Tag: dysautonomia

Long COVID and hypermobility spectrum disorders have shared pathophysiology

Abstract:

Hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) are the most common joint hypermobility conditions encountered by physicians, with hypermobile and classical EDS accounting for >90% of all cases. Hypermobility has been detected in up to 30-57% of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, postural orthostatic tachycardia syndrome (POTS), and long COVID (LC) compared to the general population.

Extrapulmonary symptoms, including musculoskeletal pain, dysautonomia disorders, cognitive disorders, and fatigue, are seen in both LC and HSD. Additionally, ME/CFS has overlapping symptoms with those seen in HSD. Mast cell activation and degranulation occurring in both LC and ME/CFS may result in hyperinflammation and damage to connective tissue in these patients, thereby inducing hypermobility.

Persistent inflammation may result in the development or worsening of HSD. Hence, screening for hypermobility and other related conditions including fibromyalgia, POTS, ME/CFS, chronic pain conditions, joint pain, and myalgia is essential for individuals experiencing LC. Pharmacological treatments should be symptom-focused and geared to a patient’s presentation. Paced exercise, massage, yoga, and meditation may also provide benefits.

Source: Ganesh R, Munipalli B. Long COVID and hypermobility spectrum disorders have shared pathophysiology. Front Neurol. 2024 Sep 5;15:1455498. doi: 10.3389/fneur.2024.1455498. PMID: 39301475; PMCID: PMC11410636. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410636/ (Full text)

Long COVID Is Not a Functional Neurologic Disorder

Abstract:

Long COVID is a common sequela of SARS-CoV-2 infection. Data from numerous scientific studies indicate that long COVID involves a complex interaction between pathophysiological processes. Long COVID may involve the development of new diagnosable health conditions and exacerbation of pre-existing health conditions. However, despite this rapidly accumulating body of evidence regarding the pathobiology of long COVID, psychogenic and functional interpretations of the illness presentation continue to be endorsed by some healthcare professionals, creating confusion and inappropriate diagnostic and therapeutic pathways for people living with long COVID.

The purpose of this perspective is to present a clinical and scientific rationale for why long COVID should not be considered as a functional neurologic disorder. It will begin by discussing the parallel historical development of pathobiological and psychosomatic/sociogenic diagnostic constructs arising from a common root in neurasthenia, which has resulted in the collective understandings of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and functional neurologic disorder (FND), respectively. We will also review the case definition criteria for FND and the distinguishing clinical and neuroimaging findings in FND vs. long COVID.

We conclude that considering long COVID as FND is inappropriate based on differentiating pathophysiologic mechanisms and distinguishing clinical findings.

Source: Davenport TE, Blitshteyn S, Clague-Baker N, Davies-Payne D, Treisman GJ, Tyson SF. Long COVID Is Not a Functional Neurologic Disorder. J Pers Med. 2024 Jul 29;14(8):799. doi: 10.3390/jpm14080799. PMID: 39201991. https://www.mdpi.com/2075-4426/14/8/799 (Full text)

Designing and optimizing clinical trials for long COVID

Abstract:

Long COVID is a debilitating, multisystemic illness following a SARS-CoV-2 infection whose duration may be indefinite. Over four years into the pandemic, little knowledge has been generated from clinical trials. We analyzed the information available on ClinicalTrials.gov, and found that the rigor and focus of trials vary widely, and that the majority test non-pharmacological interventions with insufficient evidence.

We highlight promising trials underway, and encourage the proliferation of clinical trials for treating Long COVID and other infection-associated chronic conditions and illnesses (IACCIs). We recommend several guidelines for Long COVID trials: First, pharmaceutical trials with potentially curative, primary interventions should be prioritized, and both drug repurposing and new drug development should be pursued.

Second, study designs should be both rigorous and accessible, e.g., triple-blinded randomized trials that can be conducted remotely, without participants needing to leave their homes.

