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Tag: dysautonomia
Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms.
These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.
Source: James N. Baraniuk. Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM) Brain Sci. 2022, 12(2), 132; https://doi.org/10.3390/brainsci12020132 (registering DOI) https://www.mdpi.com/2076-3425/12/2/132/htm (Full text)
Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC)
Abstract:
Objective: To describe cerebrovascular, neuropathic and autonomic features of post-acute sequelae of COVID-19 (PASC).
Methods: This retrospective study evaluated consecutive patients with chronic fatigue, brain fog and orthostatic intolerance consistent with PASC. Controls included postural tachycardia syndrome patients (POTS) and healthy participants. Analyzed data included surveys and autonomic (Valsalva maneuver, deep breathing, sudomotor and tilt tests), cerebrovascular (cerebral blood flow velocity (CBFv) monitoring in middle cerebral artery), respiratory (capnography monitoring) and neuropathic (skin biopsies for assessment of small fiber neuropathy) testing and inflammatory/autoimmune markers.
Results: Nine PASC patients were evaluated 0.7±0.3 years after a mild COVID-19 infection, treated as home observations. Autonomic, pain, brain fog, fatigue and dyspnea surveys were abnormal in PASC and POTS (n=10), compared to controls (n=15). Tilt table test reproduced the majority of PASC symptoms. Orthostatic CBFv declined in PASC (-20.0±13.4%) and POTS (-20.3±15.1%), compared to controls (-3.0±7.5%,p=0.001) and was independent of end-tidal carbon dioxide in PASC, but caused by hyperventilation in POTS. Reduced orthostatic CBFv in PASC included both subjects without (n=6) and with (n=3) orthostatic tachycardia. Dysautonomia was frequent (100% in both PASC and POTS) but was milder in PASC (p=0.013). PASC and POTS cohorts diverged in frequency of small fiber neuropathy (89% vs. 60%) but not in inflammatory markers (67% vs. 70%). Supine and orthostatic hypocapnia was observed in PASC.
Interpretation: PASC following mild COVID-19 infection is associated with multisystem involvement including: 1) cerebrovascular dysregulation with persistent cerebral arteriolar vasoconstriction; 2) small fiber neuropathy and related dysautonomia; 3) respiratory dysregulation; 4) chronic inflammation.
Source: Novak P, Mukerji SS, Alabsi HS, Systrom D, Marciano SP, Felsenstein D, Mullally WJ, Pilgrim DM. Multisystem Involvement in Post-acute Sequelae of COVID-19 (PASC). Ann Neurol. 2021 Dec 24. doi: 10.1002/ana.26286. Epub ahead of print. PMID: 34952975. https://pubmed.ncbi.nlm.nih.gov/34952975/
Stellate ganglion block reduces symptoms of Long COVID: A case series
Abstract:
After recovering from COVID-19, a significant proportion of symptomatic and asymptomatic individuals develop Long COVID. Fatigue, orthostatic intolerance, brain fog, anosmia, and ageusia/dysgeusia in Long COVID resemble “sickness behavior,” the autonomic nervous system response to pro-inflammatory cytokines (Dantzer et al., 2008). Aberrant network adaptation to sympathetic/parasympathetic imbalance is expected to produce long-standing dysautonomia. Cervical sympathetic chain activity can be blocked with local anesthetic, allowing the regional autonomic nervous system to “reboot.” In this case series, we successfully treated two Long COVID patients using stellate ganglion block, implicating dysautonomia in the pathophysiology of Long COVID and suggesting a novel treatment.
Source: Liu LD, Duricka DL. Stellate ganglion block reduces symptoms of Long COVID: A case series. J Neuroimmunol. 2021 Dec 8;362:577784. doi: 10.1016/j.jneuroim.2021.577784. Epub ahead of print. PMID: 34922127. https://www.jni-journal.com/article/S0165-5728(21)00311-8/fulltext (Full text)
Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Abstract:
Although autonomic nervous system (ANS) dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) has been proposed, conflicting evidence makes it difficult to draw firm conclusions regarding ANS activity at rest in ME/CFS patients. Although severe exercise intolerance is one of the core features of ME/CFS, little attempts have been made to study ANS responses to physical exercise. Therefore, impairments in ANS activation at rest and following exercise were examined using a case-control study in 20 ME/CFS patients and 20 healthy people.
