World ME Day posters launched exploring the 2023 theme
As we approach World ME Day on May 12th, the World ME Alliance is excited to announce the launch of six new graphics that explore different aspects of post-exertional malaise (PEM). These graphics are available for download and use by anyone, with the aim of raising awareness about the impact of ME on those living with the disease.
Post-exertional malaise is the hallmark symptom of ME, and is experienced by roughly half of those with long COVID, but what is it?
The disease where pushing harder can make you sicker.
PEM is a worsening of symptoms after physical, mental, or emotional exertion that would not have caused a problem before the illness and is the hallmark symptom of ME.
For some patients, sensory overload (light and sound) can induce PEM.
PEM intensifies the severity of symptoms and may last days, weeks, or permanently. The symptoms typically begin to worsen 12 to 48 hours after the activity or exposure.
Our first graphic focuses on the term exertion, highlighting that this can mean many things, and not just exercise. In the image a women is standing up, giving a speech, in a room full of people. For someone with ME this means being cognitively active, physically active, emotionally active and managing significant sensory input – all of which can lead to post-exertional malaise.
Our second graphic deepens the understanding of sensory overload – be it light, sound, smell, touch or taste. It can come from everything everywhere all at once.
We also chose to focus on pacing in our third and fourth graphics, as this is the key technique people with ME can use to manage post-exertional malaise and avoid getting sicker from pushing harder.
It is deeply important to our Alliance that we highlight the 25% of people with ME who are housebound or bedbound. For these individuals post-exertional malaise is even more extreme, potentially rendering them unable to eat or drink for periods of time and unable to speak. Some live in darkened rooms 24 hours a day, because of the impact of sensory overload.
Finally, we chose to emphasise that different symptoms can get worse for different people. There is no one-size-fits-all when it comes to ME, and while one person may suffer extreme brain fog and pain during post-exertional malaise, another may get new or worsening gastrointestinal symptoms.
All of these graphics are available for free download on the worldmeday.org website. By using these graphics on social media, websites, or other platforms, you can help raise awareness of PEM and its impact on those with ME. Together, we can work towards a better understanding of this debilitating illness.
We look forward to sharing more resources with you in the coming weeks. We will be creating opportunities for you to learn more about PEM, or share your lived experience of this hallmark aspect of ME.
WAMES is a founder member of the World ME Alliance
Australian researchers reviewed the research which used objective measures, rather than patient surveys, to uncover the type and extent of sleep disruption in ME/CFS.
Adult ME/CFS patients:
spend longer time in bed
longer sleep onset latency (the time it takes to fall asleep after turning the lights out)
longer awake time after sleep onset
reduced sleep efficiency (% of time asleep while in bed)
decreased stage 2 sleep
more Stage 3, and longer rapid eye movement sleep latency
Adolescent ME/CFS patients had:
longer time in bed
longer total sleep time
longer sleep onset latency (the time it takes to fall asleep)
reduced sleep efficiency (% of time spent asleep while in bed)
The four broad stages of Non Rapid Eye Movement sleep include:
stage 1 – dozing or drowsiness – you hover between being asleep and awake
stage 2 –you lose awareness of your surroundings, your body temperature starts to drop and your breathing and heart rate slow down
stages 3 and 4 – deep sleep, also known as ‘delta sleep’ – your blood pressure, heart rate and breathing become very slow and your muscles relax. Growth and repair processes occur during this stage. [from: Sleep explained]
Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often report disrupted and unrefreshing sleep in association with worsened fatigue symptoms.
However, the nature and magnitude of sleep architecture alteration in ME/CFS is not known, with studies using objective sleep measures in ME/CFS generating contradictory results. The current manuscript aimed to review and meta-analyse of case-control studies with objective sleep measures in ME/CFS. A search was conducted in PubMed, Scopus, Medline, Google Scholar, and Psychoinfo databases.
