Article

Brainstem perfusion is impaired in chronic fatigue syndrome

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Abstract

We looked for brain perfusion abnormalities in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). An initial pilot study revealed widespread reduction of regional brain perfusion in 24 ME/CFS patients, compared with 24 normal volunteers. Hypoperfusion of the brainstem (0.72 +/- 0.05 vs. 0.80 +/- 0.04, p < 0.0001) was marked and constant. We then tested whether perfusion to the brainstem in ME/CFS patients differs from that in normals, patients with major depression, and others with epilepsy. Data from a total of 146 subjects were included in the present study: 40 normal volunteers, 67 patients with ME/CFS (24 in the pilot study, 16 with no psychiatric disorders, 13 with ME/CFS and depression, 14 with ME/CFS and other psychiatric disorders), 10 epileptics, 20 young depressed patients and 9 elderly depressed individuals. Brain perfusion ratios were calculated using 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) and single-photon emission tomography (SPET) with a dedicated three-detector gamma camera computer/system (GE Neurocam). Brain-stem hypoperfusion was confirmed in all ME/CFS patients. Furthermore, the 16 ME/CFS patients with no psychiatric disorders and the initial 24 patients in the pilot study showed significantly lower brainstem perfusion (0.71 +/- 0.03) than did depressed patients (0.77 +/- 0.03; ANOVA, p < 0.0001). Patients with ME/CFS have a generalized reduction of brain perfusion, with a particular pattern of hypoperfusion of the brainstem.

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... Most of the SPECT studies investigating potential CBF abnormalities in CFS have reported areas of significant cerebral hypoperfusion, at either a global [20,192] or regional level [193,194] compared with unaffected controls. However, a minority of researchers reported no significant CBF impairments in comparison with unaffected controls or MDD participants [195,196]. ...
... The reasons for such discrepant findings are unclear, but fewer participants and differences in selection methods may be relevant. The much larger studies conducted by Ichise, Schwartz, Costa and Goldstein, and their colleagues [20,[192][193][194] appear worthy of particular consideration as they examined multiple brain regions and perhaps even more importantly, apart from Ichise and others [192], examined differences in patterns of abnormal perfusion between participants with CFS and MDD, which is currently a contentious area. ...
... The largest study examining potential 99m Tc-HMPAO SPECT differences between CFS and MDD patients was carried out by Costa and others [193]. It included 40 healthy participants, 67 CFS participants (both with and without psychiatric co-morbidity) and 29 early-and lateonset MDD participants [193]. ...
Article
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There is copious evidence of abnormalities in resting-state functional network connectivity states, grey and white matter pathology and impaired cerebral perfusion in patients afforded a diagnosis of multiple sclerosis, major depression or chronic fatigue syndrome (CFS) (myalgic encephalomyelitis). Systemic inflammation may well be a major element explaining such findings. Inter-patient and inter-illness variations in neuroimaging findings may arise at least in part from regional genetic, epigenetic and environmental variations in the functions of microglia and astrocytes. Regional differences in neuronal resistance to oxidative and inflammatory insults and in the performance of antioxidant defences in the central nervous system may also play a role. Importantly, replicated experimental findings suggest that the use of high-resolution SPECT imaging may have the capacity to differentiate patients afforded a diagnosis of CFS from those with a diagnosis of depression. Further research involving this form of neuroimaging appears warranted in an attempt to overcome the problem of aetiologically heterogeneous cohorts which probably explain conflicting findings produced by investigative teams active in this field. However, the ionising radiation and relative lack of sensitivity involved probably preclude its use as a routine diagnostic tool.
... Neuroimaging research in chronic fatigue has found white matter lesions in the frontal area on MRI and cerebral hypoperfusion in the brain stem on SPECT [29], although hypoperfusion has been found in several brain regions, and the findings varied across research centers. Patients with fatigue and without comorbid psychopathology have been found to have more white matter lesions on MRI [30], and more brain stem hypoperfusion [31]. Fischler et al. found positive associations between frontal blood flow, objective and subjective measure of cognitive function, and depressive symptoms [32]. ...
... Patients with chronic fatigue had reduced global cerebral blood flow in Yoshiuchi et al. study [35], supported the previous results regarding global hypoperfusion using SPECT brain imaging [33,36]. Chronically fatigued patients had decreased blood flow in bilateral middle cerebral artery territories with increased perfusion in cerebellum [25,31]. Thus, the result of the recent study, together with the results of Carbone et al. study [37] pointed to possible new aspects of fatigue in PBC, i.e. higher brain sensitivity to reduced blood flow in female patients. ...
... Results in some studies have suggested involvement of white matter (Lange et al., 1999;Natelson, Cohen, Brassloff, & Lee, 1993), but other studies found only grey matter abnormalities (de Lange et al., 2005;de Lange et al., 2004;de Lange et al., 2008;Okada, Tanaka, Kuratsune, Watanabe, & Sadato, 2004;Puri et al., 2012) and two studies reported no significant abnormalities in ME (Cope & David, 1996;Perrin, Embleton, Pentreath, & Jackson, 2010). Regarding functional characteristics in ME, cerebral hypoperfusion was found using single-photon emission computed tomography (SPECT) in some (Biswal, Kunwar, & Natelson, 2011;Costa, Tannock, & Brostoff, 1995;Ichise et al., 1992;Schwartz, Komaroff, et al., 1994) but not all studies (Lewis et al., 2001;MacHale et al., 2000;Schmaling, Lewis, Fiedelak, Mahurin, & Buchwald, 2003). Results of metabolic activity from two positron emission tomography (PET) studies were inconclusive (Siessmeier et al., 2003;Tirelli et al., 1998), but abnormalities involving neurotransmitter biosynthesis was suggested in a line of more recent studies (Cleare, Messa, Rabiner, & Grasby, 2005;Nakatomi et al., 2014;Yamamoto et al., 2012). ...
... Schwartz, Komaroff, et al. (1994) hypothesized ME may be caused by a viral infection of neurons, glia, or vasculature. Support for the deficient metabolism in ME was offered in some PET and SPECT imaging studies (Costa et al., 1995;Schwartz, Garada, et al., 1994;Tirelli et al., 1998). Morris and Maes (2012) proposed an immune-inflammatory model for ME, which accounts for fatigue, post-exertional malaise, and neurocognitive symptoms. ...
Article
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Myalgic Encephalomyelitis (ME) is a chronic illness with debilitating neurocognitive impairment that remains poorly understood. Previous studies have characterized cognitive deficits as a process by which brain abnormalities are inferred from pre-established testing paradigms using neuroimaging with low temporal resolution. Unfortunately, this approach has been shown to provide limited predictive power, rendering it inadequate for the study of neuronal communication between synchronized regions. More recent developments have highlighted the importance of modeling spatiotemporal dynamic interactions within and between large-scale and small-scale neural networks on a millisecond time scale. Here, we focus on recent emergent principles of complex cortical systems, suggesting how subtle disruptions of network properties could be related to significant disruptions in cognition and behavior found in ME. This review, therefore, discusses how electrical neuroimaging methods with time-dependent metrics (e.g., coherence, phase, cross-frequency coupling) can be a useful approach for the understanding of the cognitive symptoms in ME. By providing a platform for utilizing real-time alterations of the perpetual signals as an outcome, the disruptions to higher-level cognition typically seen in ME can be readily identified, creating new opportunities for better diagnosis and targeted treatments.
... Structurally, CFS has been associated with bilateral white matter atrophy, diffusion tensor imaging changes in the right arcuate fasciculus (Zeineh et al., 2015), as well as reduced grey matter volume and leukoaraiosis in the frontal cortex, limbic areas, basal ganglia, thalami, and brainstem (Barnden et al., 2011;Barnden, Crouch, Kwiatek, Burnet, & Del Fante, 2015;de Lange et al., 2005;Lange et al., 1999;Puri et al., 2012). Functionally, measures of central fatigue 1 in CFS correlate with reduced cerebral metabolism and reduced cortical blood flow (Biswal, Kunwar, & Natelson, 2011;Costa, Tannock, & Brostoff, 1995;MacHale et al., 2000;Schwartz et al., 1994;Tirelli et al., 1998;Yoshiuchi, Farkas, & Natelson, 2006). Tirelli et al. (1998) found that hypometabolism in the brainstem distinguished non-depressed patients with CFS from patients with major depressive disorder only. ...
... The viral-lesion hypothesis is supported in earlier imaging studies (Costa et al., 1995;Tirelli et al., 1998) showing brainstem hypometabolism and, more recently, grey/white matter abnormalities in the midbrain (Barnden et al., 2011). Dickinson (1997) reviewed the virallesion hypotheses in detail, hypothesizing that a previous viral infection could cause multiple small lesions in the ARAS. ...