Different autonomous variables, including cardiac, respiratory, and electrodermal responses were assessed at rest and following an acute exercise bout. At rest, parameters in the time-domain represented normal autonomic function in ME/CFS, while frequency-domain parameters indicated the possible presence of diminished (para)sympathetic activation. Reduced parasympathetic reactivation during recovery from exercise was observed in ME/CFS.
This is the first study showing reduced parasympathetic reactivation during recovery from physical exercise in ME/CFS. Delayed HR recovery and/or a reduced HRV as seen in ME/CFS have been associated with poor disease prognosis, high risk for adverse cardiac events, and morbidity in other pathologies, implying that future studies should examine whether this is also the case in ME/CFS and how to safely improve HR recovery in this population.
Source: Van Oosterwijck J, Marusic U, De Wandele I, Meeus M, Paul L, Lambrecht L, Moorkens G, Danneels L, Nijs J. Reduced Parasympathetic Reactivation during Recovery from Exercise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Clin Med. 2021 Sep 30;10(19):4527. doi: 10.3390/jcm10194527. PMID: 34640544; PMCID: PMC8509376. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509376/ (Full text)
Autonomic dysfunction post-acute COVID-19 infection
Introduction:
SARS-CoV-2 infection which causes the disease COVID-19 is most known for its severe respiratory complications. However, a variety of extrapulmonary effects have since been described, with cardiovascular complications being amongst the most common [ 1 ]. Those who recover from the acute phase of COVID-19 may be left with residual symptoms such as chest pain and dyspnea, resulting in a decreased quality of life and a syndrome sometimes described as “long COVID”[ 2 ].
Recent evidence suggests that survivors with some of these chronic symptoms may have autonomic dysfunction with features of postural orthostatic tachycardia syndrome (POTS) and/or inappropriate sinus tachycardia (IST)3 , 4. POTS is characterized by symptoms that occur with standing, an increase in heart rate of ≥30 beats per minute (or heart rate >120 bpm) when moving from a supine to a standing position, and the absence of orthostatic hypotension[ 5 ]. IST is defined as a sinus heart rate >100 beats per minute at rest without an identifiable cause of sinus tachycardia[ 6 ]. Cardiac manifestations of autonomic dysfunction lie on a wide spectrum and can therefore be classified as either POTS, IST, or other unspecified symptoms such as tachycardia and palpitations without a clear, single underlying pathological mechanism.[ 7 ]
The treatment of these arrhythmias includes nonpharmacologic management, such as increasing salt and fluid intake, as well as the use of oral medications. Beta-blockers or off label use of ivabradine have used reported to be used in both syndromes with the goal of controlling heart rate to reduce the symptoms 8 , 9. Other therapies more common in POTS include fludrocortisone, midodrine, pyridostigmine, and alpha-2 agonists[ 8 ].
There is a need to understand the patient characteristics and risk factors for developing AD as a sequela of COVID-19. Furthermore, there is limited management information specific to patients suffering from AD following COVID-19. It is unclear how treatment of these patients and their prognoses may differ from other cases of POTS or IST. In this study, we investigated a small cohort of patients diagnosed with suspected AD post SARS-CoV-2 infection to elucidate possible risk factors and treatment strategies in this population.
Source: Desai AD, Boursiquot BC, Moore CJ, Gopinathannair R, Waase MP, Rubin GA, Wan EY. Autonomic dysfunction post-acute COVID-19 infection. HeartRhythm Case Rep. 2021 Nov 27. doi: 10.1016/j.hrcr.2021.11.019. Epub ahead of print. PMID: 34868880; PMCID: PMC8626157. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626157/ (Full text)
Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form
Abstract:
Post COVID-19 Syndrome (PCS) is a complex of various symptoms developing a month or more after the acute phase of the disease. The cases of PCS development among patients with asymptomatic/mild forms are frequently reported; however, the pathogenesis of PCS in this group of patients is still not completely clear. The publications about COVID-19 which were published in online databases from December 2019 to September 2021 are analyzed in this review. According to the analysis, PCS develops on average in 30-60% of patients, mainly among women. Fatigue, shortness of breath, cough, and anosmia were reported as the most common symptoms. The possible association between the described PCS symptoms and brain damage was revealed.
We assume the possibility of an alternative course of COVID-19, which develops in genetically predisposed individuals with a stronger immune response, in which it predominantly affects the cells of the nervous system, possibly with the presence of an autoimmune component, which might have similarity with chronic fatigue syndrome or autoimmune disautonomia. Thus, the gender (female) and the presence of anosmia during an asymptomatic or mild course of the disease can be predictive factors for the development of PCS, which can be caused by autoimmune damage to neurons, glia, and cerebral vessels.
