Chronic Fatigue Syndrome: A Special Issue of applied Neuropsychology

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Komaroff is frustrated that the current state of CFS research has only yielded therapies of limited value. Nonetheless, since tricyclic drugs such as amitriptyline Elavil has helped in a number of cases he feels patients should consider their use. Komaroff states.

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Although Dr. Komaroff recommends tricyclics, drugs normally used for depression, it is not an endorsement by him of the assertion that CFS is a form of depression. A reason Komaroff sees for the distinction is the difference in time and dosage required for tricyclics to benefit CFS as opposed to depression.

Other CFS symptoms can be addressed with medications as well. For pain and headaches, Dr. Komaroff feels nonsteroidal anti-inflammatory drugs aspirin, Ibuprofen, naproxen, etc. In patients with anxiety or panic problems, anxiolytic drugs Buspar, Klonopin, Paxil, etc. Regarding hypotension, Dr. Although research seems to support viral activity in a portion of CFS patients, studies on antiviral medications have not proven the merit of this therapy. Likewise, no drugs have been able to relieve the immune system dysfunction often seen with CFS. Further, Dr. Komaroff thinks the side effects of hydrocortisone weigh against its use in counteracting diminished cortisone levels.

The IR scores for each test are then summed together for each participant and divided by the number of tasks the participant completed to give an overall IR for each participant. This summed IR was adjusted for any difference in education among the groups and used in subsequent analyses.

It should be noted that 92 of participants completed all of the tests in the battery. Of the remaining 9 participants, 7 completed all but one or two of the tests in the battery, and 1 participant completed 17 out of the 22 tests. Thus, the IR was based on the mean number of tests completed, rather than on the sum of the ratings assigned to each test. Multiple regression analysis was used to evaluate the relation between the cognitive measures and potential modifying factors of psychiatric symptomatology and medication. Results The mean scores for each neuropsychological test were grouped according to cognitive domains, based on factor analysis, as follows: attention, memory, language, spatial ability, and executive function.

These scores, adjusted for educational level, are shown in Table 1. A separate MANCOVA was performed for each of the five major cognitive domains using educational level as the covariate to determine whether the patient groups demonstrated selective impairments within specific cognitive areas. Education was used as a covariate because two of the four groups were significantly different in educational achievement, and individuals with lower levels of education tend to perform more poorly on cognitive tasks than those with higher levels of education.

To further examine the specific cognitive tests within each of these three domains that differed among the groups, a series of post hoc planned comparisons, using ANCOVA, were performed, with years of education as the covariate. The results of the ANCOVAs are also shown in Table 2, which also summarizes the neuropsychological tests on which the patient groups differed from the controls.

The post hoc planned comparisons within the memory domain demonstrated that on three out of four of the memory tests, all three patient groups were impaired in comparison to controls. Two of the three patient groups, the CFS group and the depression group, were significantly impaired in comparison to controls, on the nonverbal Pattern Recognition task.

Only the MS group was not impaired in comparison to controls on this task. When memory performance was compared among the patient groups, the results varied depending on the task in question and the groups that were being compared. The depression and MS groups did not differ from one another on the memory tasks. The post hoc planned comparisons within the language domain indicated that the depression patients were the most impaired overall.

Table 1. The CFS and MS patients were only impaired in comparison to controls on the category fluency test for animals. When language performance was compared among the patient groups, the depression patients were impaired in comparison to the CFS and MS patients on one task the Boston Naming Test. The depression patients were also impaired in comparison to the CFS group on the letter fluency task. However, on both of the category fluency tasks, the patient groups did not differ from one another.

The post hoc planned comparisons within the spatial domain indicated, although several of the tests approached significance contributing to the overall significance of the domain , only the cube copying task significantly differentiated the groups. On this task, the depressed patients were impaired in compari- 16 son to the controls.