Third, studies should have multiple illness comparator cohorts for IACCIs such as myalgic encephalomyelitis (ME/CFS) and dysautonomia, and screen for the full spectrum of symptomatology and pathologies of these illnesses.

Fourth, studies should consider inclusion/exclusion criteria with an eye towards equity and breadth of representation, including participants of all races, ethnicities, and genders most impacted by COVID-19, and including all levels of illness severity.

Fifth, involving patient-researchers in all aspects of studies brings immensely valuable perspectives that will increase the impact of trials. We also encourage the development of efficient clinical trial designs including methods to study several therapies in parallel.

Source: Vogel JM, Pollack B, Spier E, McCorkell L, Jaudon TW, Fitzgerald M, Davis H, Cohen AK. Designing and optimizing clinical trials for long COVID. Life Sci. 2024 Aug 13;355:122970. doi: 10.1016/j.lfs.2024.122970. Epub ahead of print. PMID: 39142505. https://www.sciencedirect.com/science/article/pii/S0024320524005605 (Full text)

Clinical and Diagnostic Features of Post-Acute COVID-19 Vaccination Syndrome (PACVS)

Abstract:

Post-acute COVID-19 vaccination syndrome (PACVS) is a chronic disease triggered by SARS-CoV-2 vaccination (estimated prevalence 0.02%). PACVS is discriminated from the normal post-vaccination state by altered receptor antibodies, most notably angiotensin II type 1 and alpha-2B adrenergic receptor antibodies. Here, we investigate the clinical phenotype using a study registry encompassing 191 PACVS-affected persons (159 females/32 males; median ages: 39/42 years).

Unbiased clustering (modified Jaccard index) of reported symptoms revealed a prevalent cross-cohort symptomatology of malaise and chronic fatigue (>80% of cases). Overlapping clusters of (i) peripheral nerve dysfunction, dysesthesia, motor weakness, pain, and vasomotor dysfunction; (ii) cardiovascular impairment; and (iii) cognitive impairment, headache, and visual and acoustic dysfunctions were also frequently represented.

Notable abnormalities of standard serum markers encompassing increased interleukins 6 and 8 (>80%), low free tri-iodine thyroxine (>80%), IgG subclass imbalances (>50%), impaired iron storage (>50%), and increased soluble neurofilament light chains (>30%) were not associated with specific symptoms.

Based on these data, 131/191 participants fit myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and simultaneously also several other established dysautonomia syndromes. Furthermore, 31/191 participants fit none of these syndromes. In conclusion, PACVS could either be an outlier of ME/CFS or a dysautonomia syndrome sui generis.

Source: Mundorf AK, Semmler A, Heidecke H, Schott M, Steffen F, Bittner S, Lackner KJ, Schulze-Bosse K, Pawlitzki M, Meuth SG, Klawonn F, Ruhrländer J, Boege F. Clinical and Diagnostic Features of Post-Acute COVID-19 Vaccination Syndrome (PACVS). Vaccines (Basel). 2024 Jul 18;12(7):790. doi: 10.3390/vaccines12070790. PMID: 39066428; PMCID: PMC11281408. Mundorf AK, Semmler A, Heidecke H, Schott M, Steffen F, Bittner S, Lackner KJ, Schulze-Bosse K, Pawlitzki M, Meuth SG, Klawonn F, Ruhrländer J, Boege F. Clinical and Diagnostic Features of Post-Acute COVID-19 Vaccination Syndrome (PACVS). Vaccines (Basel). 2024 Jul 18;12(7):790. doi: 10.3390/vaccines12070790. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11281408/ (Full text)

Plasma Neurofilament Light Chain: A Potential Biomarker for Neurological Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by heterogeneous symptoms, which lack specific biomarkers for its diagnosis. This study aimed to investigate plasma neurofilament light chain (NfL) levels as a potential biomarker for ME/CFS and explore associations with cognitive, autonomic, and neuropathic symptoms.

