Tuesday 29 November 2022

About Post Exertional Neuroimmune Exhaustion (PENE) in Myalgic Encephalomyelitis (ME)

Myalgic Encephalomyelitis (ME) & the cardinal feature Post Exertional Neuro-Immune Exhaustion have long been misunderstood derided & ignored. Believing this illness can be cured by attitude & effort is stigmatizing, harmful for individuals who blame themselves or get blamed for their suffering, & for the community of people deeply affected.

Image by JS

Post Exertional Neuroimmune Exhaustion - PENE, is the cardinal feature of ME according to the International Consensus Criteria (2011) on ME.

Post Exertional Neuroimmune Exhaustion - PENE is the cardinal feature of ME according to the International Consensus Criteria and Primer on ME.

Post Exertional Neuroimmune Exhaustion - PENE is a feature that is synonymous with ME. PENE in ME is a distinct measurable feature related to exhaustion and the nervous and immune systems.

Post Exertional Neuroimmune Exhaustion - PENE is particular to ME, however we recognise and appreciate that PEM can be used when referring to this cardinal feature in ME, though PEM is common in other illnesses too.

There is a long list of atypical symptoms that occur when a person with ME suffers from Post Exertional Neuro-Immune Exhaustion - PENE; marked debilitating illness and weakness, cognitive dysfunction, symptom flare-up and possible paralysis as seen in severe ME, can follow ANY physical or cognitive exertion requiring energy, no matter how small or insignificant the exertion. 

Essentially what it means is that any exertion, physical, cognitive or even emotional stress creates a prolonged reaction in the body where a relapse or worsening of these ME symptoms occur and can last for days, weeks, months or longer. 
Indeed, many people who have pushed far too hard beyond their limits have become bedbound and carer dependent for years.

Worsening symptoms in ME as a result of Post Exertional Neuroimmune Exhaustion -PENE may include exhaustion, extreme chronic pain, paralysis, brain fog, cognitive dysfunction, unrefreshing sleep, headaches, migraines, muscle pain and muscle fatigability, orthostatic intolerance, neurally mediated hypotension, or POTS, inability to eat, swallow or digest food, and much more. 

Another distinctive element of Post Exertional Neuroimmune Exhaustion - PENE is often described as a loss of stamina and/or functional capacity. (more on symptoms further below)

Note: It is important to realise that at the severe end of the spectrum people with Severe ME don’t need to exert themselves for the phenomenon PENE to operate, there can be a critical response to the slightest movement by the patient or by the movement of a visitor to the patient's bedroom. Even simple brain activity can lead to worsening of illness in ME, e.g., hearing noise from outside the bedroom.
For very severely affected ME sufferers there is virtually no ‘safe’ level of physical or mental activity, orthostatic stress or sensory input; no level which does not produce a worsening of symptoms, and perhaps also contribute to disease progression.

The onset of Post Exertional Neuroimmune Exhaustion - PENE can occur immediately, hours later or delayed up to 24-72 hours and depending on ME severity can last days, weeks, or even months.
We explored the differences between patients in an informal survey during May awareness month 2023. The survey feedback shows differences among ME patients in the response time for PENE to occur and to last, and the differences an individual may have, showing that most with ME don't have a set pattern re PENE occurring or with regards to how long symptoms associated with PENE will last. See the response to survey question about these features of PENE below:

Does PENE (also referred to as PEM) happen straight away or minutes after exertion or hours after exertion or a day or more after exertion?
Responses here

Post Exertional Neuroimmune Exhaustion - PENE Vs Fatigue

There is great importance in recognising Post Exertional Neuro-immune Exhaustion (PENE), when it comes to diagnosing Myalgic Encephalomyelitis (ME)There is a significant difference between what a healthy person experiences after activity and what a person with ME experiences. 
The use of the same word ‘fatigue’ for both experiences often leads to endless misunderstandings and as a consequence can have a whole series of profound impacts on the person with ME and especially on those with Severe ME .

Let’s further explain about Post-Exertional Neuroimmune Exhaustion (PENE) as described in one of the best international guidelines for diagnosis and management we currently have.

As per the International Consensus Criteria (ICC) 2011, a patient will meet the criteria for (A) post exertional neuroimmune exhaustion, (B) at least one symptom from three neurological impairment categories, (C) at least one symptom from three immune/gastro‐intestinal/genitourinary impairment categories, and (D) at least one symptom from energy metabolism/transport impairments.