However, none of the patient groups were significantly different from one another on this task. In addition, the depression patients had significantly higher scores than the CFS and MS patients on 7 out of 10 of the subscales of the SCL—90—R they did not differ on the somatization, obsessive—compulsive, and hostility subscales. The CFS patients had higher mean scores than the MS patients on 6 of the 10 subscales, including depression, anxiety, phobic anxiety, somatization, obsessive—compulsive, and hostility. The MS patients had the lowest level of psychiatric symptomatology in comparison to the other patient groups.

Because each of the patient groups was significantly more symptomatic in the area of depression, a separate MANCOVA was performed for each of the five cognitive domains, covarying the scores from the depression subscale of the SCL—90—R, in addition to education. In addition, the SCL—90—R total score was significantly higher in the depression patients in comparison to the other patient groups see Table 3.

The depression and anxiety subscales were of particular interest, because these symptoms had been the focus of a number of previous studies in CFS patients. Each of the patient groups had significantly more symptoms of depression than controls, based on the depression subscale of the SCL—90—R. Two of the patient groups, the CFS patients and the depression patients but not the MS patients , had more anxiety symptoms than controls.

Overall, the depression group was more symptomatic than the other patient groups; they were significantly different from controls on all 10 of the subscales of the SCL—90—R. Among the patient groups, the MS patients reported the lowest level of psychiatric symptoms; they were signifiTable 2. Post hoc planned comparisons between the patient groups and the controls within the memory domain revealed a very similar pattern of impairment to that found after covarying education alone. Once again, all three patient groups were significantly impaired in comparison to controls on three out of the four memory tasks MQ of the WMS, List Learning, and Associate Learning.

Two of the three patient groups depression and CFS were also impaired in comparison to controls on the Pattern Memory task.

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When the patient groups were compared with one another in memory performance with depression covaried, the differences among the groups were very similar to those following the covariance of education alone. The depression patient group did not differ significantly from the MS group on any of the memory tasks. The pattern of difference among the groups in the spatial domain was also relatively unchanged when depression was covaried.

There continued to be a significant difference among the patient groups on the cube copying test when performance was adjusted for level of depression in addition to education. In the language domain, the differences among the groups were, however, attenuated following a statistical adjustment for level of depression in addition to education. All three groups continued to differ in comparison to controls on the category fluency test for animals, and the depression patients were also impaired in compari- The same three cognitive domains that differed among the groups following the MANCOVA in which only education was covaried differed among the groups when depression scores were also covaried i.

In addition, the level of significance was similar. The data were covaried for years of education.

A significant difference compared to controls at p Table 3. The difference between the depression patients and the controls on the other fluency tasks verbal fluency and category fluency for vegetables were no longer significant when performance was adjusted by the level of depression. A series of regression analyses were also conducted to determine if the medications used by the participants had an impact on cognitive function, over and above that of the psychiatric symptoms of the participants. In no instance was medication use a significant predictor of cognitive test score beyond that contributed by psychiatric symptoms.

Discussion These findings indicate that cognitive deficits are found in CFS patients and MS patients, but they are mild in comparison to those seen in depression. When the three patient groups are compared, the depression patients have the greatest overall level of impairment. The MS patients appeared to be slightly more impaired than the CFS patients, particularly with respect to the summed IR, but this difference was not significant. In addition, the depression patients had evidence of a different pattern of impairment across the five cognitive domains than either the CFS or MS patients.

Although the CFS patients were only mildly impaired in comparison to the depression patients, there was evidence of impairment in comparison to controls. The CFS group was impaired on all four of the memory tasks compared to controls, including the nonverbal Pattern Recognition task. In addition, compared to the control participants, CFS patients were impaired on one of the language tasks category fluency for animals , suggesting difficulties with both language skills and planning and organizational abilities related to executive function. These findings also clearly demonstrate that MS produces cognitive impairments.

The summed IR, which evaluated performance across all cognitive domains, suggested that the MS patients were slightly more impaired than the CFS patients, although this difference did not reach statistical significance. Previous studies that have compared patients with CFS and MS have found differences in the level of impairment between the groups e. The depression patients, as previously mentioned, were impaired over a broad range of cognitive domains compared to the other two patient groups and had evidence of impairment in all five cognitive domains when compared to controls.

