Leo R. Korn

Relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome

OBJECTIVES To examine the relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome, and determine whether the relation is independent of psychiatric factors. METHODS The subjects were 53 patients with chronic fatigue syndrome and 32 healthy controls who did not exercise regularly. Subjects were administered a structured psychiatric interview and completed questionnaires focusing on depression and functional disability. They also completed a battery of standardised neuropsychological tasks focusing on the cognitive domains that patients with chronic fatigue syndrome experience as particularly difficult: memory (verbal and visual), and attention/concentration. A test score was defined as failing when it was ⩾2 SD below the mean of the healthy controls after controlling for demographic factors. RESULTS Those patients with chronic fatigue syndrome with higher numbers of failing neuropsychological test scores reported significantly more days of general inactivity in the past month than those with fewer failing scores. This result remained significant even after partialling out the contribution of the presence of a comorbid axis I psychiatric episode and the overall level of depressive symptomology. Patients with failing verbal memory scores were particularly functionally disabled compared with those with passing scores. CONCLUSION A relation was found between cognitive impairment and functional disability which could not be explained entirely on the basis of psychiatric factors.

Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis

The purpose of this study was to evaluate the immune dysfunction hypothesis of chronic fatigue syndrome (CFS) by comparing immunologic data from patients with CFS with data from patients with other fatiguing illnesses--major depression and multiple sclerosis (MS)--and with data from healthy sedentary controls. The subjects were 65 healthy sedentary controls, 71 CFS patients (41 with no axis-I diagnosis), 23 patients with mild MS, and 21 patients with major depression. Blood was sampled and assayed for the following: (1) immunologic serologic variables--circulating immune complexes (i.e., Raji cell and C1q binding), immunoglobulins A, E, G, and M, and IgG subclasses; (2) cell surface activation markers--the proportion of CD4+ cells expressing CD45RA+ and CD45RO+ and the proportion of CD8+ cells expressing CD38+, CD11b-, HLA-DR+ and CD28+; and (3) natural killer (NK) total cell count as well as the proportion of lymphocytes expressing NK cell surface markers (i.e., CD3-/CD16+ and CD56+. Of the 18 variables studied, differences between CFS patients and controls were found only for IgG1 and IgG3. When CFS patients were stratified by the presence or absence of concurrent axis-I disease, it was the group with axis-I disorder that had the lowest IgG1 values-contrary to expectation. When data from patients with MS and major depression were also evaluated, the subclass deficiency was no longer significant. The one group to show evidence for immune activation (i.e., an elevated proportion of CD4+ cells expressing the CD45RA+ activation marker) was the group with mild MS. These data support neither immune dysfunction nor immune activation in CFS or in major depression, for the variables studied. The reductions in IgG subclasses may be an epiphenomenon of patient or control subject composition. In contrast, MS, even in the mild and early stages, as in the patients studied here, is associated with immune activation.

Single-Blind, Placebo Phase-in Trial of Two Escalating Doses of Selegiline in the Chronic Fatigue Syndrome

Aim: To perform a clinical trial of selegiline in 25 patients with chronic fatigue syndrome (CFS) where patients were told they would receive placebo or active agent at different times during the 6-week trial. We chose selegiline, a specific monoamine oxidase (MAO) B receptor inhibitor, because a prior trial of low-dose phenelzine, a nonspecific MAO inhibitor, showed a small but significant therapeutic effect. Methods: Questionnaires comprised of 19 tests of mood, fatigue, functional status and symptom severity were collected at the start and end of the trial as well as 2 weeks after its start. The trial was done in three 2-week blocks: in the first, 2 placebo pills were given per day; in the next, one 5-mg tablet of agent and one placebo were given per day, and in the last, a 5-mg tablet of agent was given twice a day. The plan was to compare the changes in the 19 tests during the placebo phase to those found in the active treatment phase in 19 patients completing the trial. Findings: Significant improvement in 3 variables – tension/anxiety, vigor and sexual relations – was found. A significant pattern of improvement compared to worsening was found for the 19 self-report vehicles during active treatment as compared with placebo treatment. Evidence for an antidepressant effect of the drug was not found. Conclusions: Selegiline has a small but significant therapeutic effect in CFS which appears independent of an antidepressant effect.