(A) Post exertional neuroimmune exhaustion (PENE) is the cardinal criterion for a diagnosis of ME according to the International Consensus Criteria (2011) on ME.

PENE means when you suffer from Myalgic Encephalomyelitis (ME) your symptoms get worse after you do things, and even after you do the smallest thing.
You may start to feel worse immediately afterwards or several days later. You may feel worse for a short time, or a long time, or indefinitely.
Some people experience worsened symptoms after light activity such as brushing teeth, walking to the bathroom, or after mental activity such as reading, chatting on the phone or watching tv. Some people can suffer PENE by just sitting up in bed or from the smallest movement like turning their head.
Essentially any action whether physical, cognitive, emotional, social, etc, drains available energy and if the ability to replace this energy is impaired this can lead to a worsening of all symptoms which can last for days, weeks or months – even causing permanent, non-recoverable systemic damage.

Assessment and Diagnosis of ME as per the International Consensus Criteria )(ICC)

As mentioned already, Post-Exertional Neuroimmune Exhaustion (PENE) is a compulsory criteria in the diagnosis of ME. This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions.
Meaning - My body does not produce enough energy.

Characteristics are:
1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.

Meaning - After I do physical things, I feel worse or after I read or write or do other mental tasks, I feel worse. In Severe/Very Severe/Profound ME after I carried out the smallest movement while lying motionless in bed I feel profound and debilitating symptoms.

2. Post-exertional symptom exacerbation: e.g. acute flu-like symptoms, pain and worsening of other symptoms.

Meaning - After I do things, I feel like I have the worst flu, or feel pain, or feel worse in other ways. In Severe/Very Severe/Profound ME I feel extreme widespread pain, profound multiple sensitivities, shaking, trembling, paralysis and other extreme symptoms.

3. Post-exertional exhaustion may occur immediately after activity or be delayed by hours or days.

Meaning - I may not feel worse right away. I may start to feel worse in a few hours, or the next day, or the day after that. In Severe/Very Severe/Profound ME I can feel immediately worse.

4. Recovery period is prolonged, usually taking 24 hours or longer. A relapse can last days, weeks or longer.

Meaning - I can feel worse for a day, or for a few days, or for a few weeks, or longer.

5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.

Meaning - I can no longer do the things I used to be able to do.

6. Cognitive fatigability in response to exertion.

Meaning- After I do things, I may feel worse physically or mentally. I may have problems with memory or concentration.

Information on PENE is based on the information provided in the International Consensus Criteria ICC 2011

Image by JS

Causes of Post Exertional Neuro-Immune Exhaustion (PENE) in Myalgic Encephalomyelitis (ME)
  • Physical over-exertion
  • Mental over-exertion
  • Emotional over-exertion
  • Sleep dysregulation
  • Unbalanced/poor diet and nutrition
  • Other medical issues

How to Prevent Post Exertional Neuro-Immune Exhaustion (PENE) in Myalgic Encephalomyelitis (ME)
There are a few ways to prevent PENE and to manage ME symptoms. There is no single way of managing ME that works for everyone, and it takes time to figure out what works best for you. There are several management options. Early diagnosis, taking medication to control certain symptoms, and making lifestyle changes can all help. See more options below.

  • Early Diagnosis and appropriate rest in the early stages of the illness.
  • Pacing (activity management) & Resting
  • Energy Envelope Technique - staying within your energy envelope
  • Medical Treatments
  • Management strategies e.g., Ensure good nutrition and appropriate sleep
  • Using a Heart Rate Monitor
  • Managing relapses and adrenaline surges in ME
  • Learn your health patterns
  • Practice techniques like meditation if you can
  • Build your support community e.g., family, carers, doctors, specialists
  • Maintain emotional health
  • Avoid stress
  • Treat other medical conditions
  • Management of ME as per the International Consensus Primer, the ICP 2012

There are more details on each item in the above list of ways to prevent PENE and ways to manage ME symptoms here

Note: Trial and Error

Management techniques mentioned above can help relieve some symptoms, but this is a matter of trial and error; the illness has an individual element - what helps one person might not work for the next. Your GP and/or specialist can help with a range of issues, including sleep disturbance, coping with pain and energy management.