Most of these differences remained after adjustment for degree of depressive symptomatology. In addition, the summed IR demonstrated that the depression patients were significantly more impaired overall, compared to CFS patients and to the controls, but they were not significantly different from the MS group. In these latter studies, the CFS patients were reported to be impaired to approximately the same degree as the patients with depression. One possible reason for the discrepancy between these previous studies and our study is that the patient groups examined may have differed in terms of severity of illness.

In particular, the depression patients in this study were more depressed in comparison to those used in several previous reports.

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In contrast, in previous studies comparing CFS and depression patients, the patients with depression were reported to have had either a diagnosis of dysthmia or depression, and only a minority were on antidepressant medication DeLuca et al. In contrast, whereas we used similar research criteria to define the CFS and MS groups in our study, we did not select participants on the basis of the severity of physical disability or the presence of cognitive complaints. Moreover, numerous studies have demonstrated that the presence of cognitive impairments in MS can be unrelated to the physical disability measured by the Expanded Disability Status Scale e.

It therefore seems likely that our study included a more clinically heterogeneous group of participants with CFS and MS. There has been much discussion about the role that psychiatric symptomatology plays in the cognitive deficits observed in the patient groups. We assessed a broad range of psychiatric symptomatology in this study but found that the most consistent difference between the patient groups and the controls was the presence of depressive symptomatology.

We therefore adjusted neuropsychological test scores for levels of depression. Our results support the view that the presence of depression cannot solely account for the cognitive differences among the patient groups or between the patient groups and the controls. In summary, our findings support the view that the cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology in the patients.

They are, for example, consistent with reports of brain alterations in CFS patients e. Although the cognitive deficits of CFS patients appear somewhat similar to those of patients with MS, there was a trend in this study for the MS patients to be slightly more impaired. In addition, patients with depression were clearly more impaired than either of the other patient groups.

These findings suggest that the de20 gree of cognitive impairment observed in CFS, MS, and depression is highly dependent on the criteria used to select the patients. Among a heterogeneous sample of CFS and MS patients, cognitive impairments will be present, but relatively mild in nature. The cognitive impairments seen among patients with depression appear, however, to vary greatly, depending on the severity of illness in the patients. Moreover, even after adjusting for level of depression, differences in degree of cognitive impairment among the groups are relatively unchanged.

References Abas, M. Neuropsychological deficits and CT scan changes in elderly depressives. Psychosomatic Medicine, 20, — Acker, W. A computerized approach to psychological screening—The Bexley—Maudsley category sorting test. International Journal of Manual Machine Studies, 18, — Altay, H. The neuropsychological dimensions of postinfectious neuromyasthenia CFS. International Journal of Psychiatry, 20, — Bastien, S. Patterns of neuropsychological abnormalities and cognitive impairment in adults and children.

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Journal of Clinical and Experimental Neuropsychology, 16, — Benton, A. Multilingual aphasia examination. Iowa City: University of Iowa Press. Brassington, J. Neuropsychological aspects of multiple sclerosis. Neuropsychology Review, 8, 43— Byrne, D. Affect and vigilance performance in depressive illness. Journal of Psychiatric Research, 13, — Channon, S. Working memory in clinical depression: An experimental study. Psychological Medicine, 23, 87— Cope, H. Cognitive functioning and magnetic resonance imaging in chronic fatigue syndrome.

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Archives of Neurology, 48, — Analysis of neuropsychological functioning in patients with CFS. Journal of Neurology, Neurosurgery and Psychiatry, 56, — Hanninen, H. Behavioral effects of long-term exposure to a mixture of organic solvents. Scandinavian Journal of Work Environmental Health, 2, — Hertel, P. Depressive deficits in memory: Focusing attention improves subsequent recall. Journal of Experimental Psychology: General, , — Clinical Infectious Disease, 18, S84—S Kane, R. Neuropsychological and psychological functioning in chronic fatigue syndrome. Neuropsychiatry, Neuropsychology, and Behavioral Neurology, 10, 25— Kaplan, E.