Here, 67 ME/CFS patients and 43 healthy controls (HCs) underwent comprehensive assessments, including neuropsychological evaluation, autonomic nervous system (ANS) testing, and plasma NfL level analysis. ME/CFS patients exhibited significantly higher plasma NfL levels compared to HC (F = 4.30, p < 0.05). Correlations were observed between NfL levels and cognitive impairment, particularly in visuospatial perception (r = -0.42; p ≤ 0.001), verbal memory (r = -0.35, p ≤ 0.005), and visual memory (r = -0.26; p < 0.05) in ME/CFS. Additionally, higher NfL levels were associated with worsened autonomic dysfunction in these patients, specifically in parasympathetic function (F = 9.48, p ≤ 0.003).

In ME/CFS patients, NfL levels explained up to 17.2% of the results in cognitive tests. Unlike ME/CFS, in HC, NfL levels did not predict cognitive performance. Elevated plasma NfL levels in ME/CFS patients reflect neuroaxonal damage, contributing to cognitive dysfunction and autonomic impairment.

These findings support the potential role of NfL as a biomarker for neurological dysfunction in ME/CFS. Further research is warranted to elucidate underlying mechanisms and clinical implications.

Source: Azcue N, Tijero-Merino B, Acera M, Pérez-Garay R, Fernández-Valle T, Ayo-Mentxakatorre N, Ruiz-López M, Lafuente JV, Gómez Esteban JC, Del Pino R. Plasma Neurofilament Light Chain: A Potential Biomarker for Neurological Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomedicines. 2024 Jul 11;12(7):1539. doi: 10.3390/biomedicines12071539. PMID: 39062112; PMCID: PMC11274366. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11274366/ (Full text)

Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations

Abstract:

Background: Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.

Methods: Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case–control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.

Results: Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V˙e, V˙O2, V˙CO2, V˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V˙e/V˙CO2, PetCO2, O2pulse, work, V˙O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.

Conclusions: Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.

Trial registration number: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

Source: Keller, B., Receno, C.N., Franconi, C.J. et al. Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations. J Transl Med 22, 627 (2024). https://doi.org/10.1186/s12967-024-05410-5 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05410-5#Abs1 (Full text)

 

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available.

Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease’s multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances.

This comprehensive model not only advances our understanding of ME/CFS’s pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease’s complexity and the multifaceted approach required for its study and management.

Source: Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol. 2024 Jun 3;15:1386607. doi: 10.3389/fimmu.2024.1386607. PMID: 38887284; PMCID: PMC11180809. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180809/ (Full text)

Long-COVID autonomic syndrome in working age and work ability impairment

Abstract:

Long-COVID19 has been recently associated with long-sick leave and unemployment. The autonomic nervous system functioning may be also affected by SARS-CoV-2, leading to a chronic autonomic syndrome. This latter remains widely unrecognized in clinical practice. In the present study, we assessed the occurrence of Long-COVID19 Autonomic Syndrome in a group of active workers as well as the relationships between their autonomic dysfunction and work ability.

This prospective observational study was conducted during the 2nd wave of the pandemic in Italy. Forty-five patients (53.6 ± 8.4 years; 32 M) hospitalized for COVID19, were consecutively enrolled at the time of their hospital discharge (T0) and followed-up for 6 months. Autonomic symptoms and work ability were assessed by COMPASS31 and Work Ability Index questionnaires at T0, one (T1), three and six (T6) months after hospital discharge and compared to those retrospectively collected for a period preceding SARS-CoV-2 infection. Clinical examination and standing test were also performed at T1 and T6.

One in three working-age people developed a new autonomic syndrome that was still evident 6 months after the acute infection resolution. This was associated with a significant reduction in the work ability. Recognition of Long-COVID19 Autonomic Syndrome may promote early intervention to facilitate return to work and prevent unemployment.