After review, 24 studies were included in the meta-analysis, including 20 studies with 801 adults (ME/CFS = 426; controls = 375), and 4 studies with 477 adolescents (ME/CFS = 242; controls = 235), who underwent objective measurement of sleep.
Adult ME/CFS patients spend longer time in bed, longer sleep onset latency, longer awake time after sleep onset, reduced sleep efficiency, decreased stage 2 sleep, more Stage 3, and longer rapid eye movement sleep latency.
However, adolescent ME/CFS patients had longer time in bed, longer total sleep time, longer sleep onset latency, and reduced sleep efficiency.
The meta-analysis results demonstrate that sleep is altered in ME/CFS, with changes seeming to differ between adolescent and adults, and suggesting sympathetic and parasympathetic nervous system alterations in ME/CFS.
This research paper is behind a paywall but “Patients and caregivers can make requests for individual papers… at no cost.”
Cardiovascular and haematological pathology in ME/CFS: a role for viruses
“The circulatory system (also called the cardiovascular system) is the body system that moves blood around the body. It consists of the heart and blood vessels. The blood carries various materials that the body needs, and takes away waste and harmful substances.” Wiki
Researchers Nunes, Kell and Pretorius say: Prompted by the overlap between Long COVID and ME/CFS, in this review, we sought to summarize the cardiovascular and haematological findings associated with ME/CFS.
“Haematology is the branch of medicine concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to blood.” Wiki
The influence of microbes on the coagulation system
Practice points
The evidence presented in this review resonates with the notion that ME/CFS is characterized by physiological pathology, and not psychosomatic illness. This is a biologically-driven disease characterized by vascular (including haematological) pathology.
Assessment of cardiovascular (specifically cardiac functioning) and haematological health are necessary steps in the clinical evaluation of ME/CFS patients.
Deconditioning does not seem to be responsible for the symptoms of ME/CFS.
The coagulation system and endothelium is becoming more and more implicated in ME/CFS; perhaps these systems are more involved in ME/CFS than previously suspected.
Viruses are heavily involved in ME/CFS pathology, and their role in causing in ME/CFS seems more likely when scrutinizing the etiology of the similarly-presenting Long COVID – elucidation of the mechanisms of how SARS-CoV-2 leads to Long COVID may advance ME/CFS knowledge.
“The endothelium is a thin membrane that lines the inside of the heart and blood vessels. Endothelial cells release substances that control vascular relaxation and contraction as well as enzymes that control blood clotting, immune function and platelet (a colorless substance in the blood) adhesion. Cedars
Research agenda
Future studies need to expand on the involvement of the cardiovascular and haematological system in ME/CFS pathology, and determine to what extent these systems and dysfunction thereof contributes to symptom manifestation.
The cardiac and vascular dysfunction observed in ME/CFS individuals is atypical in the sense that it is non-atherosclerotic heart disease; it seems that neurological (autonomic) dysfunction underlies these abnormalities – mechanisms need to be unveiled, and therapeutics trialled in this neurological context, especially since orthostatic symptoms greatly affect the functional capabilities of patients.
Given the complexity of ME/CFS, research and clinical efforts will require collaborative multidisciplinary involvement, that include virologists, cardiologists, neurologists, and haematologists.
There is an urgent need for biomarker establishment in ME/CFS; further investigation of the physiological systems discussed in this review may help aid in this quest, especially since these systems (or aspects thereof) are becoming more and more implicated in ME/CFS research.
In conclusion: “This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.”
ME/CFS is a debilitating chronic condition that often develops after viral or bacterial infection.
Insight from the study of Long COVID/Post Acute Sequelae of COVID-19 (PASC), the post-viral syndrome associated with SARS-CoV-2 infection, might prove to be useful for understanding pathophysiological mechanisms of ME/CFS.
Disease presentation is similar between the two conditions, and a subset of Long COVID patients meet the diagnostic criteria for ME/CFS. Since Long COVID is characterized by significant vascular pathology – including endothelial dysfunction, coagulopathy, and vascular dysregulation – the question of whether or not the same biological abnormalities are of significance in ME/CFS arises.
