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Orthostatic intolerance in ME/CFS

Orthostatic intolerance, a debilitating and often under-recognised issue for people with ME/CFS, refers to when the body fails to properly compensate for moving to an upright position, resulting in symptoms such as lightheadedness, fatigue, palpitations, and weakness. For many living with ME/CFS, orthostatic intolerance drastically restricts everyday activities.

To help you navigate this comprehensive overview, you can jump directly to any of the key sections below:

Contents:

What is orthostatic intolerance?

The NICE 2021 guidelines for ME/CFS explicitly addresses this issue, states:

“Be aware that people with ME/CFS may experience orthostatic intolerance, including postural orthostatic tachycardia syndrome (POTS).”

Orthostatic intolerance is a major manifestation of dysautonomia – an umbrella term for conditions affecting the autonomic nervous system, which controls involuntary bodily functions such as blood pressure, heart rate, digestion, and temperature regulation.

Specifically, orthostatic intolerance describes a cluster of symptoms that develop or worsen upon standing or sitting upright, and are attenuated or relieved by reclining or lying flat. Common symptoms include:

  • Dizziness and lightheadedness
  • Palpitations (sensation of heart racing)
  • Cognitive impairment
  • Nausea
  • Visual disturbances
  • Fainting or near fainting

Whilst specific conditions such as postural orthostatic tachycardia syndrome (PoTS) fall under this umbrella, many people living with ME/CFS experience significant orthostatic intolerance without receiving a formal medical diagnosis for a specific condition related to these orthostatic intolerance symptoms.

Conditions under the orthostatic intolerance umbrella

  • Postural Orthostatic Tachycardia Syndrome (PoTS): Defined by a sustained increase in heart rate (usually ≥30 bpm in adults) upon assuming an upright posture, without a major drop in blood pressure. Key physiological sub-types include neuropathic, hypovolaemic, and hyperadrenergic (which involves a blood pressure rise).
  • Orthostatic Hypotension (OH) / Postural Hypotension: Characterised by a significant, sustained drop in blood pressure upon standing.
  • Neurally Mediated Hypotension (NMH) / Vasovagal Syncope: A reflex-driven, sudden drop in blood pressure and/or heart rate, often leading to severe lightheadedness or fainting.

Diagnostic barriers

Clinical testing for orthostatic intolerance centers on evaluating how the cardiovascular system and autonomic nervous system adjust to an upright posture. In primary care, the active stand test and the standardised 10-minute NASA Lean Test, where blood pressure and heart rate are continuously monitored as an individual moves from lying flat to a standing or wall-supported position. For more comprehensive evaluations, specialised head-up tilt-table testing is used, allowing clinicians to track hemodynamic (assessment of blood flow, blood pressure, and heart rate mechanics) changes over extended periods.

Misdiagnosis of PoTS, and likely other forms of orthostatic intolerance, is a significant concern, due to symptom overlap with other conditions and limited awareness among healthcare professionals. Patients may receive inaccurate diagnoses such as anxiety or depression

According to PoTS UK, the average time to diagnosis from symptom onset is 7 years. This underscores the pressing need for increased awareness and education about PoTS to facilitate more timely diagnosis and management, ultimately enhancing the quality of life for individuals living with PoTS.

Lived experience

The many challenges of living with ME/CFS, including the profound impact of orthostatic intolerance, are highlighted in “‘Dialogues for a Neglected Illness” – a meticulously researched project supported by the Wellcome Public Engagement Fund (2018–21) and produced by Natalie Boulton with cameraman and editor Josh Biggs.

Accounts from the video series capture the heavy toll of these symptoms, such as:

“… I didn’t realise my heart rate was going up when standing, I just felt a bit woozy and strange and I knew that sometimes in public places I would have to sit on the floor. And it was only when I went for a medical assessment at a local hospital that it was one of the nurses that picked up that I had postural tachycardia syndrome or PoTS, which was really interesting for me because it matched the symptoms that I was feeling on standing…” – Dr Nina Muirhead

“Sitting up for an hour right from the beginning has meant that … I’d lose completely the ability to read and things like that and I would start to grey out and lose the ability to physically read the words on the page. And when it’s been worse, I haven’t even been able to get my head off the pillow and do that because of the orthostatic intolerance…” – Anna

What does the research say?

Research into orthostatic intolerance in ME/CFS covers a range of physiological areas that points towards understanding complex vascular, cerebrovascular, and autonomic mechanisms.

Key areas of research:

ME/CFS with co-occurring postural orthostatic tachycardia syndrome or orthostatic hypotension

A study evaluated 193 adults seeking treatment for ME/CFS, who were recruited from an outpatient clinic, utilising a head-up tilt table test to assess two common types of orthostatic intolerance – postural orthostatic tachycardia syndrome (PoTS) and orthostatic hypotension (OH). They found that 32.5% of the participants demonstrated POTS or OH. “The participants with either of these two common types of orthostatic intolerance were found to have more problems with sleep and post-exertional malaise”

Cerebral blood flow impairment

A research team showed that most participants with ME/CFS and normal HR-BP response (i.e. no PoTS) during tilt table testing had other physiological abnormalities occurring during assessment. Specifically, in comparison to healthy controls, cardiac output (how much blood heart pumps) and cerebral blood flow (how much blood brain receives) were abnormally reduced during the tilt. Cardiac output and cerebral blood flow are not always included in routine tilt table testing. Analysing the data patterns, the researchers suggested that the results indicated an “absence of compensatory vasodilation in the cerebral vasculature” i.e. blood vessels in the brain are not reacting appropriately to a change in body position. This could be an indicator of endothelial dysfunction – when the lining of blood vessels (endothelium) does not work properly.

