Downloaded from http://jim.bmj.com/ on April 7, 2017 - Published by group.bmj.com Original research CNS findings in chronic fatigue syndrome and a neuropathological case report Kimberly Ferrero,1 Mitchell Silver,1 Alan Cocchetto,2 Eliezer Masliah,3 Dianne Langford1 1Lewis Katz School of ABSTRACT Medicine at Temple Chronic fatigue syndrome (CFS) is characterized as a Significance of this study University, Philadelphia, Pennsylvania, USA persistent, debilitating complex disorder of unknown 2State University of etiology, whereby patients suffer from extreme New York at Alfred, fatigue, which often presents with symptoms that What is already known about this Engineering Technologies, include chronic pain, depression, weakness, mood subject? Alfred, New York, USA disturbances, and neuropsychological impairment. In ▸ 3University of California San Chronic fatigue syndrome (CFS) is 6 months Diego, La Jolla, California, this mini review and case report, we address central or more of persistent cognitive and physical USA nervous system (CNS) involvement of CFS and fatigue, with brain-related symptoms present neuropathological autopsy findings from a varying among patients Correspondence to patient who died with a prior diagnosis of CFS. ▸ CFS is classified as a neurological disorder Dianne Langford, Lewis Katz School of Medicine at Among the most remarkable pathological features of and increasing evidence supports CFS as a Temple University, the case are focal areas of white matter loss, neurite disease of the nervous and immune 3500 North Broad Street, beading, and neuritic pathology of axons in the systems MERB 750, Philadelphia, white matter with axonal spheroids. Atypical ▸ In the central nervous system (CNS), CFS PA 19140, USA; neurons displaying aberrant sprouting processes in [email protected] may be triggered by exposure to response to injury are observed throughout cortical radionuclides, viral or microbial infection, Accepted 14 March 2017 gray and white matter. Abundant amyloid deposits seizure, trauma, genetic mutations and/or Copyright © 2017 American identical to AD plaques with accompanying other factors. intracellular granular structures are observed as well. Federation for Medical fi Research Neurofibrillary tangles are also present in the white What are the new ndings? matter of the frontal cortex, thalamus and basal ▸ Neuropathological autopsy findings from a ganglia. Taken together, these neuropathological patient who died with a prior diagnosis of findings warrant further studies into CNS disease CFS report focal areas of white matter loss, associated with CFS. neurite beading, and neuritic pathology of axons in the white matter with axonal spheroids. ▸ Atypical neurons displaying aberrant CNSFINDINGSINCFS sprouting processes in response to injury A central theme in chronic fatigue syndrome are observed throughout cortical gray and (CFS), as the name implies, is a chronic state of white matter. Abundant amyloid deposits energy deficit experienced by patients. CFS is identical to AD plaques with accompanying defined as 6 months or more of persistent cog- intracellular granular structures are nitive and physical fatigue, with brain-related observed as well. ▸ fi symptoms varying among patients. Along with Neuro brillary tangles are also present in headache or vision problems, patients with CFS the white matter of the frontal cortex, may experience cognitive and behavioral altera- thalamus and basal ganglia. 1 tions. An excellent review by Ocon describes How might these results change the the ‘brain fog’ associated with CFS as slow fi focus of research or clinical practice? thinking, dif culty focusing, lack of concentra- ▸ Taken together, these neuropathological tion, forgetfulness or haziness in thought pro- findings warrant further studies into CNS fl cesses. Clinically, reduced cerebral blood ow, disease associated with CFS. increased activity in cortical/subcortical activa- tion during mental tasks, deficits in processing information, impaired attention, and working memory are reported.1 In the central nervous may contribute to CNS disturbances in patients system (CNS), the onset of CFS may be trig- with CFS. For a more comprehensive review of To cite: Ferrero K, gered by deleterious factors such as exposure to CNS involvement, please see Fischer et al.2 We Silver M, Cocchetto A, radionuclides, viral or microbial infection, will also present neuropathological findings et al. J Investig Med Published Online First: seizure, trauma, genetic mutations and/or other from a recent case study that illustrate vascular [please include Day factors. This manuscript will present a survey pathology, demyelination in focal areas and Month Year] doi:10.1136/ of literature reporting CNS abnormalities and diffuse reactive astrogliosis, as