Cardiac abnormalities have for a while now been documented in ME/CFS cohorts, with recent studies demonstrating major deficits in cerebral blood flow, and hence vascular dysregulation. A growing body of research is demonstrating that ME/CFS is accompanied by platelet hyperactivation, anomalous clotting, a procoagulant phenotype, and endothelial dysfunction.
Endothelial damage and dysregulated clotting can impair substance exchange between blood and tissues, and result in hypoperfusion, which may contribute to the manifestation of certain ME/CFS symptoms.
Here we review the ME/CFS literature to summarize cardiovascular and haematological findings documented in patients with the condition, and, in this context, briefly discuss the potential role of previously-implicated pathogens.
Overall, cardiac and haematological abnormalities are present within ME/CFS cohorts. While atherosclerotic heart disease is not significantly associated with ME/CFS, suboptimal cardiovascular function defined by reduced cardiac output, impaired cerebral blood flow, and vascular dysregulation are, and these abnormalities do not appear to be influenced by deconditioning. Rather, these cardiac abnormalities may result from dysfunction in the (autonomic) nervous system.
Plenty of recently published studies are demonstrating significant platelet hyperactivity and endothelial dysfunction in ME/CFS, as well as anomalous clotting processes. It is of particular importance to determine to what extent these cardiovascular and haematological abnormalities contribute to symptom severity, and if these two systems can be targeted for therapeutic purposes. Viral reservoirs of herpesviruses exist in ME/CFS, and most likely contribute to cardiovascular and haematological dysfunction directly or indirectly.
This review highlights the potential of studying cardiac functioning, the vasculature, and coagulation system in ME/CFS.
Two symptoms can accurately identify post-exertional malaise in ME/CFS
Experienced researchers into PEM at the Workwell Institute in California set out to find a way of diagnosing PEM and believe they have uncovered important clues that they now need to test further.
“Post-exertional malaise may manifest in a multitude of ways with different symptoms, timing, and intensity. Yet, the findings of this study indicate clinicians only need to focus on the presence and duration of just a few symptom categories and prolonged duration to identify its existence.”
Summary of symptom clusters at each time point during the study, which differentiated between people with ME/CFS and sedentary control subjects.
“Inquiring about post-exertional cognitive dysfunction, decline in function, and lack of positive feelings/mood may help identify PEM quickly and accurately.”
BACKGROUND:
Post-exertional malaise (PEM) is the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) yet its diverse manifestations make it difficult to recognize. Brief instruments for detecting PEM are critical for clinical and scientific progress.
OBJECTIVE:
To develop a clinical prediction rule for PEM.
METHOD:
49 ME/CFS and 10 healthy, sedentary subjects recruited from the community completed two maximal cardiopulmonary exercise tests (CPETs) separated by 24 hours. At five different times, subjects reported symptoms which were then classified into 19 categories. The frequency of symptom reports between groups at each time point was compared using Fisher’s exact test. Receiver operating characteristics (ROC) analysis with area under the curve calculation was used to determine the number of different types of symptom reports that were sufficient to differentiate between ME/CFS and sedentary groups. The optimal number of symptoms was determined where sensitivity and specificity of the types of symptom reports were balanced.
RESULTS:
At all timepoints, a maximum of two symptoms was optimal to determine differences between groups. Only one symptom was necessary to optimally differentiate between groups at one week following the second CPET. Fatigue, cognitive dysfunction, lack of positive feelings/mood and decrease in function were consistent predictors of ME/CFS group membership across timepoints.
CONCLUSION:
Inquiring about post-exertional cognitive dysfunction, decline in function, and lack of positive feelings/mood may help identify PEM quickly and accurately. These findings should be validated with a larger sample of patients.
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It is just 7 weeks since the fundraising challenge began so we are encouraged by the growing income to keep planning the new site and we hope to launch later this year.