Article
We investigated central fatigue in 50 patients with chronic fatigue syndrome (CFS) and 50 matched healthy controls (HC). Resting state EEG was collected from 19 scalp locations during a 3 min, eyes-closed condition. Current densities were localized using exact low-resolution electromagnetic tomography (eLORETA). The Multidimensional Fatigue Inventory (MFI-20) and the Fatigue Severity Scale (FSS) were administered to all participants. Independent t-tests and linear regression analyses were used to evaluate group differences in current densities, followed by statistical non-parametric mapping (SnPM) correction procedures. Significant differences were found in the delta (1-3 Hz) and beta-2 (19-21 Hz) frequency bands. Delta sources were found predominately in the frontal lobe, while beta-2 sources were found in the medial and superior parietal lobe. Left-lateralized, frontal delta sources were associated with a clinical reduction in motivation. The implications of abnormal cortical sources in patients with CFS are discussed.
... The reviewed studies have used ME/CFS diagnostic criteria including CDC-Holmes criteria [7], Oxford criteria [11], CDC-Fukuda criteria [10], Canadian consensus criteria [6], Paediatric ME/CFS definition [5], Reeves criteria [9], and their combinations. Note that four studies [13][14][15][16] included in this review used a combination of CDC-Fukuda and Reeves criteria, another two studies [17,18] used a combination of CDC-Holmes and Oxford criteria. The CDC-Fukuda definition is the most frequently used (54 out of 63 articles) criteria in the articles reviewed (Fig. 2a). ...
... Five studies from two groups reported structural abnormalities in the brain stem in ME/CFS using MRI [30][31][32][33][34]. Additionally, higher binding potential values of 11C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide, indicating local neuroinflammation, was observed in the brain stem in ME/CFS using PET [35]. Three studies reported hypoperfusion in the brain stem using 99 Tc m -hexamethyl-propylene-aminoxime ( 99 Tc m -HMPAO) SPECT [17], [2-11 C] acetyl-L-carnitine PET [36], and 18-fluorodeoxyglucose (FDG) PET [37]. ...
Article
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Background: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible. Method: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported. Results: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies. Conclusion: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.
... After three consecutive days of study participation as outlined in Table 1, it is only reasonable that the participants would be experiencing symptoms of fatigue. Hypoperfusion measured from ASL has been observed and detailed in patients with chronic fatigue syndrome [46][47][48] and associated with cognitive fatigue in healthy individuals [49]. Furthermore, hypometabolism has been observed in patients with chronic fatigue syndrome [50] and multiple sclerosis with fatigue [51]. ...
... Projections from the LC are diverse, innervating most of the central nervous system [53]. Norepinephrine is a neurotransmitter associated with increased arousal and alertness [46][47][48], enhances long-term and working memory processes [54], and promotes vigilance and sensory processing [55]. The evidence presented in this work suggests that repetitive 2 mA tDCS applied to the left prefrontal cortex sustains the metabolic activity of the LC (Figure 4) which may result in an increased production of norepinephrine and a decreased effect of fatigue. ...
Article
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The use of transcranial electrical stimulation (TES) as a method to augment neural activity has increased in popularity in the last decade and a half. The specific application of TES to the left prefrontal cortex has been shown to produce broad cognitive effects; however, the neural mechanisms underlying these effects remain unknown. In this work, we evaluated the effect of repetitive TES on cerebral perfusion. Stimulation was applied to the left prefrontal cortex on three consecutive days, and resting cerebral perfusion was quantified before and after stimulation using arterial spin labeling. Perfusion was found to decrease significantly more in a matched sham stimulation group than in a group receiving active stimulation across many areas of the brain. These changes were found to originate in the locus coeruleus and were broadly distributed in the neocortex. The changes in the neocortex may be a direct result of the stimulation or an indirect result via the changes in the noradrenergic system produced from the altered activity of the locus coeruleus. These findings indicate that anodal left prefrontal stimulation alters the activity of the locus coeruleus, and this altered activity may excite the noradrenergic system producing the broad behavioral effects that have been reported.
... Acknowledging this overlap between CFS and pain phenotypes (eg, fibromyalgia, chronic widespread pain [CWP], chronic regional pain), there is phenotypic variation between the sets of conditions, with notable immunological 55,56 and autonomic 37 differences observed between the two, as well as discordant patterns of brain activity. 18,59 Understanding the epidemiology of CFS and the overlap with pain phenotypes (eg, CWP) is important to develop treatment approaches for those with CFS as well as severe pain. 41 The presence of severe pain in adults with CFS is associated with a worse outcome with cognitive-behavioral therapy 11,29 suggesting a specific intervention to target pain may improve outcome in this group. ...
Article
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Perspective: In this cohort, 14.6% of adolescents with CFS have co-morbid CWP. The likely greater proportion of more mild cases observed in this epidemiological study means that prevalence of overlap may be underestimated compared to those attending specialist services. Clinicians should be aware of the overlap between the two conditions and carefully consider treatment options offered.
... Extending earlier studies that have shown brainstem and prefrontal changes in ME/CFS (Costa, Tannock, and Brostoff, 1995;Lange, Wang, DeLuca, and Natelson, 1998;Siessmeier et al., 2003;Tirelli et al., 1998), recent neuroimaging studies implicate the etiological role of the midbrain. Reduced white matter volume (Barnden et al., 2011), signs of neuroinflammation (Nakatomi et al., 2014), and increased plasticity in prefrontal circuits that is distinct from anxiety and depression (Barnden et al., 2015), indicate impairment in nerve conduction within the midbrain of patients with ME/CFS. ...
Article
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Background: The pursuit for clarity in diagnostic and treatment pathways for the complex, chronic condition of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) continues. This systematic review raises a novel question to explore possible overlapping aetiology in two distinct conditions. Similar neurocognitive symptoms and evidence of D-lactate producing bacteria in ME/CFS raise questions about shared mechanisms with the acute condition of D-lactic acidosis (D-la). Methods: D-la case reports published between 1965 and March 2016 were reviewed for episodes describing both neurological symptoms and high D-lactate levels. Fifty-nine D-la episodes were included in the qualitative synthesis comparing D-la symptoms with ME/CFS diagnostic criteria. A narrative review of D-la mechanisms and relevance for ME/CFS was provided. Results: The majority of neurological disturbances reported in D-la episodes overlapped with ME/CFS symptoms. Of these, the most frequently reported D-la symptoms were motor disturbances that appear more prominent during severe presentations of ME/CFS. Both patient groups shared a history of gastrointestinal abnormalities and evidence of bacterial dysbiosis, although only preliminary evidence supported the role of lactate-producing bacteria in ME/CFS. Limitations: Interpretation of results are constrained by both the breadth of symptoms included in ME/CFS diagnostic criteria and the conservative methodology used for D-la symptom classification. Several pathophysiological mechanisms in ME/CFS were not examined. Conclusions: Shared symptomatology and underlying microbiota-gut-brain interactions raise the possibility of a continuum of acute (D-la) versus chronic (ME/CFS) presentations related to D-lactate absorption. Measurement of D-lactate in ME/CFS is needed to effectively evaluate whether subclinical D-lactate levels affect neurological symptoms in this clinical population.
... Other studies also found increased perfusion in the right thalamus and basal ganglia including the pallidum and putamen (MacHale et al., 2000). On the other hand, some SPECT studies found evidence for a decreased perfusion in the brainstem of CSF patients (Costa, Tannock, & Brostoff, 1995), whilst some studies even found no differences in perfusion (Fischler et al., 1996). Some positron emission tomography (PET) studies using 18-FDG-PET found decreased cerebral metabolism in the frontal lobes (Tirelli et al., 1998) or abnormalities in the anterior cingulate cortex and mesial and orbital frontal cortices (Siessmeier et al., 2003). ...
... When cognitive impairment is worsened by orthostatic challenge, as in this study, we think a likely contributing factor is a generalized reduction in brain perfusion. In 1995, a specific pattern of hypoperfusion of the brainstem was detected in people with ME/CFS, but not in patients with major depression, epilepsy or healthy controls (55). Since then, several studies have found that many parts of the brain in people with ME/CFS have reduced blood flow (56)(57)(58)(59)(60). Furthermore, reduced regional cerebral blood flow is associated with increased symptom severity in people with ME/CFS (61). ...
Article
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Background Some patients with acute COVID-19 are left with persistent, debilitating fatigue, cognitive impairment (“brain fog”), orthostatic intolerance (OI) and other symptoms (“Long COVID”). Many of the symptoms are like those of other post-infectious fatigue syndromes and may meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Common diagnostic laboratory tests are often unrevealing. Methods We evaluated whether a simple, standardized, office-based test of OI, the 10-min NASA Lean Test (NLT), would aggravate symptoms and produce objective hemodynamic and cognitive abnormalities, the latter being evaluated by a simple smart phone-based app. Participants People with Long COVID ( N = 42), ME/CFS ( N = 26) and healthy control subjects ( N = 20) were studied just before, during, immediately after, 2 and 7 days following completion of the NLT. Results The NLT provoked a worsening of symptoms in the two patient groups but not in healthy control subjects, and the severity of all symptoms was similar and significantly worse in the two patient groups than in the control subjects ( p < 0.001). In the two patient groups, particularly those with Long COVID, the NLT provoked a marked and progressive narrowing in the pulse pressure. All three cognitive measures of reaction time worsened in the two patient groups immediately following the NLT, compared to the healthy control subjects, particularly in the Procedural Reaction Time ( p < 0.01). Conclusions A test of orthostatic stress easily performed in an office setting reveals different symptomatic, hemodynamic and cognitive abnormalities in people with Long COVID and ME/CFS, compared to healthy control subjects. Thus, an orthostatic challenge easily performed in an office setting, and the use of a smart phone app to assess cognition, can provide objective confirmation of the orthostatic intolerance and brain fog reported by patients with Long COVID and ME/CFS.