Source: Malkova A, Kudryavtsev I, Starshinova A, Kudlay D, Zinchenko Y, Glushkova A, Yablonskiy P, Shoenfeld Y. Post COVID-19 Syndrome in Patients with Asymptomatic/Mild Form. Pathogens. 2021 Oct 30;10(11):1408. doi: 10.3390/pathogens10111408. PMID: 34832564. https://pubmed.ncbi.nlm.nih.gov/34832564/
Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection
Introduction: Long-term COVID symptoms marked by autonomic dysfunction1 and cardiac damage2 following COVID-19 infection have been noted for up to 6 months after symptom onset,3 but to date have not been quantified, to our knowledge. Previous studies have found that wearable data can improve real-time detection of viral illness4 or discrimination of individuals with COVID-19 vs other viral infections.5 Wearable devices provide a way to continuously track an individual’s physiological and behavioral metrics beginning when healthy (ie, before infection), during the course of infection, and recovery back to baseline. In this cohort study, we aimed to examine the duration and variation of recovery among COVID-19–positive vs COVID-19–negative participants.
Methods: DETECT (Digital Engagement and Tracking for Early Control and Treatment) is a remote, app-based, longitudinal research study enrolling adult participants from all over the US and collecting their wearable data to better understand individual changes associated with viral illness, including COVID-19. All participants provided informed consent electronically. The protocol for this study was reviewed and approved by the Scripps Office for the Protection of Research Subjects. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
From March 25, 2020, through January 24, 2021, 37 146 participants were enrolled. This analysis focuses on 875 individuals who reported symptoms of an acute respiratory illness and underwent swab testing for COVID-19 and were found to be either positive (234 individuals) or negative (641 individuals) (eFigure in the Supplement).
The following calculation was used for resting heart rate (RHR): deviation from baseline = daily RHR − baseline RHR mean. Individuals with COVID-19 were also grouped by their mean RHR deviation from baseline 28 to 56 days after symptom onset (<1, 1-5, or >5 beats per minute).
Data analysis was conducted in SAS statistical software version 9.4 (SAS Institute). Significance was set at P < .05. P values were calculated with 1-way ANOVA (for mean age) or χ2 tests. Additional details about our methods can be found in the eAppendix in the Supplement.
Results: For this analysis, our study population consisted of 234 COVID-19–positive individuals (mean [range] age, 45.3 [18-76] years; 164 women [70.9%]) and 641 COVID-19–negative symptomatic individuals (mean [range] age, 44.7 [19-75] years; 455 women [71.1%]). Individuals with COVID-19 took longer to return to their RHR (Figure, A and B), sleep (Figure, C and D), and activity (Figure, E and F) baselines compared with symptomatic individuals who were COVID-19 negative. This difference was most marked for RHR, with COVID-19–positive individuals initially experiencing a transient bradycardia followed by a prolonged relative tachycardia that did not return to baseline, on average, until 79 days after symptom onset. Step count and sleep quantity returned to baseline sooner than RHR at 32 and 24 days, respectively. During recovery, individuals with COVID-19 experienced different trajectories in the return of their RHR to their normal compared with COVID-19–negative individuals (Figure, B). A small subset of COVID-19–positive participants (32 participants [13.7%]) maintained an RHR more than 5 beats per minute greater than their baseline RHR that did not return to their normal for more than 133 days. During the acute phase of COVID-19, individuals in this group reported higher frequencies of cough (27 participants [84.4%] vs 57 participants [55.3%] in the <1 beat per minute group and 57 participants [57.6%] in the 1-5 beats per minute group), body ache (20 participants [62.5%] vs 42 participants [40.8%] in the <1 beat per minute group and 35 participants [35.4%] in the 1-5 beats per minute group), and shortness of breath (9 participants [28.1%] vs 9 participants [8.7%] in the <1 beat per minute group and 6 participants [6.1%] in the 1-5 beats per minute group) compared with the other groups (Table).
Discussion: To our knowledge, this is the first study to examine longer duration wearable sensor data. We found a prolonged physiological impact of COVID-19 infection, lasting approximately 2 to 3 months, on average, but with substantial intraindividual variability, which may reflect various levels of autonomic nervous system dysfunction or potentially ongoing inflammation. Transient bradycardia has been noted in a case study6 approximately 9 to 15 days after symptom onset, which was also seen in our population. Our data suggest that early symptoms and larger initial RHR response to COVID-19 infection may be associated with the physiological length of recovery from this virus.
