Category: Neurology

Enteroviruses and postviral fatigue syndrome

Abstract:

Postviral fatigue syndrome (PFS) occurs both in epidemics and sporadically. Many of the original epidemics were related to poliomyelitis outbreaks which either preceded or followed them.

The core clinical symptoms are always the same: severe fatigue made worse by exercise, myalgia, night sweats, atypical depression and excessive sleep. The other common symptoms include dysequilibrium disorders and irritable bowel syndrome.

We have detected enteroviral genome sequences in muscle biopsies from cases of PFS, using specific enteroviral oligonucleotide primers in the polymerase chain reaction (PCR). In addition, whole virus particles can be demonstrated in PCR-positive muscle, using solid-phase immuno-electron microscopy.

An increase in the number and size of muscle mitochondria was found in 70% of PFS cases, suggesting an abnormality in metabolic function. Evidence of hypothalamic dysfunction was present, particularly involving 5-hydroxytryptamine metabolism.

A putative model of PFS, based on persistent enteroviral infection in laboratory mice, revealed resolving inflammatory lesions in muscle with, however, a marked increase in the production of certain cytokines in the brain. This model may help to explain the pathogenesis of PFS.

 

Source: Behan PO, Behan WM, Gow JW, Cavanagh H, Gillespie S. Ciba Found Symp. 1993;173:146-54; discussion 154-9. http://www.ncbi.nlm.nih.gov/pubmed/8387908

 

Neuro-psychiatric aspects of chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is easily differentiated from various neurological organic disorders by conventional clinical examinations. The most important disease for distinguishment from CFS is fibromyalgia syndrome, in which the prominent and cardinal feature is a deprivation of stage 4 slow wave sleep.

Experimentally, the sleep disturbance in controls can induce general myalgia, muscle tender points, severe fatigue and stiffness on awakening. The EEG abnormality is slow alpha wave contaminants on slow wave background, which is identical to EEG of CFS. The results clearly imply that CFS is not a hysterical or psychogenic disease, and that fibromyalgia may be a central fundamental of CFS.

Fibromyalgia, however, has distinct features such as no antecedent inflammatory process and no endemics. Therefore, the syndrome has features distinct from, in addition to common features to CFS. It is also very difficult to distinguish CFS from depression. The above-mentioned features can be observed in depression. Now, study of brain blood flow or metabolism by PET or SPECT can be a possible tool for establishment of the CFS identity.

 

Source: Shimizu T. Neuro-psychiatric aspects of chronic fatigue syndrome. Nihon Rinsho. 1992 Nov;50(11):2630-4. [Article in Japanese] http://www.ncbi.nlm.nih.gov/pubmed/1287239

 

Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a severely disabling illness of uncertain aetiology. It is characterized by a chronic, sustained or fluctuating sense of debilitating fatigue without any other known underlying medical conditions. It is also associated with both somatic and neuropsychological symptoms. Both physical and laboratory findings are usually unremarkable.

Regional cerebral blood flow (rCBF) was assessed in 60 clinically defined CFS patients and 14 normal control (NC) subjects using 99Tcm-hexamethylpropyleneamine oxime (99Tcm-HMPAO) single photon emission computed tomography (SPECT). Compared with the NC group, the CFS group showed significantly lower cortical/cerebellar rCBF ratios, throughout multiple brain regions (P < 0.05). Forty-eight CFS subjects (80%) showed at least one or more rCBF ratios significantly less than normal values.

The major cerebral regions involved were frontal (38 cases, 63%), temporal (21 cases, 35%), parietal (32 cases, 53%) and occipital lobes (23 cases, 38%). The rCBF ratios of basal ganglia (24 cases, 40%) were also reduced. 99Tcm-HMPAO brain SPECT provided objective evidence for functional impairment of the brain in the majority of the CFS subjects. The findings may not be diagnostic of CFS but 99Tcm-HMPAO SPECT may play an important role in clarifying the pathoaetiology of CFS. Further studies are warranted.

 

Source: Ichise M, Salit IE, Abbey SE, Chung DG, Gray B, Kirsh JC, Freedman M. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nucl Med Commun. 1992 Oct;13(10):767-72. http://www.ncbi.nlm.nih.gov/pubmed/1491843

 

Attention and short-term memory in chronic fatigue syndrome patients: an event-related potential analysis

Abstract:

We recorded event-related brain potentials (ERPs) from 13 patients with chronic fatigue syndrome (CFS) and 13 matched normal controls. To assess attentional and memory deficits in CFS patients, we used a short-term memory task in which events occurred in different spatial locations and the patients made a rapid-response (RT) when a letter in a relevant location matched a letter in the prememorized set (Attention paradigm).