Source: Rinaldi L, Rigo S, Pani M, Bisoglio A, Khalaf K, Minonzio M, Shiffer D, Romeo MA, Verzeletti P, Ciccarelli M, Bordoni MG, Stranges S, Riboli E, Furlan R, Barbic F. Long-COVID autonomic syndrome in working age and work ability impairment. Sci Rep. 2024 May 23;14(1):11835. doi: 10.1038/s41598-024-61455-y. PMID: 38782998; PMCID: PMC11116376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11116376/ (Full text)

Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19

Abstract:

Objectives: To report a case-control study of new-onset small fiber neuropathy (SFN) after COVID-19 with invasive cardiopulmonary exercise testing (iCPET). SFN is a critical objective finding in long COVID and amenable to treatment.

Methods: A retrospective chart review was conducted on patients seen in the NeuroCOVID Clinic at Yale who developed new-onset SFN after a documented COVID-19 illness. We collected demographics, symptoms, skin biopsy, iCPET testing, treatments, and clinical response to treatment or no intervention.

Results: Sixteen patients were diagnosed with SFN on skin biopsy (median age 47, 75% female, 75% White). 92% of patients reported postexertional malaise characteristic of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and 7 patients underwent iCPET, which demonstrated neurovascular dysregulation and dysautonomia consistent with ME/CFS. Nine patients underwent treatment with IVIG, and 7 were not treated with IVIG. The IVIG group experienced significant clinical response in their neuropathic symptoms (9/9) compared with those who did not receive IVIG (3/7; p = 0.02).

Discussion: Here, we present preliminary evidence that after COVID-19, SFN is responsive to treatment with IVIG and linked with neurovascular dysregulation and dysautonomia on iCPET. A larger clinical trial is indicated to further demonstrate the clinical utility of IVIG in treating postinfectious SFN.

Classification of evidence: This study provides Class III evidence. It is a retrospective cohort study.

Source: McAlpine L, Zubair AS, Joseph P, Spudich S. Case-Control Study of Individuals With Small Fiber Neuropathy After COVID-19. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3):e200244. doi: 10.1212/NXI.0000000000200244. Epub 2024 Apr 17. PMID: 38630952. https://www.neurology.org/doi/10.1212/NXI.0000000000200244 (Full text)

Impaired Hand Grip Strength Correlates with Greater Disability and Symptom Severity in Post-COVID Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Post-COVID syndrome (PCS) encompasses a diverse array of symptoms persisting beyond 3 months after acute SARS-CoV-2 infection, with mental as well as physical fatigue being the most frequent manifestations.
Methods: In 144 female patients with PCS, hand grip strength (HGS) parameters were assessed as an objective measure of muscle fatigue, with 78 meeting the Canadian Consensus Criteria for postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The severity of disability and key symptoms was evaluated using self-reported questionnaires.
Results: Patients with ME/CFS exhibited heightened overall symptom severity, including lower physical function (p < 0.001), a greater degree of disability (p < 0.001), more severe fatigue (p < 0.001), postexertional malaise (p < 0.001), and autonomic dysfunction (p = 0.004) compared to other patients with PCS. While HGS was impaired similarly in all patients with PCS and exhibited a significant correlation with physical function across the entire patient group, HGS of patients with ME/CFS uniquely demonstrated associations with key symptoms.
Conclusions: Thus, impaired HGS serves as an objective marker of physical function in patients with PCS. Only in patients meeting ME/CFS criteria is impaired HGS also associated with the severity of hallmark symptoms. This suggests a common mechanism for muscle fatigue and other symptoms in the ME/CFS subtype, distinct from that in other types of PCS.
Source: Paffrath A, Kim L, Kedor C, Stein E, Rust R, Freitag H, Hoppmann U, Hanitsch LG, Bellmann-Strobl J, Wittke K, et al. Impaired Hand Grip Strength Correlates with Greater Disability and Symptom Severity in Post-COVID Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Clinical Medicine. 2024; 13(7):2153. https://doi.org/10.3390/jcm13072153 https://www.mdpi.com/2077-0383/13/7/2153