The Boston Naming Test. Cognitive functioning with depression in patients with chronic fatigue and multiple sclerosis. Archives of Neurology, 51, — Kurtzke, J. Neurology, 33, — Lange, G. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. Journal of Neurologic Science, , 3—7. Lemelin, S. Clinical psychomotor retardation and attention in depression Journal of Psychiatric Research, 32, 81— Litvan, I. Slowed information processing in multiple sclerosis.

Archives of Neurology, 45, — Marcel, B. Cognitive deficits in patients with chronic fatigue syndrome. Biological Psychiatry, 40, — Marshall, P. Cognitive slowing and working memory difficulties in chronic fatigue syndrome Psychosomatic Medicine, 59, 58— McDonald, E. Cognitive impairment in patients with chronic fatigue: A preliminary study. Journal of Neurology and Neurosurgery, 56, — Mialet, J.

qigytegahoxi.ml Impaired attention in depressive states: A non-specific deficit? Psychosomatic Medicine, 26, — Millon, C. Psychology Health, 3, — Minden, S. Affective disorders in multiple sclerosis: Review and recommendations for clinical research. Archives of Neurology, 47, 98— Morris, J. Neurology, 39, — Paradiso, S. Cognitive impairment in the euthymic phase of chronic unipolar depression. Journal of Nervous and Mental Disease, , — Penman, M.


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Assessing the prevalence of cognitive impairment in multiple sclerosis: Implications for patient management. AXON, 13 2 , 45— Poser, C. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology, 13, — Rao, S. Neuropsychology of multiple sclerosis. Current Opinion in Neurology, 8, — Memory dysfunction in multiple sclerosis: Its relation to working memory, semantic encoding, and implicit learning.

Neuropsychology, 7, — Cognitive dysfunction in multiple sclerosis: I. Frequency, patterns and prediction. Neurology, 41, — Neuropsychological and psychiatric abnormalities in ME: A preliminary report. Journal of Consulting and Clinical Psychology, 20, — Russell, E. A multiple scoring method for the assessment of complex memory function. Journal of Consulting and Clinical Psychology, 43, — Sandman, C. Memory deficits associated with chronic fatigue immune dysfunction syndrome. Biological Psychiatry, 33, — Attention and short term memory in CFS patients: An event related potential analysis.

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Weingartner, H. Cognitive processes in depression. Archives of General Psychiatry, 38, 42— The aim of this pilot study was to determine whether a more sensitive quantitative assessment of the lateral ventricular system would support the previous qualitative findings. In this study, we compared the total lateral ventricular volume, as well as the right and left hemisphere subcomponents in 28 participants with CFS and 15 controls.

Ventricular volumes in the CFS group were larger than in control groups, a difference that approached statistical significance. Group differences in ventricular asymmetry were not observed.


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  • The results of this study provide further evidence of subtle pathophysiological changes in the brains of participants with CFS. Chronic fatigue syndrome CFS is a medically unexplained illness diagnosed by clinical case definition Fukuda et al. Its characteristic features include severe fatigue, infectious and rheumatological symptoms, affective disturbances, and cognitive dysfunction.

    There is now converging evidence suggesting structural cerebral changes exist in persons with CFS. Specifically, small nonspecific MRI white matter lesions, primarily in the frontal lobes, have been reported in several studies. The aim of this pilot study was to more rigorously examine whether lateral ventricular volume is increased in CFS patients compared to normal controls, utilizing a sensitive quantitative morphometric measurement technique.

    Lateral ventricular volume is one of the most common measurements in volumetric assessment of the brain. Enlargement of the ventricular system is nonspecific and generally regarded as an indirect measure of white matter loss, because much of the ventricular system is surrounded by white matter structures i. As established in a variety of patient populations, quantitative volumetric analysis has been proven to be an excellent tool to measure even subtle volumetric changes i.