Considerations for those with Severe and Very Severe ME. 
Due to the severity of illness in people with Severe and Very Severe ME, who would most likely be permanently confined to bed, care and treatment would be planned and catered to ensure that management of illness, dispensing of treatments and provision of meals and bathing is done in the most non-invasive way possible. As some Very Severe/Profound ME patients may be tube fed and administered meds intravenously there would be a very special care given to them.

More on Assessing PENE

1. The CPET Test

The distinctive element of PENE often described as a loss of stamina and/or functional capacity is referred to in the results of the 2-day cardiopulmonary exercise test (CPET) procedure.

The CPET is a procedure which assesses exercise capacity and recovery by performing two exercise tests 24 hours apart. The hypothesis is that ME patients display a characteristic deterioration in exercise capacity on the second test, a finding that has been reported by multiple research groups. This test is considered the gold standard for measuring physical capacity. 

A CPET is usually reproducible and normally has a test-retest difference of 7-12%. ME patients however show strikingly lower results on several measures at the second CPET compared to the first, despite meeting objective markers of maximal effort. The drop in functional capacity on the second CPET is usually not seen in other diseases.

According to Keller et al. (2014), “ME patients currently represent a unique class of ill patients who do not reproduce maximal CPET measures, unlike individuals with cardiovascular disease, lung disease, end-stage renal disease pulmonary arterial hypertension and cystic fibrosis".

A preliminary study from New Zealand suggests that patients with MS do not display the same decline on the second day of exercise testing, as do patients with ME.
“Once the disease was established the most characteristic symptom was extreme exhaustion, particularly after exercise. The exhaustion also occurred after emotional or mental strain.”

It is important to recognise that at the severe end of the spectrum people with Severe and Profound ME don’t need to exert themselves for the phenomenon PENE/PEM to operate, it can simply be caused by an attempt to read a book, watching tv or listening to a visitor. Even simple brain activity can lead to worsening of illness in ME. 

Questions raised about the clinical use of the 2-day CPET procedure in those with Severe ME by Snell et al (2013) suggested it might be unethical to use this method since many ME patients might suffer a serious relapse as a result of exercise performance. Other methods such as Heart Rate Monitoring or the De Paul DSQ-PEM Questionnaire are more suitable to those with more severe forms of ME.

2. De Paul DSQ-PEM Questionnaire

Assessments using tools such as self-reporting questionnaires, e.g. DSQ-PEM questionnaire by De Paul could be used where the CPET test may not be available to clinicians or where it is not practical for those with ME, especially people with severe ME. The questionnaire is a valuable tool for all severities to evidence PEM/PENE. Link here: DSQ-PEM Questionnaire

3. Simple Self Assessment

Ask yourself or the ME patient the following questions to simply assess PENE/PEM
  1. What kind of exertion triggers your PENE/PEM? 

  2. Does PENE/PEM happen

    1. minutes after exertion 

    2. hours after exertion

    3. a day or more after exertion

    4. not at all

  3. Please describe what happens to you when PENE/PEM occurs 

  4. How long does it take you to recover from PENE/PEM? 

    1. at least a day

    2. several days

    3. at least a week

    4. several weeks

    5. a month or more

  5. What do you do to recover from PENE/PEM? 

  6. What do you do to prevent PENE/PEM from occurring?

4. Using a Heart Rate Monitor
See section about heart rate monitor usage in previous post via link above and again here: ME Advocates Ireland (MEAI): Managing & Treating Myalgic Encephalomyelitis (ME)

Survey Feedback - The Post Exertional Neuro-immune Exhaustion (PENE) feature in ME
We held an informal survey during May awareness month 2023 to find out more about patients' individual experiences with regards to Post Exertional Neuro-Immune Exhaustion - PENE.

Here are the questions we asked:

Q1 What words do you use to describe PENE (also referred to as PEM), the response you have after exertion whether physical or mental exertion or in response to a hyper sensitivity stimulus or action, e.g. 'relapse' ?

Q2 What kind of exertion triggers your PENE/PEM?

Q3 Does PENE (also referred to as PEM) happen... straight away or minutes after exertion or hours after exertion or a day or more after exertion?

Q4 How do you avoid PENE (or PEM), the post exertion response/crisis?

Q5 What can you do to recover from PENE, the post exertion response/crisis?

Q6 If you could provide one piece of advice to a person newly diagnosed with ME or to someone who suspects ME what would it be?