A review examined different forms of orthostatic intolerance and the cerebral blood flow abnormalities contributing to orthostatic intolerance in ME/CFS and long COVID. It highlighted that approximately half of patients who meet symptomatic criteria for orthostatic intolerance do not meet the heart rate and blood pressure thresholds required for a PoTS diagnosis. Without assessing cerebral blood flow during testing, these patients may be deemed “objectively normal,” increasing the risk of their symptoms being misattributed to psychological causes.

Furthermore, a newer systematic review aimed to assess whether cerebral blood flow is reduced in ME/CFS and orthostatic intolerance, and whether the presence of both conditions leads to an additional decline in cerebral blood flow. They found that cerebral blood flow is reduced in ME/CFS and orthostatic intolerance alone and having both conditions further amplifies cerebral blood flow reductions. They conclude that observing cerebral blood flow changes in ME/CFS with and without OI may be important in monitoring disease severity.

Static total blood volume

A study evaluated whether deficits in total blood volume or red blood cell volume explain orthostatic intolerance (OI) in adults with ME/CFS. Using direct blood volume measurements alongside a 10-minute NASA Lean Test, researchers findings demonstrated that suggests that “static blood volume status is insufficient to account for the spectrum of orthostatic patterns observed” during standardised testing, pointing instead toward “contributions from autonomic, vascular, respiratory, or cerebrovascular mechanisms.”

In-office testing

A study evaluated the clinical value of simple, office-based tests for objective evidence of orthostatic intolerance and cognitive impairment in long COVID and ME/CFS. Using a 10-minute NASA Lean Test, researchers observed significant symptom worsening, blood pressure changes, and cognitive impacts in both patient groups compared with healthy controls. Consequently, the authors recommend incorporating simple orthostatic stress testing into primary care to better assess blood pressure, balance, cognition, and overall health.

Biochemical drivers

BH4 is a molecule thought to be involved in vital processes like mitochondrial energy production and neurotransmitter synthesis. Uncontrolled BH4 upregulation is associated with mitochondrial dysfunction, cognitive impairment, immune dysregulation, and inflammation – all hallmarks of ME/CFS. A pilot study revealed elevated BH4 levels in ME/CFS participants with orthostatic intolerance, prompting follow-up research into the mechanisms driving this upregulation. It is important to note that as the study was carried out “in vitro” – by analysing samples from people with ME/CFS and OI using laboratory equipment such as test tubes, the results may not fully reflect the dynamic environment within the human body. 

Distinct PoTS subgroups

Research evaluating haemodynamic profiles (assessment of blood flow during tilt-table testing identified two distinct subgroups among individuals with ME/CFS and co-occurring PoTS. Those with a moderate heart rate increase (between 30-39 beats per minute), mainly exhibited venous pooling in the lower limbs, whereas in those with a larger increase (40 beats per minute), the data suggested a hyperadrenergic response, i.e. exaggerated activation of the sympathetic nervous system. Identifying these distinct profiles may allow clinicians to tailor PoTS treatments more effectively.

Limitations of the studies

Whilst these studies collectively advance our understanding of orthostatic intolerance in ME/CFS, several methodological limitations must be considered when interpreting their findings. Cohort sizes vary significantly across the body of literature – ranging from large specialised clinic groups to smaller exploratory samples – which can affect statistical power and broader generalisability. Variation in diagnostic criteria across studies, including use of older Fukuda criteria, creates difficulty in comparing findings, whilst single point-in-time assessments fail to capture day-to-day symptom fluctuations.

Management

NICE 2021 guidance for ME/CFS states that medication for orthostatic intolerance in people with ME/CFS should only be prescribed or overseen by a healthcare professional with expertise in orthostatic intolerance. Individuals should be referred to secondary care specialist clinics if symptoms are severe, worsening, or if diagnostic uncertainty remains.

As orthostatic intolerance is an umbrella term it can cover a range of specific conditions, therefore where possible it is wise to consider the exact type of diagnosis as management might differ. However much of the management in general may overlap with PoTS management, requiring a tailored, multifaceted approach, which may include:

General advice/lifestyle changes, such as avoiding triggers and increasing fluid intake

Interventions such as wearing compression garments e.g. abdominal binders and stockings

Medications such as beta-blockers to control heart rate

Note: Because NICE provides no separate clinical guideline for PoTS, the NHS website directs individuals to PoTS UK as a valuable resource based on patient experience and opinion.

Conclusion

Orthostatic intolerance is far more than simple lightheadedness. It represents a physiological failure of the body to compensate to being upright and profoundly limits the daily lives of people living with ME/CFS.

This article is part of the Symptom Saturday series

Sources

ME Research UK articles on diagnostic criteria

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