    Therefore, based on the initial qualitative findings by Natelson et al. Method For this pilot study, MRI data were obtained from 78 participants. The data of 25 participants had to be elimiTable 1. Successful quantitative volumetric analysis was conducted on the remaining 43 participants. Participants Participants were 28 CFS patients and 15 healthy controls who did not exercise regularly.

    CFS patients and controls were similar in age, years of formal education, gender distribution, and handedness see Table 1. Participants with CFS were recruited either via self-referral based on media reports about the existence of the CFS Cooperative Research Center or by physician referral. Severity of CFS symptomatology was assessed by participants rating their level of discomfort on a Likert scale ranging from 0 no discomfort at all to 5 extreme discomfort. Premorbid and current presence of Axis I psychiatric disorders as defined by the Diagnostic and Statistical Manual of Mental Disorders 3rd ed.

    Of these, 8 participants suffered from major depressive disorder only; 1 individual had major depressive disorder plus generalized anxiety disorder; 1 had major depressive disorder plus multiple anxiety disorders generalized anxiety disorder, panic disorder, agoraphobia, social phobia ; and 1 was diagnosed with multiple anxiety disorders generalized anxiety disorder, panic disorder.

    Controls were recruited by advertising in the local community and were paid for their participation. All healthy participants also underwent medical, cognitive, and psychiatric assessments, including the Diagnostic Interview Schedule, and were excluded if any of the following were present: medical problems, premorbid or current psychiatric history, and medication use other than birth control pills. All participants gave informed consent prior to participating in the study.

    Fifty serial slices were obtained at a thickness of 3 mm without interslice gap. The scanner was calibrated before each MRI acquisition. All identifying patient information was removed from scans prior to the volumetric analysis. Brain volume was extracted by a presegmentation algorithm with optimal thresholding, morphological operations, and the Chamfer distance. The algorithm models MRI images as collections of regions with slowly varying intensity plus a white Gaussian noise.


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    • Compartments are modeled by a Markov random field with the 3-D second-order neighborhood system, where different potentials are used for in-plane and axial directions to account for anisotropical images. This incorporates spatial interactions among adjacent label voxels, which reduce degradation due to poor signal-to-noise ratio and feature contrast. A cubic B-spline function models slowly varying mean intensity of each compartment through least squares fitting. The algorithm is implemented iteratively and adaptively. Each iteration consists of a estimating mean intensities of each compartment through least squares fitting of a spline expression to the entire image and b estimation of compartment by maximizing the a posteriori probability density using the iterative conditional mode algorithm.

      Adaptation is achieved by gradually increasing the number of control points of the spline function. This optimizes estimates for both compartments and mean intensity for fixed number of control points. Combining spline representation and adaptation makes the segmentation more accurate and robust. Brain structures were identified and manually outlined with the use of a trackball. The areas corresponding to pixel values reflecting white matter, gray matter, and CSF within the outline were calculated automatically.

      Total brain, consisting of the sum of the pixel values of gray matter, white matter, and CSF, was measured automatically in every slice from the foramen magnum to the vertex. The right and left lateral ventricles, consisting of the body, the anterior horns, the occipital horns, and the temporal horns, were outlined and measured in each slice in which they were present. Pixel values for parts of the right and left lateral ventricles were summed separately for each slice and then over all slices in which they were present to determine the pixel value for the complete right and left lateral ventricles.

      Complete right and left lateral ventricles were then summed to represent the pixel value for the lateral ventricular system. Both raters were blind to group membership and other participant characteristics. To establish interrater reliability, a sample of 10 consecutive scans was analyzed by both raters. The intraclass correlation coefficient was computed for the right as well as left hemisphere lateral ventricular volume and was.

      Remaining scans were then analyzed by a single rater. Results Statistical Analysis In this pilot study, the main hypothesis was unidirectional and predicted increased lateral ventricular CSF in the CFS group based on previously published data. Instead of using a less powerful nonparametric test statistic for this type of data, we chose to normalize the distribution by log transforming the data set to be able to conduct a more powerful parametric test.