Please see the feedback from an informal survey on Post Exertional Neuro-Immune Exhaustion - PENE which we held during ME awareness month 2023 here

The Science Behind Post Exertional Neuro-Immune Exhaustion (PENE) in Myalgic Encephalomyelitis (ME)

Symptoms in ME potentially made worse due to physical or cognitive exertion

The Jason et al 2019 study entitled, ‘Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME)’ refers to a list of symptoms in ME which are potentially made worse due to physical or cognitive exertion. See the full study based on feedback from 1534 patients who responded to questions about PEM here

Table 4. from the study by Leonard Jason et al shows a list of symptoms caused or made worse by exertion, see below.

Items% (n) “Yes”% (n) at “2” ThresholdMean (SD)
1. Reduced stamina and/or functional capacity99.4 (1525)98.0 (1504)90.60 (17.16)
2. Physical fatigue98.9 (1517)98.3 (1508)87.53 (18.26)
3. Cognitive exhaustion97.4 (1494)92.0 (1412)77.64 (24.87)
4. Problems thinking97.4 (1494)92.6 (1420)78.47 (24.87)
5. Unrefreshing sleep95.0 (1457)91.1 (1398)80.57 (27.65)
6. Muscle pain87.9 (1349)81.5 (1250)69.41 (33.95)
7. Insomnia87.3 (1339)75.1 (1152)62.40 (34.30)
8. Muscle weakness/instability87.3 (1339)77.2 (1185)64.03 (33.86)
9. Temperature dysregulation86.9 (1333)75.2 (1153)63.76 (34.75)
10. Flu-like symptoms86.6 (1329)74.4 (1142)59.52 (33.43)
11. Aches all over your body85.6 (1313)79.5 (1219)68.68 (35.58)
12. Physically fatigued while mentally wired82.1 (1259)72.8 (1116)59.00 (35.65)
13. Dizziness80.7 (1238)56.0 (859)46.28 (33.19)
14. Gastro-intestinal problems78.6 (1206)59.3 (910)49.90 (36.02)
15. Headaches78.0 (1197)56.5 (866)46.48 (34.52)
16. Ataxia77.6 (1191)57.8 (886)47.62 (35.18)
17. Increased heart rate/heart palpitations  77.4 (118)64.9 (996)52.28 (36.51)
18. Weak or stiff neck74.6 (1144)61.0 (936)51.35 (38.20)
19. Joint pain73.0 (1120)59.5 (912)49.17 (37.86)
20. Problems with speech72.4 (1110)50.0 (767)40.22 (33.14)
21. Sore throats70.9 (1087)47.2 (724)38.92 (33.55)
22. Muscle twitching68.1 (1045)40.9 (627)35.12 (32.38)
23. Night sweats and chills67.7 (1038)46.9 (720)38.48 (34.69)
24. Sore eyes67.0 (1028)49.0 (752)39.91 (35.70)
25. Nerve pain  63.3 (971)48.8 (748)40.65 (38.16)
26. Sore lymph nodes  62.9 (965)44.0 (675)36.36 (35.28)
27. Nausea  62.2 (954)38.1 (584)31.89 (32.13)
28. Tinnitus  60.3 (925)39.8 (611)37.42 (38.96)
29. Trouble breathing  57.8 (887)40.9 (628)33.97 (35.67)
30. Neurological symptoms  57.0 (875)42.8 (656)34.60 (36.14)
31. Excessive sleep  54.4 (835)44.5 (682)36.23 (38.58)
32. Loss of appetite  49.0 (752)30.9 (474)25.41 (31.62)
33. Migraines  46.2 (708)24.6 (378)21.92 (29.27)
34. Cardiac pain and/or arrhythmia  41.2 (632)24.8 (381)21.12 (30.30)
35. Brain twangs  29.9 (459)17.7 (272)15.00 (26.82)
36. Severe burning sensation all over skin  29.7 (456)18.3 (280)15.96 (28.87)
37. Paralysis/inability to move  29.4 (451)9.4 (144)11.49 (21.91)
38. Premenstrual symptoms  21.1 (323)16.4 (251)13.56 (29.25)
39. Decreased heart rate  15.1 (231)7.4 (114)  6.88 (19.09)

Image by JS

More on the Science about PENE

Scientific Papers behind PENE compiled by Dr Mark Gutheridge

A study by the Workwell Foundation et al shows that ME patients have metabolic defects that cannot be explained by exercise phobias, deconditioning or 'illness beliefs'. People with ME have reduced oxygen consumption during exercise tests.
Properties of measurements obtained during cardiopulmonary exercise testing in individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - IOS Press

People with ME have an impaired ability to increase their oxygen consumption during exercise. This is entirely different to every other disease we know including cardiovascular disease, lung disease, end-stage renal disease, hypertension & cystic fibrosis.

