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Brain fog in PoTS and Long COVID: Causes and Management Clinical Senior Lecturer MQ/Versus Arthritis Fellow Brighton and Sussex Medical School : T:@BendyBrain Art credit: Beth Sutton, Scholar and SPFT EBEDisclaimer: learning from autonomic and inflammatory influences on mental fatigue pre COVID • Introduction to Mechanisms of Chronic Pain and Fatigue project • Relevance to Long COVID and potential risk factors • Role of variant connective tissue • Differences in autonomics/inflammation inmental fatigue • Relevance autonomic/inflammation induced fatigue to Long COVID • Potential clues form differences in gene expression, including response to inflammatory challenge in those with mental fatigue • Next steps: to look at brain fog in the brain and under autonomic challenge • Implications for Long COVID managementDesign of the study – Stage I Baseline inflammatory markers: CRP and ESRmyalgia (Pain>Fatigue), Controls ISRCTN78820481Design of the study – Stage II Participants: ME/CFS (Fatigue>Pain), Fibromyalgia (Pain>Fatigue), Controls Cytokines: mRNA transcriptomics and individual cytokines (IL-6) ISRCTN78820481 Results – ClassificaEccles et al 2021 • Of the 65 patients, 32% had received a clinical diagnosis of Fibromyalgia; 38% ME/CFS and 30% both diagnoses FM ME/CFS 30% 32% 38% Results – Classification Eccles et al 2021 • Of the 65 patients, 32% had received a clinical diagnosis of Fibromyalgia; 38% ME/CFS and 30% both diagnoses FM ME/CFS 30% 32% 38% 89% met ACR diagnostic criteria for fibromyalgia 94% Canadian Criteria for ME/CFS 97% Fukada Criteria for ME/CFS Results – Classification Eccles et al 2021 • Of the 65 patients, 32% had received a clinical diagnosis of Fibromyalgia; 38% ME/CFS and 30% both diagnoses Brighton Criteria for JHS: 81% patients and 37.5% healthy controls hEDS Criteria: 18% of patients and FM ME/CFS 8% controls 30% 32% 38% 89% met ACR diagnostic criteria for fibromyalgia 94% Canadian Criteria for ME/CFS 97% Fukada Criteria for ME/CFS Results – Classification Eccles et al 2021 • Of the 65 patients, 32% had received a clinical diagnosis of Fibromyalgia; 38% ME/CFS and 30% both diagnoses Brighton Criteria for JHS: 81% patients and 37.5% healthy controls hEDS Criteria: 18% of patients and 8% controls FM ME/CFS Rarely recognised 30% 32% 38% The historical, rather than current Beighton score correlated with: Fatigue Impact (p=0.028) Total pain reported on the McGill Pain Questionnaire 89% met ACR diagnostic criteria for (short form), (p=0.03) fibromyalgia Widespread Pain Index (derived from ACR diagnostic 94% Canadian Criteria for ME/CFS 97% Fukada Criteria for ME/CFS criteria) (p=0.01) ACR symptom severity ( p=0.01) interoceptive sensibility (p=0.02) Mental Clutter (p=0.043)Markers of baseline inflammation in ME/CFS and fibromyalgia • Traditionally thought that ME/CFS and fibromyalgia non-inflammatory ESR CRP There was a higher ESR in patients (mean: There was a difference in CRP between patients (mean: 13.20, SEM: 1.45, n=59) compared to 3.73, SEM: 0.53, n=60) compared to controls (mean: 1.26, controls (5.83, SEM: 1.24, n=23). Mann- SEM: 0.157, n=23). Mann-Whitney (MWU 991, Wilcoxon Whitney (MWU 1015.5, Wilcoxon W= W= 2821, p=0.001) 2785.5, p= 0.000)Markers of baseline inflammation in ME/CFS and fibromyalgia • Traditionally thought that ME/CFS and fibromyalgia non-inflammatory • Adjusting BMI, age and gender • ESR significantly predicts fatigue severity and pain level including cog fatigue and mental clutter • CRP significantly predicts fatigue severity and pain level • ESR mediates relationship between being and patient and cog fatigue impact (MFIS) at restAutonomic induced change in pain and fatigue Pain level (VAS) Fatigue level (VAS) induced by tilt, induced by tilt, p<0.001 p=0.005 No change in pain sensitivity (PPT) induced by tilt Autonomic induced change in pain and fatigue - mechanisms Joint Hypermobility b=0.129, p=.001 b=23.135, p=.085 Fibromyalgia Tilt induced pain ME/CFS Direct effect, b=7.383, p=.095 Indirect effect, b=2.989, 95% CI [0.16, 6.82] ESR p=.0093, p=.018, Fibromyalgia ME/CFS Tilt induced fatigue Eccles et al., in prep 22 Direct effect, b=5.694, p=.250 Similar findings inflamm Indirect effect, b=3.624, 95% CI [0.75, 7.39] induced pain/fatigueDifferentially expressed genes at baseline between patients and controls Total genes differentially expressed = 242 compared to controlsy upregulated genes in patients 12.40% Differentially downregulated genes in patients 30 compared to controls 212 Differentially expressed genes at baseline between patients and controls Total genes differentially expressed = 242 87.60% Differentially upregulated genes in patients compared to controls compared to controlsy downregulated genes in patients 30 212 Differentially expressed genes at baseline between patients and controls Total genes differentially expressed = 242 87.60% Differentially upregulated genes in patients compared to controls compared to controlsy downregulated genes in patients 30 Upregulated in patients due to inflammatory challenge 212 Amato et al., in prep 22Next steps – multi modal neural correlates of brain fog in PoTS to quantify relationship with cerebro-profusionImplications for management of brain fog in Long COVID and related conditionsThanks • Marisa Amato and Dr Charlie Thompson • The funders • All of the participants and research staff • Sussex ME/CFS Society • ReMEmber • CISC @ Brighton and Sussex Medical School • CIRU @BSUH • Beth Thompson • Dr Kristy Themelis • Prof Kevin Davies • Prof Neil Harrison • Prof Hugo Critchley