... The scientific process requires that theories are amended if new evidence indicates that they are inaccurate or incomplete. However, the researchers who developed the fear-avoidance model underpinning the protocols for CBT and GET have shown a clear reluctance to acknowledge findings which undermine their theory, notably reports of abnormalities in brain, muscle and immune function (Costa et al., 2005;Goudsmit et al., 2009a;Lane et al., 2003;Shepherd and Chaudhuri, 2016). Moreover, the model posits that the core symptom of ME/CFS is fatigue and not what has become known as post-exertional malaise. ...
Article
The PACE trial is one of the most recent studies evaluating cognitive behavioural therapy and graded exercise therapy for myalgic encephalomyelitis/chronic fatigue syndrome. These interventions are based on a model which assumes that symptoms are perpetuated by factors such as misguided beliefs and a lack of activity. Our analysis indicates that the researchers have shown significant bias in their accounts of the literature and may also have overstated the effectiveness of the above treatments. We submit that their approach to criticisms undermines the scientific process and is inconsistent with best practice.
... To better understand CNS functioning in patients with CFS, regional cerebral blood flow (rCBF) has been measured using arterial spin labelling (ASL) fMRI. Studies have shown that individuals with CFS have lower global rCBF (Costa et al., 1995;Yoshiuchi et al., 2006;Biswal et al., 2011), which may be indicative of reduced metabolic function of cerebral tissue (Petcharunpaisan et al., 2010) and changes in functional neural networks (Bullmore & Sporns, 2012). ASL has several advantages over blood oxygenation leveldependent (BOLD) fMRI when used for resting-state FC analysis, including better correspondence to underlying patterns of neuronal activity and lack of increasing noise at low frequencies (Biswal et al., 2011;Fernandez-Seara et al., 2015). ...
Article
Studies using arterial spin labelling (ASL) have shown that individuals with chronic fatigue syndrome (CFS) have decreased regional cerebral blood flow, which may be associated with changes in functional neural networks. Indeed, recent studies indicate disruptions in functional connectivity (FC) at rest in chronically fatigued patients including perturbations in static FC (sFC), that is average FC at rest between several brain regions subserving neurocognitive, motor and affect-related networks. Whereas sFC often provides information of functional network reorganization in chronic illnesses, investigations of temporal changes in functional connectivity between multiple brain areas may shed light on the dynamic characteristics of brain network activation associated with such maladies. We used ASL fMRI in 19 patients with CFS and 15 healthy controls (HC) to examine both static and dynamic changes in FC among several a priori selected brain regions during a fatiguing cognitive task. HC showed greater increases than CFS in static FC (sFC) between insula and temporo-occipital structures and between precuneus and thalamus/striatum. Furthermore, inferior frontal gyrus connectivity to cerebellum, occipital and temporal structures declined in HC but increased in CFS. Patients also showed lower dynamic FC (dFC) between hippocampus and right superior parietal lobule. Both sFC and dFC correlated with task-related fatigue increases. These data provide the first evidence that perturbations in static and dynamic FC may underlie chronically fatigued patients’ report of task-induced fatigue. Further research will determine whether such changes in sFC and dFC are also characteristic for other fatigued individuals, including patients with chronic pain, cancer and multiple sclerosis.
... In addition, given that alterations in rCBF can result in changes of functional brain networks [52], it is possible that individual differences in rCBF response to PASAT performance in critical nodes resulted in alterations of fatigue-related networks in a manner moderated by ME/CFS status. Indeed, our group has recently published results indicating perturbations in functional connectivity related to both resting and task-related fatigue [31,32] between brain regions where structural or functional alterations have been previously noted in ME/CFS patients (e.g., [7,43,45,46,53,54]. Further interrogation of such nodes/networks by directly modulating their function through pharmacological means or via transcranial magnetic stimulation may help elucidate the neural underpinnings of fatigue, as well as potential treatments for ME/CFS. ...
Article
Purpose: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial. Methods: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory-Serial-Addition-Testing (PASAT). Results: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC. Conclusions: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF of several brain regions associated with memory, goal-oriented attention, and visual function was differentially associated with recovery from fatigue in ME/CFS patients and HC.
... CIHH increases the activity of alpha 1 ADRs, which is possibly one of the mechanisms for the cardioprotection of CIHH [42]. Importantly, the cardiovascular system in CFS/ME has been reported to be compromised as manifested by postural orthostatic tachycardia syndrome, poor peripheral circulation, intolerance to physical exercise and poor cerebral perfusion and systemic perfusion [43][44][45][46][47]. Collectively, these symptoms and signs suggest a clinical presentation of dysautonomia. ...
Article
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Background Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME) is a debilitating condition of unknown aetiology. It is characterized by a range of physiological effects including neurological, sensory and motor disturbances. This study examined candidate genes for the above clinical manifestations to identify single nucleotide polymorphism (SNP) alleles associated with CFS/ME compared with healthy controls. Methods DNA was extracted and whole genome genotyping was performed using the HumanOmniExpress BeadChip array. Gene families for transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors, and acetylcholinesterase were targeted. The frequency of each SNP and their association between CFS/ME and healthy controls was examined using Fisher’s exact test, and to adjust for multiple testing, False Detection Rate (FDR) and Bonferroni corrections were applied (p < 0.05). Results The study included 172 participants, consisting of 95 Fukuda defined CFS/ME patients (45.8 ± 8.9; 69 % female) and 77 healthy controls (42.3 ± 10.3; 63 % female). A total of 950 SNPs were included for analysis. 60 significant SNPs were associated with CFS/ME compared with healthy controls. After applying FDR and Bonferroni corrections, SNP rs2322333 in adrenergic receptor α1 (ADRA1A) was higher in CFS/ME compared with healthy controls (45.3 % vs. 23.4 %; p = 0.059). The genotype class that was homozygous minor (AA) was substantially lower in CFS/ME compared with healthy controls (4.2 % vs. 24.7 %). Conclusions This study reports for the first time the identification of ADRA1A and a possible association between CFS/ME and genotype classes. Further examination of the functional role of this class of adrenergic receptors may elucidate the cause of particular clinical manifestations observed in CFS/ME.
... Extending earlier studies that have shown brainstem and prefrontal changes in ME/CFS (Costa, Tannock, and Brostoff, 1995;Lange, Wang, DeLuca, and Natelson, 1998;Siessmeier et al., 2003;Tirelli et al., 1998), recent neuroimaging studies implicate the etiological role of the midbrain. Reduced white matter volume (Barnden et al., 2011), signs of neuroinflammation (Nakatomi et al., 2014), and increased plasticity in prefrontal circuits that is distinct from anxiety and depression (Barnden et al., 2015), indicate impairment in nerve conduction within the midbrain of patients with ME/CFS. ...
Chapter
Sleep abnormalities, neurocognitive disturbances and comorbid depressive symptoms are some of the particularly debilitating symptoms experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This complex condition with currently evasive etiology involves a multisystemic symptom presentation that can reflect dysfunction in several organs and biological systems. The microbiota-gut-brain axis provides one possible pathway where dysfunction in communication between enteric microbiota, the gastro-intestinal system, and the brain may precipitate some ME/CFS symptoms. Sleep, neurocognitive and depressive symptoms are examined with recent microbiome research highlighting the potential etiological role of dysfunction in gut-brain communication. Treatment alternatives are reviewed with a focus on addressing underlying pathophysiology and possible causal mechanisms. The burgeoning field of microbiota research across diverse health fields provides an avenue of hope for future therapeutic advances and improved health outcomes for patients with ME/CFS.
... CFS is also associated with cerebral hypoperfusion [13][14][15][16], though this is not a universal finding [17]. Whether or not this hypoperfusion is related to differences in ICC and may account for symptoms of OI is not yet clear. ...
Article
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Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.
... Many reports have described overall decreases in the CBF in CFS patients. Two reports used SPECT imaging (17,18), one performed neuroimaging using arterial spin labelling (19), one reported a decrease in the CBF in the brainstem using SPECT imaging (20), one reported a decrease in the CBF in the anterior cingulate gyrus using SPECT imaging (21), and one reported a decrease in the absolute CBF in the distribution of the left and right middle cerebral arteries using SPECT imaging (22). However, some reports have indicated no changes in the CBF (23)(24)(25). ...