An Approach for Quantitatively Balancing Methylmercury Risk and Omega-3 Benefit in Fish Consumption Advisories

Background: Nearly all fish consumption advisories for methylmercury (MeHg) are based only on risk. There is a need to also address benefits, especially those from polyunsaturated fatty acids (PUFAs), in neurodevelopmental function and cardiovascular health. However, because MeHg and PUFA generally act on these same end points, disentangling risk and benefit is challenging. Objectives: We propose an approach for balancing risk and benefit that is based on the use of statistically dissociated measures of risk and benefit. Discussion: Because of mutual coexposure of MeHg and PUFAs in population-based studies and their opposite effect on many of the same end points, MeHg risk and PUFA benefit are tightly linked statistically, which results in mutual (negative) confounding. Thus, neither MeHg risk nor PUFA benefit can be accurately quantified without taking the other into account. A statistical approach that generates unconfounded risk and benefit coefficients for each end point can permit their subsequent recombination to describe the overall risk–benefit profile of each species of fish or fish diet. However, it appears that some end points may be adversely affected by MeHg without experiencing counterbalancing benefit from PUFAs. Such end points may drive consumption advisories and may preclude balancing of risk and benefit on the basis of other end points. Conclusions: Our thinking about fish consumption advisories now recognizes the need to balance risk and benefit. However, although statistical analysis of the appropriate data can eliminate mutual confounding, care is required to address the most sensitive end points that may be sensitive to risk and not benefit.

Cardiovascular stress responses and their relation to symptoms in Gulf War veterans with fatiguing illness.

Objective The objective of this study was to examine whether inappropriate cardiovascular responses to stressors may underlie symptoms in Gulf War veterans with chronic fatigue. Methods Psychophysiological stress testing was performed on 51 Gulf War veterans with chronic fatigue (using the 1994 case definition of the Centers for Disease Control and Prevention) and 42 healthy veterans. Hemodynamic responses to cold pressor, speech, and arithmetic stressors were evaluated using impedance cardiography. Results Veterans with chronic fatigue had diminished blood pressure responses during cognitive (speech and arithmetic) stress tests due to unusually small increases in total peripheral resistance. The cold pressor test, however, evoked similar blood pressure responses in the chronic fatigue and control groups. Low reactivity to cognitive stressors was associated with greater fatigue ratings among ill veterans, whereas an opposite relation was observed among healthy veterans. Self-reported neurocognitive decline was associated with low reactivity to the arithmetic task. Conclusions These results suggest a physiological basis for some Gulf War veterans’ reports of severe chronic fatigue. A greater deficit with responses processed through cerebral centers, as compared with a sensory stimulus (cold pressor), suggests a defect in cortical control of cardiovascular function. More research is needed to determine the specific mechanisms through which the dissociation between behavioral and cardiovascular activities identified in this study may be contributing to symptoms in Gulf War veterans.

Prevalence of and potential risk factors for symptoms associated with insecticide use among animal groomers.

Pet groomers make numerous insecticide applications during the flea season, but few studies have examined their health complaints. The Pesticide Control Program of the New Jersey Department of Environmental Protection conducted a health and safety survey of this population. All licensed pet applicators in New Jersey were contacted, as were New Jersey veterinarians listed as pet-animal practitioners by the American Veterinary Medical Association. Approximately 36% of the respondents indicated that during the 1994 flea season, they had experience at least one of the 17 symptoms associated with insecticide application. Central nervous system symptoms (headache, dizziness, or confusion) and skin symptoms (skin rash or numbness/tingling) were reported most frequently. Logistic regression results suggest that applications per season, years as an applicator, certain hygiene variables, certain classes of products, and status of applicator (veterinary vs veterinary) are potentially important risk factors.

Robust Estimation for Chemical Concentration Data Subject to Detection Limits

Chemical concentration data are almost always left censored and often-contain a few large outliers. This complicates the estimation of location and scale. To analyze such data sets, we propose a family of M-estimators for censored data, which include the maximum likelihood estimates of location and scale for censored t-distributions. Unlike the uncensored case, we note that the location M-estimators are not consistent under the censored normal model, and so a modification to them is introduced in order to obtain consistency at the censored normal model. Since a large class of M-estimators for censored data can be computed via an EM-algorithm, their computations are not considerably more complicated than the computations of the maximum likelihood estimates under the censored normal distribution. The asymptotic relative efficiency, influence function and simulations using contaminated censored normal distributions demonstrate the robustness and efficiency properties of the estimators. From these results we conclude that almost nothing is sacrificed but much is gained by using M-estimators, especially when a fair proportion of the data lies below the detection. Finally, our methods are applied to an example involving nitrate concentrations in well water. This example demonstrates the advantages of using M-estimators with redescending influence functions.