Symptom data were collected only during the acute phase of infection, which limited our ability to compare long-term physiological and behavioral changes with long-term symptoms. In the future, with larger sample sizes and more comprehensive participant-reported outcomes, it will be possible to better understand factors associated with interindividualized variability in COVID-19 recovery.
Source: Radin JM, Quer G, Ramos E, et al. Assessment of Prolonged Physiological and Behavioral Changes Associated With COVID-19 Infection. JAMA Netw Open. 2021;4(7):e2115959. doi:10.1001/jamanetworkopen.2021.15959 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2781687 (Full article)
Reduced Heart Rate Variability in Patients with Medically Unexplained Physical Symptoms: A Meta-Analysis of HF-HRV and RMSSD
Abstract:
Objectives: Medically unexplained physical symptoms (MUPS) and related syndromes are common and place a substantial burden on both patients and society. Chronic psychological distress and dysregulation of the autonomic nervous system may be common factors associated with MUPS, although previous studies have reported mixed results. The aim of this meta-analysis is to provide an updated synthesis of studies investigating heart rate variability (HRV) indices associated with autonomic nervous system functioning in three common MUPS-syndromes and to explain inconsistencies in previous study findings.
Method: Literature search yielded 58 studies comparing HRV indices of reduced parasympathetic activity of healthy individuals to patients with chronic fatigue syndrome (Npatients = 271), irritable bowel syndrome (Npatients = 1005), and fibromyalgia (Npatients = 534). Separate random-effects meta-analyses were conducted on studies measuring root mean square of successive differences (RMSSD) and high frequency HRV (HF-HRV).
Results: Regardless of syndrome type, patients had significantly lower RMSSD (k = 22, Hedges’ g = – 0.37 [-0.53; -0.21], p < .001) and HF-HRV (k = 52, Hedges’ g = -0.69 [-1.03; -0.36], p < .001) than healthy individuals. Sample age and publication year explained substantial variation in RMSSD, whereas controlling for confounders in statistical analyses explained variation in HF-HRV.
Conclusions: Lower RMSSD and HF-HRV in patients with MUPS versus healthy controls indicates that autonomic nervous system dysregulation, particularly lower parasympathetic activity, may play a role in patients with these conditions. This conclusion may have important implications for the underlying mechanisms and treatment of MUPS and related syndromes.
Source: Vreijling SR, Troudart Y, Brosschot JF. Reduced Heart Rate Variability in Patients with Medically Unexplained Physical Symptoms: A Meta-Analysis of HF-HRV and RMSSD. Psychosom Med. 2020 Oct 14. doi: 10.1097/PSY.0000000000000874. Epub ahead of print. PMID: 33065584. https://pubmed.ncbi.nlm.nih.gov/33065584/
Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis
Abstract:
In this study we set out to define the characteristics of autonomic subgroups of patients with Chronic Fatigue Syndrome (CFS). The study included 131 patients with CFS (Fukuda criteria). Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Fatigue Impact Scale, Fatigue Severity Scale, Epworth Sleepiness Scales, the self-reported Composite Autonomic Symptom Scale. Autonomic parameters were measured at rest with a Task Force Monitor (CNS Systems) and arterial stiffness using an Arteriograph (TensioMed Kft.).
Principal axis factor analysis yielded four factors: fatigue, subjective and objective autonomic dysfunction and arterial stiffness. Using cluster analyses, these factors were grouped in four autonomic profiles: 34% of patients had sympathetic symptoms with dysautonomia, 5% sympathetic alone, 21% parasympathetic and 40% had issues with sympathovagal balance.
Those with a sympathetic-dysautonomia phenotype were associated with more severe disease, reported greater subjective autonomic symptoms with sympathetic over-modulation and had the lowest quality of life. The highest quality of life was observed in the balance subtype where subjects were the youngest, had lower levels of fatigue and the lowest values for arterial stiffness. Future studies will aim to design autonomic profile-specific treatment interventions to determine links between autonomic phenotypes CFS and a specific treatment.
Source: Słomko J, Estévez-López F, Kujawski S, et al. Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis. J Clin Med. 2020;9(8):E2531. Published 2020 Aug 5. doi:10.3390/jcm9082531 https://www.mdpi.com/2077-0383/9/8/2531 (Full text)