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Objective Chronic fatigue syndrome (CFS) is a complex disorder, with no consensus on therapeutic options. However, Waon therapy has been reported to be an effective treatment. The purpose of this study was to evaluate changes in the cerebral blood flow (CBF) before and after Waon therapy in CFS patients and to investigate the correlation between such changes and the therapeutic efficacy of Waon therapy. Methods Eleven patients (2 men and 9 women, mean age 27 years old) diagnosed with CFS participated in the study. The disease duration was 8-129 months, and the performance status was 5-8 (on a scale of 0-9). All patients underwent CBF scintigraphy using brain single-photon emission computed tomography (SPECT) with technetium-99m ethyl cysteinate dimer (99mTc-ECD) before and after Waon therapy. CBF changes after Waon therapy were evaluated using a statistical analysis of imaging data, which was performed with a statistical parametric mapping software program (SPM5). Results Waon therapy reduced symptoms in all 11 patients. We also observed an increase in the CBF within the prefrontal region, orbitofrontal region, and right temporal lobe. These results indicated that an improvement in clinical symptoms was linked to an increase in the CBF. Conclusion The results indicated abnormalities of the cerebral function in the prefrontal region, orbitofrontal region, and right temporal lobe in CFS patients and that Waon therapy improved the cerebral function and symptoms in CFS patients by increasing the regional CBF. To our knowledge, this is the first report to clarify the CBF changes in CFS patients before and after Waon therapy.
... Wind-up takes place under long-term potentiation (LTP), in the context of temporal summation effected by repetitive nociceptive stimulation (which may be low/subclinical in intensity) (Woolf, 1991). ME/CFS patients have demonstrably low nociceptive thresholds of the muscle tissues (Vecchiet et al., 1996), and many have significant cerebral (brain) hypoperfusion (Hamre, 1995), including in the parahippocampus (Gay et al., 2016) and brain stem (Costa et al., 1995), which may contribute to abnormal function of the locus ceruleus, involved in the control of descending inhibitory nociceptive pathways (Meeus and Nijs, 2007). Along with NO and pro-inflammatory cytokine activity, excitotoxicity may play a role in migraine pathogenesis (Longoni and Ferrarese, 2006). ...
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic illness of unknown etiology, classified as a neurological disorder by the World Health Organization (WHO). The symptomatology of the condition appears to emanate from a variety of sources of chronic neurological disturbance and associated distortions, and chronicity, in noxious sensory signaling and neuroimmune activation. This article incorporates a summary review and discussion of biomedical research considered relevant to this essential conception perspective. It is intended to provide stakeholders with a concise, integrated outline disease model in order to help demystify this major public health problem. The primary etiopathological factors presented are: (A) Postural/biomechanical pain signaling, affecting adverse neuroexcitation, in the context of compression, constriction, strain, or damage of vertebral-regional bone and neuromuscular tissues; (B) Immune mediated inflammatory sequelae, in the context of prolonged immunotropic neurotrophic infection—with lymphotropic/gliotropic/glio-toxic varieties implicated in particular; (C) A combination of factors A and B. Sustained glial activation under such conditions is associated with oxidative and nitrosative stress, neuroinflammation, and neural sensitivity. These processes collectively enhance the potential for multi-systemic disarray involving endocrine pathway aberration, immune and mitochondrial dysfunction, and neurodegeneration, and tend toward still more intractable synergistic neuro-glial dysfunction (gliopathy), autoimmunity, and central neuronal sensitization.
... 208,209 Er zijn aanwijzingen voor hypo-perfusie van de hersenen, met name van de subcorticale witte stof en hersenstam. 210,211 De door veel ME/CVS-patiënten gemelde visusstoornissen, coördinatiestoornissen, geheugenproblemen, spraakproblemen, en sensaties van niet aan de omgevingstemperatuur gerelateerde kou in de extremiteiten lijken inderdaad te wijzen in de richting van een aandoening van het centraal zenuwstelsel. ...
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A practical approach to chronic fatigue.
... For instance, focal enterovirus encephalitis caused by coxsackievirus A3 is associated with focal hypoperfusion in the right frontal lobe that cleared upon patient recovery from the neurotropic enteroviral infection. This example case is largely similar to multiple SPECT studies indicating ME/CFS patients have significant hypo-perfusion in regions of the brain consistent with their patient-specific symptoms (87)(88)(89)(90)(91)(92). ...
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Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, multi-system disease whose etiological basis has not been established. Enteroviruses (EVs) as a cause of ME/CFS have sometimes been proposed, as they are known agents of acute respiratory and gastrointestinal infections that may persist in secondary infection sites, including the central nervous system, muscle, and heart. To date, the body of research that has investigated enterovirus infections in relation to ME/CFS supports an increased prevalence of chronic or persistent enteroviral infections in ME/CFS patient cohorts than in healthy individuals. Nevertheless, inconsistent results have fueled a decline in related studies over the past two decades. This review covers the aspects of ME/CFS pathophysiology that are consistent with a chronic enterovirus infection and critically reviews methodologies and approaches used in past EV-related ME/CFS studies. We describe the prior sample types that were interrogated, the methods used and the limitations to the approaches that were chosen. We conclude that there is considerable evidence that prior outbreaks of ME/CFS were caused by one or more enterovirus groups. Furthermore, we find that the methods used in prior studies were inadequate to rule out the presence of chronic enteroviral infections in individuals with ME/CFS. Given the possibility that such infections could be contributing to morbidity and preventing recovery, further studies of appropriate biological samples with the latest molecular methods are urgently needed.
... One of the most consistent findings in ME/CFS is abnormal global and regional CBF in response to regulatory challenges including head tilt maneuvers as well as cognitive and physical exercise (Ichise et al., 1992;Costa et al., 1995;Fischler et al., 1996;Tirelli et al., 1998;MacHale et al., 2000;Siessmeier et al., 2003;Yoshiuchi et al., 2006;Barnden et al., 2011;Biswal et al., 2011;Stewart et al., 2012;van Campen et al., 2020;Li et al., 2021;Rayhan and Baraniuk, 2021). The decrease in CBF on tilt table provocation can be independent of heart rate and blood pressure (BP) response (van Campen et al., 2020), independent of normocapnia versus hypocapnia (van Campen et al., 2021), and has also been found in the subset of ME/CFS patients with joint hypermobility . ...
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Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.
... Oxidative stress and increased isoprostanes in ME/CFS have been correlated with clinical symptoms (60). Reduced brain blood flow is common in ME/CFS patients, accompanied by lowered circulation and nutrient/waste exchange (61)(62)(63)(64)(65). ...
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Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a multisystem medical condition with heterogeneous symptom expression. Currently, there is no effective cure or treatment for the standard care of patients. A variety of ME/CFS symptoms can be linked to the vital life functions of the brainstem, the lower extension of the brain best known as the hub relaying information back and forth between the cerebral cortex and various parts of the body. Objective/Methods: Over the past decade, Magnetic Resonance Imaging (MRI) studies have emerged to understand ME/CFS with interesting findings, but there has lacked a synthesized evaluation of what has been found thus far regarding the involvement of the brainstem. We conducted this study to review and evaluate the recent MRI findings via a literature search of the MEDLINE database, from which 11 studies met the eligibility criteria. Findings: Data showed that MRI studies frequently reported structural changes in the white and gray matter. Abnormalities of the functional connectivity within the brainstem and with other brain regions have also been found. The studies have suggested possible mechanisms including astrocyte dysfunction, cerebral perfusion impairment, impaired nerve conduction, and neuroinflammation involving the brainstem, which may at least partially explain a substantial portion of the ME/CFS symptoms and their heterogeneous presentations in individual patients. Conclusions: This review draws research attention to the role of the brainstem in ME/CFS, helping enlighten future work to uncover the pathologies and mechanisms of this complex medical condition, for improved management and patient care.
... However, studies in progress are just beginning to identify the neural correlates of the symptom of fatigue; these may enhance our understanding of the brain mechanisms underlying the sense of effort. 59 ...
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Objective: We reviewed previous studies that have described an association between abnormal functioning of the hypothalamicpituitary-adrenal axis and depression. In addition to melancholic depression, a spectrum of conditions may be associated with increased and prolonged activation of the hypothalamic-pituitary-adrenal axis. In contrast another group of states is characterized by hypoactivation of the stress system, rather than sustained activation, in which chronically reduced secretion of corticotropin releasing factor may result in pathological hypoarousal and an enhanced hypothalamic-pituitary-adrenal negative feedback. Patients with atypical depression, seasonal affective disorder and chronic fatigue syndrome fall in this category. Method: The literature data on the overlap between the key-words were reviewed, summarized and discussed. Results: Many studies suggest that these conditions themselves overlap biologically, showing hypofunction of central corticotropin releasing factor neuronal systems. Conclusions: Therefore, in the real world of clinical practice, patients often present in a grey area between classical idiopathic fatigue and early chronic atypical depression and/or seasonal depression. This underscores the potential common biological links underpinning commom symptom clusters not only between depression (atypical and seasonal) and chronic fatigue syndrome, but also other conditions characterized by in the hypothalamic-pituitary-adrenal axis mainly diminished the corticotropin realising factor activity. Descriptors: Melancholic depression; Seasonal affective disorder; Fatigue syndrome, chronic; Hypothalamus-hypophyseal system; Corticotropin releasing factor
... However, structural findings yielded inconsistent atrophy and signal intensity (Cope & David, 1996). Functional neuroimaging using singlephoton emission computed tomography (SPECT) showed lowered regional cerebral blood flow in ME/CFS patients (Costa et al., 1995;Goldstein et al., 1995). Another study using positron emission tomography (PET) detected neuroinflammation in ME/CFS (Nakatomi et al., 2014). ...