      Thus, by using logn transformed data, the distribution was normalized ratio of skewness to its standard error Group differences in total ventricular volume are illustrated in Figure 1. Figure 2 provides an illustration of ventricular differences between participants with CFS and controls.

      Compared to control groups, the CFS group showed a larger mean volume of the lateral ventricular system p Figure 1. In the equivalent quantile—quantile plot shown, logn of total ventricular volume of CFS versus controls are ranked from smallest to largest and then plotted. Note that the data lie to the right of the line of identity, corroborating the statistic that participants with CFS have greater total ventricular volume than controls.

      Examples of ventricular size in two contiguous slices in a participant with CFS left and a control participant right shown according to radiologic convention. The near statistically significant relation between CFS and control groups was maintained even after controlling for total brain volume by calculating ventricle-to-brain ratios see Table 3.

      We also considered whether groups would differ in the frequency of lateral ventricular asymmetry or whether the ventricular subcomponents within each group may have different mean volumes. Table 3. Figure 3, both the CFS and control groups tended to have larger left than right ventricles, which is consistent with previous reports in normal adults e.

      In addition, no significant mean differences were found between the size of right and left lateral ventricles within groups. Discussion The results of this quantitative volumetric study support earlier qualitative findings of ventricular enlargement in individuals with CFS Natelson et al. On average, there was a marginally significant trend toward enlargement of the lateral ventricles in the CFS group relative to age, gender, handedness, and education-matched controls. In addition, the statistical significance of the finding was not diminished by controlling for individual differences in total brain volume ventricle-to-brain ratio.

      This is the first study to quantitatively document ventricular enlargement in CFS patients. Ventricular enlargement is a nonspecific finding. Its pathophysiological significance is unclear and has been linked to a variety of causes, including white matter loss in patients with vascular problems Gorelick et al.

      Given the preliminary nature of this study, future volumetric studies in patients with CFS need to replicate and extend the scope of this initial 28 Figure 3. Frequency of ventricular asymmetry in controls and participants with CFS. The correlation between the mean volume of the lateral ventricular system, as well as left and right ventricles separately, with current Axis I disorder, duration of illness, and degree of severity of CFS symptoms was analyzed in participants with CFS only.

      None of the relations examined was significant. Given the increasing number of studies showing cerebral pathology in CFS using structural Buchwald et al. Future volumetric studies should focus on understanding the possibly subtle involvement of specific gray and white matter structures in CFS. This type of probe is very sensitive in detecting even subtle changes in ventricular volume, and we were thus able to find the modest ventricular enlargement in participants with CFS versus controls. Thus, this study was underpowered, failing to appropriately guard against false negative claims.

      To ensure appropriate power to detect a medium effect size at the. Therefore, a follow-up study with a larger sample of participants with CFS and controls is necessary to confirm the important findings of this quantitative volumetric study. Because we were also interested in the functional significance of these findings, we examined the relation between increased ventricular volume in participants with CFS and factors such as presence of coexisting psychiatric diagnoses, duration of illness, and overall degree of perceived severity of CFS symptoms. None of these factors explained a significant portion of the variance in the volumetric measurements.

      It is possible, however, that an increase in ventricular CSF may be related to specific CFS symptoms or to objective cognitive function, which were not evaluated in this work. Again, these possibilities should be examined in a larger follow-up study. In conclusion, although the reasons for changes in ventricular size in CFS are unclear, findings of this carefully conducted study may have marked significance in the understanding of the pathophysiology of CFS.

      If these findings are replicated, this would suggest that at least a subset of CFS patients may have underlying brain pathology producing subtle cerebral loss. Significantly increased lateral ventricular volume in the group of participants with CFS would further add to the growing body of evidence suggesting the existence of an underlying neurological disease process e.

      Blatter, D. Quantitative volumetric analysis of brain MR: Normative database spanning 5 decades of life. American Journal of Neuroradiology, 16, — Buchwald, D. L, Henry, B.