Prof Leonard Jason’s team in Chicago surveyed 617 adults and found a surprisingly high number (43%) had begun feeling ill while adolescents. They analysed their symptoms and experiences and found common themes, which they believe can lead to a better understanding of the experience of ME/CFS.
Table 3. Summary of themes from qualitative analysis (N = 70)
Themes
Central meanings
% (n)
Feeling misunderstood
Comments related to being misunderstood, dismissed, or not believed by peers, educators, and medical practitioners
20.0 (14)
Mental health
Descriptions of poor or adverse mental health experiences, either as a trigger for ME/CFS, or as a result of the unique burden of this illness
18.6 (13)
Family pattern/history
Mention of a family history of ME/CFS or related chronic illness
17.1 (12)
Healthy childhood preceding sick adulthood
Descriptions of being previously very healthy, active children before illness onset in adulthood
15.7 (11)
School attendance
Descriptions of poor school attendance or problems functioning in a school setting
14.3 (10)
Lack of clarity until adulthood
Descriptions of being ill for most of the patient’s life, and not having received a formal diagnosis or understanding the cause of illness until much later in life
8.6 (6)
Sharing of resources
Attempts to share valuable resources or information related to illness experiences with fellow blog participants
8.6 (6)
Isolation/poor social supports
Feelings of loneliness or isolation as a result of functional limitations or stigmatization
5.7 (4)
Coping mechanisms
Methods that patients used to deal with their illness, either in terms of symptom management or the mental/emotional toll brought about by illness challenges
2.9 (2)
“The present study has several implications for future investigation. It is important that researchers and clinicians better understand patient-reported illness and family genetic history, patterns of symptom onset, and environmental exposure throughout the lifespan for patients with ME/CFS.
Representation of these issues in the literature will bolster our understanding of possible illness triggers or predispositions to ME/CFS in childhood and adolescence, as were revealed in the present study. It will also aid in legitimizing the lived experiences of patients who do not feel believed of their illness. There continues to be a lack of representation and knowledge of this illness despite its prevalence.”
BACKGROUND:
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic illness that impacts pediatric populations.
OBJECTIVE:
The current study aimed to better understand adult perceptions of their experiences leading up to their diagnosis of ME/CFS.
METHOD:
Patients provided data regarding symptoms of ME/CFS they may have experienced during childhood through a popular community blog forum, with participants interacting via blog comments in real-time and across various geographical locations.
RESULTS:
Descriptive analyses indicated that roughly 43% of adult survey participants reported having developed ME/CFS prior to age 18. A standard content analysis of patient blog commentary revealed several themes, such as poor mental health, family pattern/history, healthy childhood preceding sick adulthood, feeling misunderstood, lack of clarity until adulthood, sharing of resources, poor school functioning, isolation/poor social supports, and coping mechanisms.
CONCLUSION:
There are unique benefits and insights that can be used by investigators who collaborate with patient organizations as a means of better understanding ME/CFS illness severity, presentation, and lived experiences.
Experience and attitudes towards Pacing using a heart rate monitor: survey results
A survey by researchers who were led by the Physios for ME group, found over 30 benefits to the use of heart rate monitors (HRM) by people with ME (PwME). The monitors reduced the severity of ME, and severity and duration of PEM, but a lack of knowledge meant some people were misusing their devices.
“The concerning aspect of the use of the HRM was that some participants were using too high a level of estimated VAT or were attempting to use zones when working with the heart rate monitor. “
The main difficulties identified in using the monitors were lack of support, financial cost and too restrictive. “There is a clear need for people with ME and healthcare professionals advising them to know how to use these devices specifically for ME.”
Over 100 devices were used by participants with the most popular being the Apple watch, followed by Garmin, Fitbit and Polar devices. The results show that all the devices have the potential to improve the level of severity of ME, the severity of PEM and rate of recovery from PEM, independent of whether a chest strap is used, but there is a need for a more bespoke device that is easy to use with functions designed for people with ME.