Time-on-task effects on the ERP and behavioral measures were assessed over the 2 1/4-hour duration of this task. Both groups also performed a visual Oddball paradigm, with an RT, before and after the Attention paradigm. The patients’ RTs were much more variable and, in nine of 13 cases, slower than the mean RT of the controls in both paradigms.

The patients’ memory performance was not significantly different from that of the controls and there were no group differences in the overall amplitude, latency, or scalp distribution of the N1, P2, N2, or P300 components of the ERP in either paradigm. The ERP and performance data from both paradigms suggest that perceptual, attentional, and short-term memory processes were unaffected in CFS patients and that the differences were limited to response-related processes.

 

Source: Scheffers MK, Johnson R Jr, Grafman J, Dale JK, Straus SE. Attention and short-term memory in chronic fatigue syndrome patients: an event-related potential analysis. Neurology. 1992 Sep;42(9):1667-75. http://www.ncbi.nlm.nih.gov/pubmed/1513453

 

Postviral fatigue syndrome

Comment on: Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. [BMJ. 1992]

 

EDITOR, -A M 0 Bakheit and colleagues recently reported’ a possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with the postviral fatigue syndrome, giving some evidence for hypothalamic functional abnormalities in these patients, which are different from others with depression. There is a growing body of evidence which claims that this clinical condition is organic and cannot be simply perceived as a somatisation disorder in patients with predisposition to psychiatric disease.”

We reviewed and quantitatively analysed with Ceretec and single photon emission tomography the brain perfusion of 14 patients fulfilling the Oxford criteria for diagnosis of myalgic encephalomyelitis. They had all had disease for more than six months (more than half the time) manifested with generalised malaise and myalgia, as well as significant physical and intellectual disability. None had any medical condition known to produce fatigue or had recently or in the past had psychiatric disease. When compared with a group of 24 nondepressed age and sex matched controls (normal volunteers) there was significant reduction of the perfusion to several areas of the brain cortex but particularly the brain stem (table).

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882397/pdf/bmj00077-0053b.pdf

 

Source: Costa DC, Brostoff J, Douli V, Ell PJ. Postviral fatigue syndrome. BMJ. 1992 Jun 13;304(6841):1567. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882397/

 

Postviral fatigue syndrome

Comment on: Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. [BMJ. 1992]

 

EDITOR,-A M 0 Bakheit and colleagues report enhanced release of prolactin after administration of buspirone in patients with the postviral fatigue syndrome compared with controls and patients with depression. Their report would have been improved if they had described more fully the differences between the two groups of patients. As they point out, depression can be difficult to distinguish clinically from the postviral fatigue syndrome.

The authors used the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised to define depressive illness, but to qualify for this diagnosis a patient need complain of only four symptoms such as fatigue, hypersomnia, retardation, and loss of concentration in addition to depressed mood. The criteria they used for the postviral fatigue syndrome included depression, fatigue, reversed sleep pattern, and constipation alternating with diarrhoea. It would be surprising if there was not a substantial overlap between the two groups and if one of the main factors affecting diagnosis was not whether the patient presented first to a psychiatrist or a neurologist.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882437/pdf/bmj00077-0052e.pdf

 

Source: Curtis D, Bullock T. Postviral fatigue syndrome. BMJ. 1992 Jun 13;304(6841):1566-7. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882437/

 

Postviral fatigue syndrome

Comment on: Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. [BMJ. 1992]

 

EDITOR,-A M 0 Bakheit and colleagues suggest that the buspirone challenge test may be useful in distinguishing between a “primary depressive illness” and the postviral fatigue syndrome. It is difficult to assess the truth of this from the data presented in their paper. To know the usefulness of this test the numbers of controls and patients scored above or below an appropriately chosen cut off point of serum prolactin concentration needs to be known. Unfortunately, the authors present the prolactin concentrations as mean values. If the aim of the test is to exclude major depression then a cut off which produces few false negative results should be chosen. Were the high mean values in the postviral fatigue group due to one or two extreme outliers? It is noteworthy that the standard deviations in the patients were much higher in the controls at baseline assessment. Why was this?

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882426/pdf/bmj00077-0052c.pdf

 

Source: Hatcher S. Postviral fatigue syndrome. BMJ. 1992 Jun 13;304(6841):1566; author reply 1567. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882426/

 

Postviral fatigue syndrome

Comment on: Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. [BMJ. 1992]

 

EDITOR,-A M 0 Bakheit and colleagues report an enhanced prolactin response to buspirone in patients with postviral fatigue syndrome and suggest this may be due to upregulation of hypothalamic 5-hydroxytryptamine receptors. They fail to mention the considerable evidence indicating that the drug is a moderately potent dopamine antagonist, a pharmacological action which suggests an alternative explanation for their data.