People with ME also show impaired oxygen consumption and reduced anaerobic threshold compared to Multiple Sclerosis.

Exercise testing provides an explanation for why people with ME can crash even after modest exertion. The reduced aerobic capacity of people with ME results in a switch to anaerobic metabolism that likely impacts their ability to do simple daily activities.

ME patients can 'crash' if they over-exert resulting in a post-exertional malaise (PEM). Triggering PEM reduces the threshold at which anaerobic metabolism accelerates which impairs the ability of patients to do non-strenuous tasks.

And exercise that triggers PEM in ME patients leads to a sustained immune inflammatory response that is distinct from that in sedentary or deconditioned people.

People use aerobic metabolism for the majority of daily activities such as walking and seated tasks, but a reduced aerobic capacity of ME patients likely forces a switch to less efficient anaerobic metabolism leading to premature fatigue and PEM.

Exercise studies also show that the increased reliance on anaerobic metabolism in ME patients results in increased metabolites such as lactic acid which likely leads to an inability to maintain work and a reduction in activity.

Physical therapists should be aware that post-exertional malaise (PEM) in people with ME is due to objectively measurable deficits in metabolism. So yes, exercise is beneficial for nearly every illness.....but the science shows that ME is the exception.

This Frontiers review by Workwell discusses how cardiopulmonary exercise testing (CPET)can be used to help diagnose & research ME.
Frontiers | Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (frontiersin.org)
Included in the study is Table 1. which provides a helpful list of definitions for patients and doctors to investigate ME.

The Problems that arise when the Science is Ignored

Myalgic Encephalomyelitis (ME), & PENE in ME has long been misunderstood, derided & ignored. Believing this illness can be cured by attitude & effort is stigmatizing, harmful for individuals who blame themselves or get blamed for their suffering, & for the community of people deeply affected.

PENE is not ......
‘imagining it’
‘being overweight’
‘normal, everyone gets tired’
‘work refusal’
‘exercise intolerance’
‘a woman’s illness’
‘extreme tiredness’
‘mental illness’
‘chronic fatigue’
‘conversion disorder’
‘middle age issue’
‘Munchausen syndrome by proxy’
‘school avoidance’
‘emotionally distressed’

More Educational Pieces about PENE in Myalgic Encephalomyelitis (ME)

‘Dialogues For a Neglected Illness’

The short films about PENE, referred to as PEM, ‘A Brief Guide to PEM’, ‘Understanding PEM’ and 'Patients' Accounts of Symptoms - Post Exertional Malaise' from ‘Dialogues for a neglected illness’ (Dialogues for ME) raise awareness of the effects of activity/exertion within ME, in particular within the severe category, how some may be affected by pottering for an hour whereas for others the slightest exertion such as thinking of trying to read, will trigger PENE.
The films show how exertion does not necessarily need to be what would normally be described as exertion, yet can still have a deteriorative impact leading to a worsening of symptoms.
The films portray reality where at the severe end of the spectrum people with Severe ME don’t need to exert themselves for the phenomenon PENE to operate, it can simply be caused by reading a book or listening to a visitor, even simple brain activity can lead to worsening of illness in ME.
A common characteristic of PENE described is that it can be elicited by multiple types of triggers.

“ME patients describe post–exertional malaise as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover.”

Image by JS

'What a failure of our medical “system” that people go years with PEM and no one puts the pieces together for them. I can’t even conceive of the othering my patients have to live with daily but I’m reminded every time a patient cries when we simply discuss the science of PEM.'
~ Todd Davenport, Professor & Vice Chair, Department of Physical Therapy, University of the Pacific Stockton, California, US

Disclaimer: The information in this post is for general information purposes only. While we endeavour to keep the information up to date and correct, we make no representations or warranties of any kind, express or implied, about the completeness, accuracy, reliability, suitability or availability with respect to the post or the information, products, services, etc contained in the post for any purpose. Any reliance you place on such information is therefore strictly at your own risk.The suitability of any solution is totally dependent on the individual. It is strongly recommended to seek professional advice and assistance.