The researchers say: “It is important to recognise that HRM is a management tool that needs to be used in conjunction with many other management strategies such as rest, prioritising, and planning. HRM is not a cure for ME, but it can be used as a management tool with the potential to help most PwME.”
BACKGROUND:
Myalgic encephalomyelitis (ME) is a complex, multi-system neurological condition. The defining feature of ME is post-exertional malaise (PEM) with over 30 symptoms triggered by physical, cognitive, emotional and social activity. The cause of PEM is unclear but one area of research using cardio-pulmonary exercise tests show a reduced ventilatory anaerobic threshold (VAT) with repeated tests leading to PEM.
Pacing with heart rate monitoring (HRM) provides feedback to maintain activity intensity below the VAT. There is only one piece of research investigating the use of HRM although a number of guidelines recommend it.
OBJECTIVE:
To identify the experiences and attitudes of people with ME towards HRM.
METHODS:
A 40 question online survey was devised and released on ME websites, Twitter and Facebook pages. People with ME read the information sheet and followed an online link to the survey. The survey was open for three weeks and all answers were anonymous.
RESULTS:
488 people with ME completed the survey. Most participants were female, 35-50 years and with a reported illness of greater than 5 years. Over 100 types of HR monitor used. Over 30 benefits and over 30 negatives identified. HRM reduced severity of ME and severity and duration of PEM.
CONCLUSION:
Although there are limitations, HRM has many benefits including helping PwME to understand and manage their PEM and support them to increase their activities, including work. There is a need for more research and education of healthcare professionals in the safe use of HRM.
Post-Exertional Malaise in long COVID compared to ME/CFS
Researchers at the Bateman Horne clinic in Utah, USA asked long COVID and ME/CFS patients about PEM which they described as:
“an unusual worsening of symptoms after minimal physical or mental exertion, which can occur or persist 24 hours or more after the exertion”
The majority in both groups indicated PEM occurred within hours of exertion and lasted for several days. Fatigue, muscle and joint pain, infection and immune reaction, neurologic and gastrointestinal symptoms, and orthostatic intolerance all worsened.
Long COVID respondents reported significantly more sleepiness, respiratory issues, depression and anxiety, irregular body temperature and excessive thirst than ME/CFS patients. Difference could be due to the nature of the COVID virus or because ME/CFS patients had been sick longer and had learned to manage some symptoms better.
The majority of both groups rested to recover from PEM, plus a variety of things to recover including sleep, hydration, and diet. Most ME/CFS patients used physical awareness to prevent PEM whereas Long COVID respondents prevented PEM by avoiding triggers.
The researchers believe “Asking about PEM in people that have lingering symptoms following COVID-19 is essential to mitigate progression and possible development of ME/CFS.”
Background:
Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Objective:
We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS.
Methods:
A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence.
Results:
All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM.
Conclusion:
People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.
US researchers used a 2-day exercise study (CPET) to discover how long it took people with ME/CFS to recover from exercise. The 80 participants with ME/CFS took an average of almost 2 weeks to recover from a 2-day CPET, whereas healthy people only needed an average of two days.
Almost 10% of those with ME/CFS took more than 3 weeks to recover, with one person feeling he had not recovered after a full year. Recovery time back to the pre-exercise level was not affected by the severity of symptoms prior to taking part in the study.
Excerpts:
“it is likely that persons with ME constantly live in the long tail of the recovery response. While activities of daily living are not as stressful as the 2-day CPET, recovery from less intense activities of daily living is likely to follow a similar decay curve.
Such a response to physical activity would be consistent with the ubiquitous complaint from persons with ME that they have constant and persistent PEM. Most persons with ME would constantly experience exertion falling on an incompletely recovered decay curve, and thus their symptoms would increase to a high steady-state level.”
“Our data suggests that around 7–8% will have a prolonged recovery of 1–2 months, with a very small percentage of ME subjects feeling that they never recover.”
