Here in the UK the ME community is struggling, nearly 3 years later, to get local and regional ICB’s to implement the new guideline from NICE which was issued in October 2021. It is quite clear that the medical establishment in the UK still does not take the education of health professionals about ME seriously. I speak to medical students at my local university on a regular basis and none have had any training about ME never mind the fact that many have not even heard of our illness.
The coroner’s inquest into the tragic death of Maeve Boothby O’Neill from ME, at the young age of 27, has further revealed the many failings of the NHS when it comes to the treatment and care of people with severe ME. Lack of education of health professionals regarding the understanding and treatment of ME stood out like a sore thumb.
To compound matters, here in the UK there is a derisory amount of money being invested into biomedical research into ME. Both the medical establishment and politicians from the Labour government display no sense of urgency about improving the lives of people with our illness. As the U.S. NIH/NINDS ME research roadmap of May 2024 notes, ‘Time is life, especially where life diminishing diseases are concerned.’ This lack of urgency fits perfectly with the damning report issued by the UN Committee on Disabilities in April of this year. This UN report noted that disabled people in the UK face ‘systemic violations’ of their human rights.
There is some comfort to be had from the research and plans for further research from NIH/NINDS in the United States. A new study from the NIH in the United States, which lasted eight years, and had more than 70 authors from 15 countries was published in Nature Communications in February of this year. This study Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome clearly states that ME is a biological illness whose primary characteristics are immune dysfunction and brain abnormalities.
The study has been widely welcomed by scientists in the field of ME research and beyond. Prof Karl Morten, Principle Investigator, Nuffield Department of Women’s & Reproductive Health (NDWRH), John Radcliffe Hospital, University of Oxford, said:
“This is such an important paper and one I am so pleased to see come out. With our meagre research budgets we can only dream of running a study like this.
“The brain appears to be potentially driving the patient response. The big question is why? Is something still going on we are not yet aware of? The immune system is dysregulated and appears to still be showing an antigen response. Is this suggesting a foreign entity is still present or has the system gone rogue? The differences in many of the symptoms appear linked to male/female differences. This is important as we have perhaps got bogged down trying to understand the vast number of different and changing symptoms for too long.
“Can we now start to hone in on what is really important? I am very excited about next steps and the major funders now need to step up and provide sustainable global funding for ME/CFS research”
Dr Katharine Seton, Research Scientist, Quadram Institute Bioscience, said:
“This comprehensive study on a well-defined subgroup of ME/CFS patients serves as a prime example of the research required to deepen our limited understanding of this complex disease and ultimately identify treatments. Historically, studies investigating ME/CFS have often focussed on singular aspects of the disease, largely due to inadequate funding for this disease. These fragmented studies merely offer isolated pieces of a larger jigsaw puzzle. However, the current paper stands out with its extensive author list, featuring experts from diverse disciplines collaborating to assemble these pieces and reveal a more complete picture. This interdisciplinary approach is crucial for advancing our understanding of this disease.”
This study as important as it is was not perfect and had a number of important weaknesses. It did not include people with severe ME, it only had 17 participants, it did not include people with ME without an infection prior to onset and it included a somewhat dubious term to explain why people with ME respond differently to healthy people in physical exercise challenges.
Dr Avindra Nath, Clinical Director and Senior Investigator at NINDS and one of the co-authors of the above study, took time out from his busy schedule to talk about the findings of this 8 year study. Meanwhile, his colleague Dr Vicky Whittmore, Programme Director at NINDS, also gave some input regarding the ME research roadmap agreed by NIH/NINDS in May of this year.
Responses to questions 1-4 by Avindra Nath, M.D, Clinical Director and Senior Investigator at NINDS. Responses to questions 5-6 by Dr Vicky Whittemore, Programme Director at NINDS.
How did you get involved in the field of ME research?
Avindra Nath: I have had a long-standing interest in studying inflammatory and infectious diseases of the brain, particularly how viruses establish a chronic infection in the brain and/or cause a neuroinflammatory process. In 2015, Dr. Francis Collins, the NIH Director at that time, approached me to see if I would be interested in taking a fresh look at ME/CFS and develop a clinical protocol to study it. With the help of Dr. Brian Walitt, a rheumatologist, we put together a team of 75 experts across NIH to take a deep dive into the clinical characteristics and pathophysiology of the illness. Due to my expertise in infections, we recruited a specific cohort of patients whose ME/CFS was clearly triggered by an infection and made sure that there was no other underlying illness that could explain their symptoms. These patients were admitted to the NIH Clinical Center for a period of one to two weeks and underwent a very large battery of tests. This is the most extensive study done to date on ME/CFS and has transformed our understanding of the disease.
Sadly, here in the UK and in many other countries there are many doctors who still believe that ME/CFS is a somatic psychological illness. This has held back treatments for people with ME who have suffered decades of health inequalities. Yet earlier this year you and a group of colleagues from NIH in the United States, published a new detailed study, Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome, which looks inside the bodies of people with ME. The NIH recruited 17 people with ME and 21 healthy volunteers without the illness, for comparison. Each person underwent an extensive array of tests, including brain scans, cognitive exams, sleep tests, blood tests, spinal taps and exercise challenges. The study paper has more than 70 authors from 15 of the 27 NIH institutes. From looking at your findings it appears that you clearly noted that ME is a physical disease whose key characteristics are immune dysfunction and brain abnormalities. Is that fair assessment of your findings? If so, please can briefly explain these findings for the layperson?