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Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS) patients suffer from a variety of physical and neurological complaints indicating the central nervous system plays a role in ME/CFS pathophysiology. Diffusion tensor imaging (DTI) has been used to study microstructural changes in neurodegenerative diseases. In this study, we evaluated DTI parameters to investigate microstructural abnormalities in ME/CFS patients. We estimated DTI parameters in 25 ME/CFS patients who met Fukuda criteria (ME/CFSFukuda), 18 ME/CFS patients who met International Consent Criteria (ICC) (ME/CFSICC) only, and 26 healthy control subjects (HC). In addition to voxel-based DTI-parameter group comparisons, we performed voxel-based DTI-parameter interaction-with-group regressions with clinical and autonomic measures to test for abnormal regressions. Group comparisons between ME/CFSICC and HC detected significant clusters (a) with decreased axial diffusivity (p=0.001) and mean diffusivity (p=0.01) in the descending cortico-cerebellar tract in the midbrain and pons, and (b) with increased transverse diffusivity in the medulla. The mode of anisotropy was significantly decreased (p=0.001) in a cluster in the superior longitudinal fasciculus region. Voxel-based group comparisons between ME/CFSFukuda and HC did not detect significant clusters. For ME/CFSICC and HC, DTI parameter interaction-with-group regressions were abnormal for the clinical measures of information processing score, SF36 physical, sleep disturbance score, and respiration rate in both grey and white matter regions. Our study demonstrated that DTI parameters are sensitive to microstructural changes in ME/CFSICC and could potentially act as an imaging biomarker of abnormal pathophysiology in ME/CFS. The study also shows that strict case definitions are essential in investigation of the pathophysiology of ME/CFS.
... In addition, patterns of functional brain activity in patients with fibromyalgia are quite different from those in patients with CFS. Compared to healthy controls, patients with CFS show significantly lower blood perfusion in the brain stem (15,16), while patients with fibromyalgia exhibited significantly lower regional cerebral blood flow in the thalamus and caudate nucleus (17). Furthermore, Substance P has been found to be elevated in cerebrospinal fluid samples of patients with fibromyalgia (18) and not in patients with CFS (19). ...
Article
Background: Besides chronic fatigue, patients with chronic fatigue syndrome (CFS) have debilitating widespread pain. Yet pain from CFS is often ignored by clinicians and researchers. Objectives: To examine whether pain is a unique feature of CFS, or does it share the same underlying mechanisms as other CFS symptoms? Second, it is examined whether effective treatments for pain from CFS are currently available. Study Design: Narrative review covering the scientific literature up through December 2011. Setting: Several universities. Results: From the available literature, it is concluded that musculoskeletal factors are unlikely to account for pain from CFS. Pain seems to be one out of many symptoms related to central sensitization from CFS. This idea is supported by the findings of generalized hyperalgesia (including widespread increased responsiveness to painful stimuli) and dysfunctional endogenous analgesia in response to noxious thermal stimuli. Pain catastrophizing and depression partly account for pain from CFS. Pain increases during exercise is probably due to the lack of endogenous analgesia and activation of several genes in response to exercise in CFS. There is currently no evidence in support for the efficacy of complementary medicine in the treatment of pain from CFS. Intensive education about the biology of pain from CFS (within the framework of central sensitization) has positive short-term effects for patients with CFS, and fatigue-targeting cognitive behavioral therapy appears to be effective for pain from CFS as well. Limitations: The role of the deficient hypothalamus-pituitary-adrenal axis in relation to pain from CFS, as well as the interactions with immune (dys)functioning require further study. Conclusion: Recent research has increased our understanding of pain from CFS, including its treatment. It is advocated to optimize current CFS treatment protocols by targeting the underlying mechanism for those patients having severe pain. Key words: Chronic pain, chronic fatigue syndrome, fibromyalgia, central sensitization, catastrophizing, exercise, cognitive behavioral therapy.
... The existence of regional or global cerebral hypoperfusion indicative of reduced bioenergetic capacity has also been consistently reported by research teams utilising xenon-computed tomography, arterial spin labelling and high-resolution singlephoton emission computed tomography (SPECT) (Biswal et al. 2011;Machale et al. 2000;Patrick Neary et al. 2008;Yoshiuchi et al. 2006). These findings have also been reported in large studies utilising older SPECT techniques either globally (Ichise et al. 1992;Schwartz et al. 1994) or regionally (Costa et al. 1995;Goldstein et al. 1995) but the results in studies with far fewer participants have been negative (Fischler et al. 1996;Peterson et al. 1994). ...
Article
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A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals. The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities. Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation. The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next. Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.
... Though it is thought to originate from a genetic predisposition and/or an interaction with a host of environmental factors (e.g., frequent injury), the exact precursors of this disorder are still not well-understood [1]. Researchers have, however, observed some uniformity in attempting to distinguish the properties of this illness; for example, patients with ME/CFS have been observed to have a reduced blood perfusion rate in the brain stem [2]. Additionally, abnormality in multiple brain structures that regulate pain has been observed [3], leading recent research studies to theorize that the ME/CFS brain's homeostatic processes that react to pain are aberrant in nature [1]. ...
Article
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This article provides a narrative review on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) through a psychosocial lens and examines how this impairment affects its sufferers during adolescence and adulthood, as well as how it impacts family caregivers and healthcare professionals' mental health. Since there has been a lack of investigation in the literature, the primary psychosocial stressor that this review focuses on is loneliness. As such, and in an attempt to help establish a theoretical framework regarding how loneliness may impact ME/CFS, loneliness is comprehensively reviewed, and its relation to chronic illness is described. We conclude by discussing a variety of coping strategies that may be employed by ME/CFS individuals to address their loneliness. Future directions and ways with which the literature may investigate loneliness and ME/CFS are discussed.
Chapter
Chronic fatigue syndrome (CFS) or myalgic encephalitis (ME) comprises a group of disorders generally defined by persistent fatigue accompanied by a range of other symptoms that may fluctuate in intensity and severity and with great variability in the symptoms between individual persons. The underlying pathophysiology is still not fully explained, but literature continues to demonstrate an involvement of the central nervous system. This book chapter reviews all SPECT and PET studies in patients with CFS/ME that have been published. No corresponding findings were found in all these studies. Some papers mention a global cerebral hypoperfusion and some hypoperfusion of the brainstem; others did not find any differences compared with healthy controls or found hyperperfusion of a certain brain region. However, for the future, there are several possibilities in which nuclear medicine may help to solve the problem of the aetiology of CFS/ME. Imaging the serotonergic system, targeted imaging of specific molecules and cytokines involved in this disease and imaging the role of neuroinflammation are areas that may be worthwhile to investigate.
Chapter
Chronic fatigue syndrome and myalgic encephalomyelitis are classified as two distinct illnesses in the World Health Organization’s International Classification of Diseases. However, they are indistinct and comprise a series of debilitating symptoms, mainly fatigue, impaired cognition (memory difficulties) and sleep disturbances. There are still those who do not believe that this condition deserves a full credit as an independent disease entity. No biological markers have been identified and pathophysiology is uncertain. There are no objective brain abnormalities identified specific to CFS/ME. Brainstem hypoperfusion and other perfusion and metabolic abnormalities observed with functional brain imaging need further confirmation and evaluation. Success of therapeutic measures is doubtful. Further studies with more specific markers of neurotransmitter systems are warranted.
Chapter
The term dementia is often used to describe chronic, irreversible and progressive development of multiple cognitive deficits that include memory impairment (Criterion A1) and at least one of the following other cognitive abnormalities (Criterion A2): aphasia, apraxia, agnosia, or a disturbance in executive functioning [1, 2]. These cognitive deficits must be severe enough to produce impairment in occupational or social functioning (Criterion B) and there must be a clear-cut decline from previously higher levels of functional capacity. The nature and degree of impairment are variable and often influenced by the social setting and sometimes also by the cultural environment. Approximately one-third of patients initially presenting with dementia have reversible syndromes at their final diagnosis [3].
Chapter
The brain is protected from internal and external injury by special and specific physiological barriers. These are of three main types: (i) the blood-brain barrier (BBB) that separates the blood from the brain parenchyma; (ii) the blood-CSF barrier between the blood and the cerebrospinal fluid (CSF); and (iii) the CSF-brain barrier separating the CSF from the brain parenchyma [1].
Chapter
In patients with a late whiplash syndrome, a statistically significant metabolic reduction in the posterior parietal occipital region of the brain is found. This could be shown in several studies with altogether over 500 investigated patients both by cerebral blood flow single-photon emission tomography (SPET) and by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In individual cases, the patients showed also regions with decreased metabolism which were not in the posterior parietal occipital localization, but in these, no statistically significant group differences to a healthy control group could be determined. Posterior parietal occipital findings can also be observed in other diseases with brain affection, e.g., in systemic lupus erythematosus, in Alzheimer’s disease, or in migraine. Such other diseases can easily be excluded by a purposeful clinical and neurological assessment. There are also diseases, which show a similar clinical component as the late whiplash syndrome, e.g., primary depression. In these diseases, the posterior parietal occipital region is, however, not affected.
