North American study of plasmapheresis in Guillain-Barré syndrome (GBS) included early, standardized electrodiagnostic testing in 210 of the 245 patients. To determine the types of abnormalities and the relation to outcome, we analyzed the prospectively collected motor conduction data obtained during the first 30 days of illness. For each parameter of motor conduction data, means were computed based on institutional normal data. Mean distal motor and F wave latencies commonly were abnormal in these early studies. In univariate analysis, mean compound muscle action potential (CMAP) amplitude from distal and proximal stimulation and mean motor conduction velocity were found to be related to the four predetermined outcome measures. In multivariate analysis of the motor conduction parameters, mean distal CMAP amplitude was the single best predictor of prognosis; other measures did not add to its predictive value. In further multivariate analysis of all factors relating to outcome, mean distal CMAP amplitude was determined to be the most powerful predictor of outcome, followed by plasmapheresis. These two factors were always statistically significant over and above all other variables. Our results indicate that prognostic information can be obtained from motor conduction studies even when performed early in the course of GBS; a mean distal CMAP amplitude of 0 to 20% of the lower limit of normal is associated with a markedly increased probability of a poor outcome. Nevertheless, even in patients with a low mean distal CMAP amplitude, the predicted outcome is improved with plasmapheresis therapy.

Effect of sodium benzoate and sodium phenylacetate on brain serotonin turnover in the ornithine transcarbamylase-deficient sparse-fur mouse.

Herein we examine the effects of sodium benzoate and sodium phenylacetate on feeding and central serotonin turnover in a child with citrullinemia and in an animal model of congenital hyperammonemia, the ornithine transcarbamylase-deficient sparse-fur (spf/y) mouse. In the child, when the benzoate/phenylacetate dosage was increased from 200 to 375 mg/kg/day each, feeding decreased. There was an accumulation of benzoate and phenylacetate in blood and cerebrospinal fluid as well as an increased concentration of 5-hydroxyindoleacetic acid, a neurochemical marker for serotonin turnover, in cerebrospinal fluid. In the mouse, sodium benzoate had a biphasic effect on both plasma ammonium levels and brain serotonin turnover. Two percent oral benzoate was associated with an increase in ammonium level, while a 3% dose led to a decrease in ammonium. There was a similar effect on serotonin turnover noted in both the hyperammonemic spf/y and control CD-1/y mice. Sodium phenylacetate did not have a consistent effect on serotonin turnover. The mechanism by which benzoate increases brain serotonin turnover appears to involve competition with tryptophan for albumin binding sites. This results in increased free tryptophan in serum and brain. We speculate that some of the clinical symptoms of benzoate intoxication may be a consequence of altered serotonin turnover in the brain. We suggest that drug levels be monitored during therapy.

Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid.

Traditional clinical monitoring of children with epilepsy does not appear to be sufficiently sensitive to cognitive functioning and behavioral problems. Although subtle, these changes may alter a child's ability to perform well in school and in society. Physicians must prevent seizures without producing intolerable side effects, and ways of more appropriately assessing these side effects must be developed. In this double-blind, counter-balanced, crossover study of 21 children, the effects of phenobarbital and valproic acid on cognitive functioning and behavior were measured. There was no difference in seizure control between the drugs, and each medication was maintained in the therapeutic range for 6 months (mean phenobarbital level, 21.2 micrograms/mL; mean valproic acid level, 94.1 micrograms/mL). Children were treated with each drug for 6 months. Differences between the drugs were seen on measurements of cognitive function and behavior. On four tests of neuropsychologic function, children performed significantly less well while receiving phenobarbital (P less than .01). There was no evidence that the patients were sedated or less able to perform continuous performance tasks while receiving phenobarbital. Parental assessment of behavior indicated significantly worse behavior with the phenobarbital regimen for three items (P less than .01) and children were measurably more "hyperactive" (P less than .05). Routine clinical assessment of the patients did not reveal differences between the drugs with respect to routine laboratory measurements or side effects as assessed by history or physical examination. Although children may appear to tolerate a medication without clinically apparent problems, subtle but significant changes in intellectual function and behavior may be occurring. Additional, more sensitive, methods of monitoring patients while receiving these drugs is necessary.

The relationship between the level of lead absorption in children and the age, type, and condition of housing.

A group of 184 preschool-aged children with pretreatment blood lead concentrations (PbB) greater than or equal to 50 micrograms/dl, who received inpatient chelation therapy, were followed prospectively as outpatients for 12 months after discharge. Of these, 160 were followed for 24-30 months. Serial PbB data were analyzed according to the type of housing to which each child was discharged. Following therapy, PbB stabilized by 3 months. Thereafter, highly significant differences (P less than 0.001) existed between those living in or visiting old houses in which lead-in-paint hazards had been abated according to local ordinances (m PbB = 38.5 micrograms/dl) and those discharged to "lead-free" public housing (m PbB = 28.8 micrograms/dl) or to recently, totally gutted and renovated old housing (m PbB = 28.7 micrograms/dl). During the period of study (1978-1982), no downward trend in PbB within housing groups was found during the first 12 months of follow-up. Of the 152 children discharged to old housing, 75 had 127 recurrences of PbB greater than or equal to 50 micrograms/dl. This emphasizes the need for close and prolonged follow-up in all cases. These data indicate that substantially improved methods of detection, classification, and abatement of lead hazards must replace traditional methods if lead exposure for young children in old housing is to be reduced to an acceptable level.

Haloperidol, fluphenazine and clonidine in Tourette syndrome: controversies in treatment.

The value of haloperidol, fluphenazine and clonidine as therapeutic agents for Tourette's syndrome was retrospectively reviewed. Haloperidol improved tic symptoms in 50/60 patients, but side effects often nullified these benefits. Fluphenazine was an effective drug for tic suppression in 24/31 patients. Direct comparison of these drugs in 23 patients confirmed the efficacy of fluphenazine and showed it to produce fewer adverse effects than haloperidol. Clonidine was helpful in 47% and caused few side effects. These results support the use of clonidine for the treatment of tics and suggest that fluphenazine can be considered an alternative to other neuroleptic drugs.