They administered a single 60 mg dose of buspirone-in excess of the daily maximum of 45 mg recommended by the British National Formulary-so antidopaminergic effects may well have been significant in their studies. The fact that the prolactin releasing effect of buspirone can be blocked by the drug metergoline does not prove 5-hydroxytryptamine receptor specificity. Indeed, metergoline is used commonly as an alternative dopamine agonist to bromocriptine in managing hyperprolactinaemia. Thus enhanced prolactin release after buspirone in postviral fatigue syndrome may reflect, at least in part, inhibition of increased hypothalamic dopaminergic tone on the  It would be interesting to study the same groups of patients using a specific D2 dopamine antagonist (such as domperidone) to see whether this is the case.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882431/pdf/bmj00077-0052d.pdf

 

Source: Bevan JS. Postviral fatigue syndrome. BMJ. 1992 Jun 13;304(6841):1566; author reply 1567. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1882431/

 

Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome

Abstract:

OBJECTIVE: To study the dynamic function of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome.

DESIGN: Prospective comparison of patients with postviral fatigue syndrome with two control groups.

SETTING: Department of neurology, University of Glasgow, Southern General Hospital; department of psychiatry, St James’s Hospital, Dublin.

SUBJECTS: 15 patients with postviral fatigue syndrome, 13 age and sex matched healthy subjects, and 13 patients with primary depression.

MAIN OUTCOME MEASURES: Serum prolactin concentrations before and one, two, and three hours after administration of buspirone.

RESULTS: Because of the effects of sex hormones on prolactin secretion data for men and women were analysed separately. There was no significant difference in baseline prolactin concentrations between patients with postviral fatigue syndrome and healthy subjects or those with primary depression. However, the percentage difference between peak and baseline values was significantly higher in patients with postviral fatigue syndrome than the control groups (one way analysis of variance: women, p = 0.003; men, p = 0.004).

CONCLUSIONS: The results suggest upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. The buspirone challenge test may therefore be useful in distinguishing these two conditions. Larger studies are required to explore the potential value of drugs acting on central 5-hydroxytryptamine receptors in the treatment of patients with the postviral fatigue syndrome.

Comment in:

Postviral fatigue syndrome. [BMJ. 1992]

Postviral fatigue syndrome. [BMJ. 1992]

Postviral fatigue syndrome. [BMJ. 1992]

Postviral fatigue syndrome. [BMJ. 1992]

 

Source: Bakheit AM, Behan PO, Dinan TG, Gray CE, O’Keane V. Possible upregulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome.BMJ. 1992 Apr 18;304(6833):1010-2. http://www.ncbi.nlm.nih.gov/pubmed/1586780

Note: You can read the full article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1881733/

 

A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection

Abstract:

OBJECTIVE: To conduct neurologic, immunologic, and virologic studies in patients with a chronic debilitating illness of acute onset.

DESIGN: Cohort study with comparison to matched, healthy control subjects.

PATIENTS: We studied 259 patients who sought care in one medical practice; 29% of the patients were regularly bedridden or shut-in.

MAIN OUTCOME MEASURES: Detailed medical history, physical examination, conventional hematologic and chemistry testing, magnetic resonance imaging (MRI) studies, lymphocyte phenotyping studies, and assays for active infection of patients’ lymphocytes with human herpesvirus type 6 (HHV-6).

MAIN RESULTS: Patients had a higher mean (+/- SD) CD4/CD8 T-cell ratio than matched healthy controls (3.16 +/- 1.5 compared with 2.3 +/- 1.0, respectively; P less than 0.003). Magnetic resonance scans of the brain showed punctate, subcortical areas of high signal intensity consistent with edema or demyelination in 78% of patients (95% CI, 72% to 86%) and in 21% of controls (CI, 11% to 36%) (P less than 10(-9)). Primary cell culture of lymphocytes showed active replication of HHV-6 in 79 of 113 patients (70%; CI, 61% to 78%) and in 8 of 40 controls (20%; CI, 9% to 36%) (P less than 10(-8], a finding confirmed by assays using monoclonal antibodies specific for HHV-6 proteins and by polymerase chain reaction assays specific for HHV-6 DNA.

CONCLUSIONS: Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system. The active replication of HHV-6 most likely represents reactivation of latent infection, perhaps due to immunologic dysfunction. Our study did not directly address whether HHV-6, a lymphotropic and gliotropic virus, plays a role in producing the symptoms or the immunologic and neurologic dysfunction seen in this illness. Whether the findings in our patients, who came from a relatively small geographic area, will be generalizable to other patients with a similar syndrome remains to be seen.

Comment in:

The chronic fatigue syndrome controversy. [Ann Intern Med. 1992]

The chronic fatigue syndrome controversy. [Ann Intern Med. 1992]

 

Source: Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, Ablashi DV, Salahuddin SZ, Saxinger C, Biddle R, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. 1992 Jan 15;116(2):103-13. http://www.ncbi.nlm.nih.gov/pubmed/1309285