Article
Chronic fatigue syndrome (CFS) is medically unexplained fatigue lasting at least 6 months and accompanied by infectious, rheumatological, and neuropsychiatric symptoms. CFS is primarily a problem in women's health because approximately 75% of patients seeking care for chronic fatigue are women. Because of complaints of muscle weakness and achiness, early work focused on peripheral mechanisms of fatigue via muscle dysfunction. However, those studies were unable to confirm any consistent anatomical or physiological abnormality. The lack of an obvious peripheral mechanism for fatigue led to a change in focus to central mechanisms. This change was supported by a set of studies, including those from this laboratory, which showed objective evidence of neuropsychological dysfunction.
Chapter
Somatoforme Störungen umfassen eine Gruppe heterogener Störungen, denen als führende klinische Beschwerden körperliche Symptome ohne eine hinreichende organmedizinische Erklärung gemeinsam sind. Dass Konzept der „Somatisierung“ liegt den somatoformen Störungen, aber auch anderen primären psychischen Störungen zugrunde, die wie z. B. Depression oder Angst vorrangig in ihren integralen körperlichen Symptomen dargestellt werden. Ursache, Entstehung und Aufrechterhaltung von somatoformen Störungen werden multifaktoriell vermittelt. Akute und chronische psychosoziale Stressoren spielen eine wichtige Rolle. Es kommen unterschiedliche Schweregrade und Verlaufstypen vor. Zu beachten sind eine bedeutsame psychiatrische Komorbidität, eine häufige psychosoziale Behinderung sowie eine intensive Inanspruchnahme vielfältiger medizinischer Ressourcen. Nicht selten gestaltet sich die Arzt-Patient-Beziehung emotional konfliktträchtig. Es existieren differenzierte störungsbezogene psychotherapeutische Ansätze. Pharmakotherapeutische Interventionen sind v. a. bei koexistenten psychischen Störungen indiziert, besitzen aber auch unabhängig davon eine gewisse Evidenzbasierung. Das diagnostische Konzept der somatoformen Störungen spielt bisher für die ärztliche Versorgung nur eine untergeordnete Rolle. Die Herausforderungen hier sind in erster Linie in der hohen Anzahl von Patienten zu sehen, die entweder nur vereinzelte oder nur wenige körperliche Symptome ohne mögliche somatisch-medizinische Zuordnung präsentieren und daher häufig nur „Symptom-Diagnosen“ erhalten, oder aber bei denen meist auf einer fachärztlichen Ebene ein fachspezifisch definiertes „funktionelles Körpersyndrom“ diagnostiziert wird. Beide eigenständigen diagnostischen Zugangsweisen sind häufig nicht spannungsfrei und klinisch sinnvoll in das psychiatrische Diagnosesystem übersetzbar. Das DSM-5 hat eine Reihe von formalen und inhaltlichen Kritikpunkten an der früheren Diagnosegruppe der „somatoformen Störungen“ aufgenommen und schlägt nunmehr die Gruppe der „somatischen Belastungsstörung und verwandter Störungen“ vor. Es ist derzeit noch unklar, zu welchen Positionen und Bezeichnungen die für die nächsten Jahre angekündigte Revision von ICD-11 kommen wird.
Chapter
Patienten mit andauernden Symptomen nach einer Schleudertraumaverletzung (dem so genannten Late-Whiplash-Syndrom) werden oft alleine gelasse.. Ihre Beschwerden beschränken sich jedoch nicht nur auf neuropathische Schmerzen in der Kopf- und Nackenregion, sondern manche Symptome gehen vom Gehirn aus. Zu diesen Gehirn-Symptomen gehören Schwindel, Benommenheit, Tinnitus, Störungen der Konzentration, der Aufmerksamkeit und des Gedächtnisses. Auch Augensymptome wie Flimmersehen oder Verschwommensehen können auftreten.
Article
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, is an unprecedented challenge for the global community. The pathogenesis of COVID-19, its complications and long term sequelae (so called Long/Post-COVID) include, in addition to the direct virus-induced tissues injury, multiple secondary processes, such as autoimmune response, impairment of microcirculation, and hyperinflammation. Similar pathological processes, but in the settings of neurological, cardiovascular, rheumatological, nephrological, and dermatological diseases can be successfully treated by powerful methods of Therapeutic Apheresis (TA). We describe here the rationale and the initial attempts of TA treatment in severe cases of acute COVID-19. We next review the evidence for the role of autoimmunity, microcirculatory changes and inflammation in pathogenesis of Long/Post COVID and the rationale for targeting those pathogenic processes by different methods of TA. Finally, we discuss the impact of COVID-19 pandemic on patients, who undergo regular TA treatments due to their underlying chronic conditions, with the specific focus on the patients with inherited lipid diseases being treated at the Dresden University Apheresis Center.
Chapter
Patients with persisting symptoms after a whiplash injury (the so-called late whiplash syndrome) are often left alone. However, their complaints are not only limited to neuropathic pain in the head and neck region, but there are also symptoms, which proceed from the brain. These brain symptoms comprise vertigo, dizziness, tinnitus, as well as concentration, attention and memory disturbances; also visual problems such as blurred vision and oscillopsia can occur. The whiplash injury is frequent, although only a small proportion of the patients develop the late whiplash syndrome. The incidence of whiplash injury in the industrialized countries is estimated up to 3.8 cases per 1,000 inhabitants per year. Rear-end car collisions are the most frequent causes of whiplash injury and only low speeds between 10 and 20 km/h are necessary to cause large acceleration forces on the head. The usual methods for the diagnosis of whiplash injury such as the neurological investigation or radiography of the cervical spine unfortunately forget that the brain (in addition to the cervical spine) can be damaged by an acceleration trauma. Therefore, research methods are necessary which objectively represent the condition of the brain. Conventional radiological imaging such as computerized tomography or magnetic resonance tomography of the brain can, however, only represent the morphological structures and not the possible functional alterations of the brain, as caused by whiplash injury. In contrast, the relatively new methods of nuclear medicine currently offer the only possibility of imaging such functional changes. In patients with late whiplash syndrome, a statistically significant metabolic reduction in the posterior parietal occipital region of the brain is found. This was shown in several studies with over 500 patients investigated by both cerebral blood flow single-photon emission computed tomography and fluorodeoxyglucose positron emission tomography. In individual cases, patients also showed regions with decreased metabolism which were not in the posterior parietal occipital location, but no statistically significant group differences could be determined between these patients and a healthy control group. In a further study from a research group in Zurich, somewhat different results were found; the results of this study seem, however, doubtful. — Posterior parietal occipital findings can also be observed in other diseases with brain affection, for example, in systemic lupus erythematosus, Alzheimer’s disease or migraine. Other diseases can easily be excluded by a purposeful clinical and neurological assessment. There are also diseases which show a similar clinical component like the late whiplash syndrome, for instance, primary depression. In these diseases, the posterior parietal occipital region is not affected however. In light of the ongoing medico-legal discussion in the field, a critical approach to the interpretation of these new research data from functional neuroimaging is of utmost importance. All treating physicians in the field should be familiar with these tools.
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Chronic fatigue syndrome (CFS) is characterized as a persistent, debilitating complex disorder of unknown etiology, whereby patients suffer from extreme fatigue, which often presents with symptoms that include chronic pain, depression, weakness, mood disturbances, and neuropsychological impairment. In this mini review and case report, we address central nervous system (CNS) involvement of CFS and present neuropathological autopsy findings from a patient who died with a prior diagnosis of CFS. Among the most remarkable pathological features of the case are focal areas of white matter loss, neurite beading, and neuritic pathology of axons in the white matter with axonal spheroids. Atypical neurons displaying aberrant sprouting processes in response to injury are observed throughout cortical gray and white matter. Abundant amyloid deposits identical to AD plaques with accompanying intracellular granular structures are observed as well. Neurofibrillary tangles are also present in the white matter of the frontal cortex, thalamus and basal ganglia. Taken together, these neuropathological findings warrant further studies into CNS disease associated with CFS.
Article
Introduction: Chronic fatiguing illnesses like cancer, multiple sclerosis, chronic fatigue syndrome, or depression are frequently associated with comorbidities including depression, pain, and insomnia, making the study of their neural correlates challenging. To study fatigue without such comorbidities, functional connectivity (FC) analyses were used in healthy individuals to study brain activity during recall of a fatiguing event inside the MRI scanner. A positive mood induction served as control condition. Method: Using SPM8 and the CONN toolbox, FC was tested using seed- and independent component- based (ICA) analyses. Differences in the FC correlations between seed-to-voxel and ICA clusters between conditions were assessed with permutation testing. Results: 17 participants (59% women) achieved mean (SD) in-scanner fatigue VAS ratings of 31.85 (20.61). Positive mood induction resulted in happiness ratings of 46.07 (18.99) VAS. Brain regions where alterations in FC correlated with fatigue included the globus pallidum, left lateral occipital cortex, and cuneus. FC of happiness involved the parahippocampal gyrus, both supplemental motor areas, as well as right superior frontal gyrus. Using data-driven ICA, we identified an intra-cerebellar network where several regions were significantly associated with fatigue, but not happiness ratings. Results of permutation testing provided evidence that the detected clusters correlated differentially with self-reported fatigue and happiness. Conclusions: Our study suggests that functional interactions between globus pallidum and occipital structures contribute to experimental fatigue in healthy individuals. They also highlight the important role of cortico-cerebellar interactions in producing feelings of fatigue. FC of occipital structures contributed to both experimental fatigue and happiness ratings.