The researchers had not found this response to exercise outside ME/CFS, until people with long COVID began to report PEM from 2020.
Recovery from Exercise in Persons with Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS), by Geoffrey E Moore, Betsy A Keller, Jared Stevens, Xiangling Mao, Staci R Stevens, John K Chia, Susan M Levine, Carl J Franconi and Maureen R Hanson inMedicina 2023, 59(3), 571; [doi.org/10.3390/medicina59030571] 15 March 2023
(This article belongs to the Special Issue Advances in ME/CFS Research and Clinical Care)
Research abstract:
Background and Objectives:
Post-exertional malaise (PEM) is the hallmark of myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS), but there has been little effort to quantitate the duration of PEM symptoms following a known exertional stressor. Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS, we sought to characterize the duration and severity of PEM symptoms following two cardiopulmonary exercise tests separated by 24 h (2-day CPET).
Materials and Methods: Eighty persons with ME/CFS and 64 controls (CTL) underwent a 2-day CPET. ME/CFS subjects met the Canadian Clinical Criteria for diagnosis of ME/CFS; controls were healthy but not participating in regular physical activity. All subjects who met maximal effort criteria on both CPETs were included. SSS scores were obtained at baseline, immediately prior to both CPETs, the day after the second CPET, and every two days after the CPET-1 for 10 days.
Results: There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001). The range of ME/CFS patient recovery was 1–64 days, while the range in CTL was 1–10 days; one subject with ME/CFS had not recovered after one year and was not included in the analysis. Less than 10% of subjects with ME/CFS took more than three weeks to recover. There was no difference in recovery time based on the level of pre-test symptoms prior to CPET-1 (F = 1.12, p = 0.33).
Mean SSS scores at baseline were significantly higher than at pre-CPET-1 (5.70 ± 0.16 vs. 4.02 ± 0.18, p < 0.0001). Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET.
Conclusions:
ME/CFS subjects took an average of about two weeks to recover from a 2-day CPET, whereas sedentary controls needed only two days. These data quantitate the prolonged recovery time in ME/CFS and improve the ability to obtain well-informed consent prior to doing exercise testing in persons with ME/CFS. Quantitative monitoring of PEM symptoms may provide a method to help manage PEM.
8am to midnight, 7 days a week
Our first graphic focuses on the term exertion, highlighting that this can mean many things, and not just exercise. In the image a women is standing up, giving a speech, in a room full of people. For someone with ME this means being cognitively active, physically active, emotionally active and managing significant sensory input – all of which can lead to post-exertional malaise.
Our second graphic deepens the understanding of sensory overload – be it light, sound, smell, touch or taste. It can come from everything everywhere all at once.
We also chose to focus on pacing in our third and fourth graphics, as this is the key technique people with ME can use to manage post-exertional malaise and avoid getting sicker from pushing harder.
It is deeply important to our Alliance that we highlight the 25% of people with ME who are housebound or bedbound. For these individuals post-exertional malaise is even more extreme, potentially rendering them unable to eat or drink for periods of time and unable to speak. Some live in darkened rooms 24 hours a day, because of the impact of sensory overload.
Finally, we chose to emphasise that different symptoms can get worse for different people. There is no one-size-fits-all when it comes to ME, and while one person may suffer extreme brain fog and pain during post-exertional malaise, another may get new or worsening gastrointestinal symptoms.
A big thank you to 2 south Wales donors whose £50 donation takes us to £400!
Prof Leonard Jason’s team in Chicago surveyed 617 adults and found a surprisingly high number (43%) had begun feeling ill while adolescents. They analysed their symptoms and experiences and found common themes, which they believe can lead to a better understanding of the experience of ME/CFS.
A survey by researchers who were led by the 
The majority in both groups indicated PEM occurred within hours of exertion and lasted for several days. Fatigue, muscle and joint pain, infection and immune reaction, neurologic and gastrointestinal symptoms, and orthostatic intolerance all worsened.