well as the jim-2016-000390 studies related to potential mechanisms that presence of Aβ plaques and axonal and Ferrero K, et al. J Investig Med 2017;0:1–10. doi:10.1136/jim-2016-000390 1 Copyright 2017 by American Federation for Medical Research (AFMR). Downloaded from http://jim.bmj.com/ on April 7, 2017 - Published by group.bmj.com Original research neurofibrillary pathology. Robust tauopathy was also correlated with severity of the fatigue state.28 In other observed, with evidence of aberrant sprouting and the studies, fMRI was used to determine the association presence of abundant Aβ+ plaques in frontal cortex white between BOLD brain responses and mental fatigue as matter. determined by a variety of mood state tests including the Although the etiology and pathogenesis of CFS have not State-Trait Anxiety Inventory, the Beck Depression been fully elucidated, the WHO classifies CFS as a neuro- Inventory and visual analog scales.15 Results showed that logical disorder (IDC10 (international statistical classification mental fatigue tasks caused changes in brain activity in CFS of disease and health related problems), G93.3) and increas- participants compared with controls. Specifically, observed ing evidence supports CFS as a disease of the nervous and changes included positive correlations in cerebellar, tem- immune systems.3 In fact, as early as 1959, Acheson4 poral, cingulate and frontal regions, with negative correla- described the clinical syndrome as having cerebral damage. tions in the left posterior parietal cortex.15 Similar studies Among the most striking evidence supporting CNS involve- with BOLD fMRI analyses indicated that during working ment are hundreds of imaging studies that point to brain memory tasks, patients with CFS process challenging audi- abnormalities in patients with CFS. Neuroanatomically, tory information as accurately as controls, but exerted – reductions in gray and white matter are reported.2510 greater effort to process the information than controls.16 In Neural perfusion impairments have also been reported in fact, other studies reported reduced blood flow in middle – some, but not all, patients with CFS.21114 Several studies cerebral arteries in patients with CFS compared with con- used blood oxygen level-dependent functional MRI (BOLD trols.29 fMRI studies have also reported decreased basal fMRI) and reported abnormal activities in patients with CFS ganglia activity in patients with CFS compared with compared with control participants.271516Among the chief normal controls during a reward processing task.30 From neurocognitive alterations in CFS are poor concentration, these studies, it appears that patients with CFS have attenu- short-term memory loss, word-finding inability, delayed ated task-driven activity levels compared with normal con- information processing and reaction times, and short atten- trols and may be required to expend more energy to tion span.17 Conflicting reports exist as to whether these defi- complete mental tasks than control participants. ciencies are distinguishable from those observed in Metabolic system dysfunction has long been proposed to depression, or whether they correlate with fatigue sever- contribute to CFS31 and imaging studies support these – ity.21720 Finally, as described in a review by Fischer et al, hypotheses. Studies by Shungu et al32 reported elevated neurochemical abnormalities in CFS include hypothalamic ventricular lactate, decreased cortical glutathione, and – pituitary axis disruptions.21 27 While it is well beyond the lower regional cerebral blood flow, which taken together scope of this survey to address all previous studies, we wish point to increased oxidative stress as a potential contributor to highlight some of these studies that illustrate CNS involve- to CFS. Normal fatigue involves increases in blood levels ment in CFS. of tryptophan, the amino acid precursor of 5-HT.33 In Numerous neuroanatomical imaging studies have shown turn, brain levels of 5-HT increase, leading to the feeling volumetric changes in patients with CFS (for a review, see of fatigue. In studies with patients with CFS, increased ref. 5). For example, a voxel-based morphometric study by levels of 5-HIAA, the breakdown product of 5-HT, were Okada et al6 reported significantly reduced gray matter observed in cerebrospinal fluid of patients with CFS. This volume in the bilateral prefrontal cortex of patients with suggests that patients with CFS experience an increased CFS compared with normal controls. Conversely, another central turnover of 5-HT in the CNS.34 Recently, Cleare study reported an 8% reduction in gray matter; however, et al35 reported decreased 5-HT 1A receptor expression or regional focal loss was not observed.7 Other studies affinity in the brains