Article
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying. The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement. The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable. We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies. We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.
Chapter
In patients with late whiplash syndrome, early studies showed a statistically significant metabolic reduction in the posterior parietal occipital region of the brain. This could be observed in several studies with altogether over 500 investigated patients both by cerebral blood flow single-photon emission tomography (SPET) and by ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In individual cases, the patients exhibited also regions with decreased metabolism which were not in the posterior parietal occipital localization, but in these, no statistically significant group differences to a healthy control group could be determined. Posterior parietal occipital findings can also be seen in other diseases with brain affection, e.g., in systemic lupus erythematosus, in Alzheimer’s disease, or in migraine. Such other diseases can easily be excluded by a purposeful clinical and neurological assessment. There are also diseases that show a similar clinical component as the late whiplash syndrome, e.g., primary depression. In these diseases, the posterior parietal occipital region is, however, not affected.
Chapter
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious, debilitating disorder with a wide spectrum of symptoms, including fatigue, pain, depression and neurocognitive deterioration. Over 17 million people around the world have ME/CFS, predominantly women with peak onset at 30–50 years. Given the wide spectrum of symptoms and unclear etiology, specific biomarkers for diagnosis and stratification of ME/CFS are lacking. Here the results from PET/SPECT/MRI/fMRI studies are reviewed to understand the pathophysiology and to develop therapies of this severe syndrome.
Article
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic systemic disease that manifests via various symptoms such as chronic fatigue, post-exertional malaise, and cognitive impairment described as “brain fog”. These symptoms often prevent patients from keeping up their pre-disease onset lifestyle, as extended periods of physical or mental activity become almost impossible. However, the disease presents heterogeneously with varying severity across patients. Therefore, consensus criteria have been designed to provide a diagnosis based on symptoms. To date, no biomarker-based tests or diagnoses are available, since the molecular changes observed also largely differ from patient to patient. In this review, we discuss the infectious, genetic, and hormonal components that may be involved in CFS pathogenesis, we scrutinize the role of gut microbiota in disease progression, we highlight the potential of non-coding RNA (ncRNA) for the development of diagnostic tools and briefly mention the possibility of SARS-CoV-2 infection causing CFS.
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Chronic fatigue syndrome (CFS) is an operational concept for clarifying the unknown etiology of the syndrome characterized by the sensation of abnormally prolonged fatigue. The vast majority of patients with CFS are interrupted in their daily or social lives by prolonged fatigue, headache, myalgia, arthralgia, sleep disturbance, or brain dysfunctions. However, the pathogenesis of CFS remains unclear, and so there are still many medical doctors around the world who are skeptical about the disease. Recently, we organized a study group of Japanese investigators from various fields, such as virology, immunology, endocrinology, physiology, biochemistry, psychiatry, and neuroscience, and as a result of the efforts of this group the mechanism underlying CFS is now becoming a little clearer. We are now able to suggest that CFS can be understood to be a special condition based on an abnormality of the psycho-neuro-endocrino-immunological system caused by psycho-social stress, and which has some genetic components. A reactivation of various types of herpes virus infections and/or chronic mycoplasma infection might occur as a result of immune dysfunction, causing the abnormal production of several cytokines. A distinctive feature of CFS is thought to be a secondary brain dysfunction caused by the abnormal production of such cytokines. In this chapter, we would like to introduce not only the recent findings on the pathogenesis of CFS, but also the prevalence, diagnosis, therapy, and prognosis of CFS in Japan.
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To conduct neurologic, immunologic, and virologic studies in patients with a chronic debilitating illness of acute onset. Cohort study with comparison to matched, healthy control subjects. We studied 259 patients who sought care in one medical practice; 29% of the patients were regularly bedridden or shut-in. 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). 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. 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.
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To study the dynamic function of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome. Prospective comparison of patients with postviral fatigue syndrome with two control groups. Department of neurology, University of Glasgow, Southern General Hospital; department of psychiatry, St James's Hospital, Dublin. 15 patients with postviral fatigue syndrome, 13 age and sex matched healthy subjects, and 13 patients with primary depression. Serum prolactin concentrations before and one, two, and three hours after administration of buspirone. 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). 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.
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The chronic fatigue syndrome (CFS), formerly known as chronic Epstein-Barr virus syndrome, is a clinical state of some complexity and uncertain etiology. In order to characterize in a comprehensive manner the status of laboratory markers associated with cellular immune function in patients with this syndrome, 30 patients with clinically defined CFS were studied. All of the subjects were found to have multiple abnormalities in these markers. The most consistent immunological abnormality detected among these patients, when compared with normal controls, was low natural killer (NK) cell cytotoxicity. The number of NK cells, as defined by reactivity with monoclonal antibody NKH.1 (CD56), was elevated, but the killing of K562 tumor cells per CD56 cell was significantly diminished. Lymphoproliferative responses after stimulation with phytohemagglutinin and pokeweed mitogen were decreased in most patients when compared with those in normal controls, as was the production of gamma interferon following mitogen stimulation. Lymphocyte phenotypic marker analysis of peripheral blood lymphocytes showed that there were significant differences between patients with CFS and controls. There was an increase in the percentage of suppressor-cytotoxic T lymphocytes, CD8, and a proportionally larger increase in the number of CD8 cells expressing the class II activation marker. Most patients had an elevated number of CD2 cells which expressed the activation marker CDw26. The numbers of CD4 cells and the helper subset of CD4+CD29+ cells in patients with CFS were not different from those in controls. There was, however, a significant decrease in the suppressor inducer subset of CD4+ CD45RA+ cells. The number of B cells, CD20 and CD21, were elevated, as were the numbers of a subset of B cells which coexpressed CD20 and CD5. The patterns of immune marker abnormalities observed was compatible with a chronic viral reactivation syndrome.
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The chronic Epstein-Barr virus syndrome is a poorly defined symptom complex characterized primarily by chronic or recurrent debilitating fatigue and various combinations of other symptoms, including sore throat, lymph node pain and tenderness, headache, myalgia, and arthralgias. Although the syndrome has received recent attention, and has been diagnosed in many patients, the chronic Epstein-Barr virus syndrome has not been defined consistently. Despite the name of the syndrome, both the diagnostic value of Epstein-Barr virus serologic tests and the proposed causal relationship between Epstein-Barr virus infection and patients who have been diagnosed with the chronic Epstein-Barr virus syndrome remain doubtful. We propose a new name for the chronic Epstein-Barr virus syndrome--the chronic fatigue syndrome--that more accurately describes this symptom complex as a syndrome of unknown cause characterized primarily by chronic fatigue. We also present a working definition for the chronic fatigue syndrome designed to improve the comparability and reproducibility of clinical research and epidemiologic studies, and to provide a rational basis for evaluating patients who have chronic fatigue of undetermined cause.
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We present preliminary data on the utility of functional brain imaging with [99mTc]-d,l-HM-PAO and single photon emission computed tomography (SPECT) in the study of patients with dementia of the Alzheimer type (DAT), HIV-related dementia syndrome, and the "on-off" syndrome of Parkinson's disease. In comparison with a group of age-matched controls, the DAT patients revealed distinctive bilateral temporal and posterior parietal deficits, which correlate with detailed psychometric evaluation. Patients with amnesia as the main symptom (group A) showed bilateral mesial temporal lobe perfusion deficits (p less than 0.02). More severely affected patients (group B) with significant apraxia, aphasia, or agnosia exhibited patterns compatible with bilateral reduced perfusion in the posterior parietal cortex, as well as reduced perfusion to both temporal lobes, different from the patients of the control group (p less than 0.05). SPECT studies of HIV patients with no evidence of intracraneal space occupying pathology showed marked perfusion deficits. Patients with Parkinson's disease and the "on-off" syndrome studied during an "on" phase (under levodopa therapy) and on another occasion after withdrawal of levodopa ("off") demonstrated a significant change in the uptake of [99mTc]-d,l-HM-PAO in the caudate nucleus (lower on "off") and thalamus (higher on "off"). These findings justify the present interest in the functional evaluation of the brain of patients with dementia. [99mTc]-d,l-HM-PAO and regional cerebral blood flow (rCBF)/SPECT appear useful and highlight individual disorders of flow in a variety of neuropsychiatric conditions.
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Chronic fatigue syndrome is an illness of unknown origin that begins abruptly with a flulike state and has symptoms suggesting both a chronic viral encephalitis and an affective disorder. We compared single-photon emission computed tomography (SPECT) scans of patients with chronic fatigue syndrome with those of patients with AIDS dementia complex and unipolar depression. We used 99mTc-hexamethylpropyleneamine oxime to examine 45 patients with chronic fatigue syndrome, 27 patients with AIDS dementia complex, and 14 patients with major unipolar depression. Scans of 38 healthy persons were used as controls. Comparison of regional defects between groups, as well as midcerebral uptake indexes (an objective measure of global radionuclide uptake), was performed by using analysis of variance with the Student-Newman-Keuls option. Correlation between the number of regional defects and the midcerebral uptake index was determined by using the Spearman rank-correlation test. Patients with AIDS dementia complex had the largest number of defects (9.15 per patient) and healthy patients had the fewest defects (1.66 per patient). Patients with chronic fatigue syndrome and depression had similar numbers of defects per patient (6.53 and 6.43, respectively). In all groups, defects were located predominantly in the frontal and temporal lobes. The midcerebral uptake index was found to be significantly lower (p < .002) in the patients with chronic fatigue syndrome (.667) and patients with AIDS dementia complex (.650) than in patients with major depression (.731) or healthy control subjects (.716). Also, a significant negative correlation was found between the number of defects and midcerebral uptake index in patients with chronic fatigue syndrome and AIDS dementia complex, but not in depressed patients or control subjects. These findings are consistent with the hypothesis that chronic fatigue syndrome may be due to a chronic viral encephalitis; clinical similarities between chronic fatigue syndrome and depression may be due to a similar distribution and number of defects in the two disorders.
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To determine whether patients with the chronic fatigue syndrome have abnormalities of sleep which may contribute to daytime fatigue. A case-control study of the sleep of patients with the chronic fatigue syndrome and that of healthy volunteers. An infectious disease outpatient clinic and subjects' homes. 12 patients who met research criteria for the chronic fatigue syndrome but not for major depressive disorder and 12 healthy controls matched for age, sex, and weight. Subjective reports of sleep from patients' diaries and measurement of sleep patterns by polysomnography. Subjects' anxiety, depression, and functional impairment were assessed by interview. Patients with the chronic fatigue syndrome spent more time in bed than controls (544 min v 465 min, p < 0.001) but slept less efficiently (90% v 96%, p < 0.05) and spent more time awake after initially going to sleep (31.9 min v 16.6 min, p < 0.05). Seven patients with the chronic fatigue syndrome had a sleep disorder (four had difficulty maintaining sleep, one had difficulty getting to sleep, one had difficulty in both initiating and maintaining sleep, and one had hypersomnia) compared with none of the controls (p = 0.003). Those with sleep disorders showed greater functional impairment than the remaining five patients (score on general health survey 50.4% v 70.4%, p < 0.05), but their psychiatric scores were not significantly different. Most patients with the chronic fatigue syndrome had sleep disorders, which are likely to contribute to daytime fatigue. Sleep disorders may be important in the aetiology of the syndrome.
Article
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.
Article
Many different neurological and psychiatric syndromes follow viral infections, but their clinical pictures and pathogeneses are poorly understood. The syndromes include acute disseminated encephalomyelitis (post-infectious encephalomyelitis), the Guillain-Barre syndrome (post-infectious neuritis) and Reye's syndrome. Recently, attention has been focused on another common postviral neurological syndrome, i.e. the postviral fatigue syndrome (PVFS)--termed myalgic encephalomyelitis (ME) and a host of other designations. PVFS occurs both sporadically and in epidemics, with cases being reported from all over Europe, the United States, Australasia and South Africa. It is difficult to make the diagnosis and this has meant, in the past, that it is not until an epidemic has occurred that random cases which presented in the preceding years are realised to represent the same condition. With renewed interest in the syndrome and greater attention from physicians, however, diagnosis of sporadic cases is now becoming more common.
Article
Clinical, serologic, virologic, and immunologic evaluations for 31 adults with chronic illness and fatigue suggested that 23 had persisting Epstein-Barr virus infection. Among these 23 patients, cellular immune mechanisms were generally normal, but 4 had mild immunoglobulin deficiencies. However, 20 patients had abnormal serologic profiles specific for Epstein-Barr virus shown by significantly elevated titers of antibodies to the viral capsid antigen or early antigen, or by a deficiency of late-appearing antibodies. In 11 of 15 patients tested, circulating immune complexes were found. Circulating interferon was not found in 18 patients tested, but the activity of 2-5 oligoadenylate synthetase, an interferon-induced enzyme, was increased in 5 patients studied. Of 19 patients, 18 had persisting suppressor T-cell activity typically found in patients recovering from acute infectious mononucleosis. We believe that the Epstein-Barr virus may be associated with chronic illness in adults.
Article
76 patients with the postviral fatigue syndrome (PVFS) and 30 matched controls were investigated. Virus isolation was attempted from concentrated faecal samples by direct culture and after acid dissociation of virus from antibody. Positive cultures of enteroviruses were obtained from 17 (22%) patients and 2 (7%) controls. An enterovirus-group-specific monoclonal antibody, 5-D8/1, directed against the VP1 polypeptide, was used to detect enteroviral antigen in the circulation, either free or complexed with antibody. VP1 antigen was detected in the serum of 44 (51%) of a further group of 87 PVFS patients. The number of patients positive for VP1 antigen was greater (42/44) when IgM complexes were detectable than when they were not (2/23). 1 year later, the 17 patients of the first group of 76 with positive cultures were again studied. The same virus was again isolated from 5 (29%), 13 (76%) had detectable IgM responses to enteroviruses, and 9 (53%) were positive for VP1 antigen in the serum. These results show that chronic infection with enteroviruses occurs in many PVFS patients and that detection of enterovirus antigen in the serum is a sensitive and satisfactory method for investigating infection in these patients.
Article
Intracerebral infection of mice with HSV-1 was found to produce a 2-3-fold increase in dopamine and serotonin metabolism in cortex, striatum, diencephalon and brain stem. Neurochemical markers of GABA and acetylcholine neurones, and neurotransmitter receptor binding sites were unchanged. The immunohistochemical distribution of virus antigen revealed high levels of immunoreactivity in s. nigra, ventral tegmental area, locus coeruleus and dorsal raphe nucleus, whilst other areas of brain stem were clear of virus antigen. The changes in monoamine metabolism observed in experimental HSV encephalitis may be related to the concentration of virus in monoamine neurones.
Epidemiology of CFS: the CDC study
  • W J Cunn
  • D B Connel
  • B Randall
Cunn WJ, Connel DB, Randall B. Epidemiology of CFS: the CDC study. In: Kleinman A, Strauss SE, eds. Chronic Fatigue Syndrome. Chichester, Wiley, 1993; Ciba Foundation Symposium no. 173:83-101.
The postviral fatigue syndrome-an analysis of the findings in 50 cases
  • P O Behan
  • Wmh Behan
  • E J Bell
Behan PO, Behan WMH, Bell EJ. The postviral fatigue syndrome-an analysis of the findings in 50 cases. J. Infect 1985; 10:211-22.
Structured Clinical Interview for DSM Ill-R Patient Version (SCID-P 7/1/85)
  • R L Spitzer
  • Jbw Williams
Spitzer RL, Williams JBW. Structured Clinical Interview for DSM Ill-R Patient Version (SCID-P 7/1/85). New York, Biometrics Research Department, Psychiatric Institute, 1985.
Physical assessment of the CE/CGR Neurocam and comparison with a single rotating gamma-camera
  • K Kouris
  • P H Jarritt
  • D C Costa
  • P J Ell
Kouris K, Jarritt PH, Costa DC, Ell PJ. Physical assessment of the CE/CGR Neurocam and comparison with a single rotating gamma-camera. EurJ Nucl Med 1992; 19:236-42.
The effect of ROI size and plane of reconstruction on HMPAO/SPET rCBF studies
  • Costa Dc
  • P H Jarritt
  • P J Ell
Costa Dc, Jarritt PH, Ell PJ. The effect of ROI size and plane of reconstruction on HMPAO/SPET rCBF studies. Nuc Med Commun 1989; 10(4):253.
Brainstem hypoperfusion in patients with Myalgic Encephalomyelitis -Chronic Fatigue Syndrome
  • D C Costa
  • J Brostoff
  • V Douli
  • P J Ell
Costa DC, Brostoff J, Douli V, Ell PJ. Brainstem hypoperfusion in patients with Myalgic Encephalomyelitis -Chronic Fatigue Syndrome. EurJ Nucl Med 1992; 19:733.
  • D Wakefield
  • A Lloyd
Wakefield D, Lloyd A. Pathophysiology of Myalgic Encephalomyelitis. Lancet1987; ii:918-19.
99m Tc-HMPAO SPET in Chronic Fatigue Syndrome
  • A H Troughton
  • R Blacker
  • G Vivian
Troughton AH, Blacker R, Vivian G. 99m Tc-HMPAO SPET in Chronic Fatigue Syndrome. Clin Radiol 1992; 45:59.
Tc-99m HMPAO SPECT in the diagnosis of CFS
  • R B Schwartz
  • B M Garada
  • R Vasile
  • A Komaroff
  • B L Holman
Schwartz RB, Garada BM, Vasile R, Komaroff A, Holman BL. Tc-99m HMPAO SPECT in the diagnosis of CFS. J Nucl Med 1993; 34:47P.