Avindra Nath: Yes, that is correct. We hope that one of the major takeaways from our study is that we have convincingly demonstrated the biological basis of the disease that cannot be explained by deconditioning and psychological factors. We have further identified several novel targets for modifying the course of the disease. We hope these findings will change the minds of many. All the same, I am certain that once we have a biological therapy for ME/CFS, it will provide definitive evidence for the biological basis of the disease.
We found that post-infectious ME/CFS is a multisystemic disease, with involvement of the immune system, autonomic nervous system, the brain and the gut. We believe that the primary defect is in the maturation of B cells that leads to immune exhaustion and activation of innate immune responses.
There were also distinct sex differences; women had markers of overactive B cells and men had greater T cell activation. This suggests that potential immune therapies would need to be tailored accordingly.
We found that several metabolites in the cerebrospinal fluid of individuals with PI-ME/CFS were dysregulated. Of all the tests that we performed, these had the best potential for serving as a biomarker of the disease.
We also found differences in an area of the brain called the temporal-parietal junction, which plays a role in integrating information, evaluating and initiating physical action. This area, which drives the motor cortex, showed decreased activation in the ME/CFS participants. Abnormalities in this brain network and imbalances in catecholamines, chemicals that help regulate the nervous system, might help explain some disease symptoms.
We did not find any structural abnormalities but multiple functional or network abnormalities, which gives hope that the disease is treatable and possibly reversible.
The study acknowledges that post-exertional malaise is central to the disease. However, some researchers and many people in the ME community felt unhappy with the term 'altered effort preference' as an explanation for the origin of fatigue. Your study suggests that healthy people chose harder physical tasks than those with ME. For those of us with ME it is not simply a matter of choice. I often don’t leave the house not because I don’t want to go outside but because I am physically unable to leave the house most of the time. Can you explain why you chose the term ‘altered effort preference’? Do you accept that people with ME are physically unable to do the same physical tasks as healthy people?
Avindra Nath: Yes, we agree, that could very well be the case. Effort-Expenditure for Rewards Task (EEfRT) is a well-established neurophysiological test. As shown in our manuscript, effort preference is a neurobiological consequence of an immune response to the infection.
For many of us with ME the pace of research into our illness appears agonizingly slow. There has been a dire lack of research into potential treatments which may mitigate some of the symptoms of ME. Does your research point to any potential treatments for ME?
Avindra Nath: Yes, our study suggests that immune modulatory therapies should be considered as disease modifying treatments. These would need to the tailored to the patients to target the predominant immune abnormality in that individual. These medications can have serious side effects; hence they need to be studied in the context of a clinical trial.
It is necessary to conduct clinical trials and study pathophysiology in the context of these clinical trials. One such method might be to consider a platform trial where multiple agents can be studied and compared against one another with a single placebo arm.
NIH Research Roadmap for ME
Many scientists in the field of ME research welcome the study as presenting a number of ‘compelling findings’ which will be of great benefit to future research into the illness. Having said this, the low number of study participants is one limiting factor of this study. It is quite clear that further research is needed to find the causes of ME, to find a biomarkers for the illness and discover potential treatments as well. Can you tell our readers about the NIH initiative, the NIH ME/CFS Research Roadmap, for further research to improve our understanding of this debilitating neuro-immune disease? Does this roadmap include the involvement of the ME community?
Vicky Whittemore: The ME/CFS Research Roadmap is an ambitious report developed by a Working Group of NINDS Council that included researchers, clinicians, leaders of advocacy organizations, as well as five people with lived experience. These individuals were absolutely essential to creating the Roadmap so that future research and clinical trials are not only scientifically valid and impactful but carried out with the needs of people with ME/CFS in mind.
The goal of the Roadmap was to assess current ME/CFS research activities and identify opportunities and gaps in ME/CFS research to identify targets for the development of treatments.
Twenty one people with ME/CFS, caregivers, spouses, and others with lived experience planned and ran eight topic area webinars with open Q&A sessions. Speakers included people with lived experience and leading experts in ME/CFS from around the world. We focused on answering three key questions: what do we know, what don’t we know, and what do we need to do to accelerate research to move toward clinical trials?
The broader ME/CFS community played a major role in the Roadmap. We hosted public webinars and crowdsourcing campaigns, resulting in over 400 suggestions for research directions from the community.
The Roadmap report was presented to and accepted by the NINDS Council in May 2024.
Our next steps may include plans to form a clinical trial working group, genetics working group, and new NIH funding mechanisms to support exploratory research.
The full ME/CFS Research Roadmap report and topic area webinars (also called the ME/CFS Research Roadmap Webinar Series) are posted on the NINDS website.
Vicky Whittemore: The ME/CFS Research Roadmap report is finalized and has been accepted by the NINDS Advisory Council. The Trans-NIH ME/CFS Working Group is moving forward with follow-up from the initiative to address the research priorities identified in the report. We acknowledge that there are important areas, like suicidality, that were not addressed in the report and may be addressed through additional working groups going forward.
National Institutes of Health (NIH):
If you or someone you know is struggling or having thoughts of suicide, call or text 988 or chat online to connect with the 988 Suicide & Crisis Lifeline. The Lifeline provides free and confidential support to people in suicidal crisis or emotional distress 24 hours a day, 7 days a week, across the United States. In life-threatening situations, call 911.
In the UK you can get support from the Samaritans 116223 https://www.samaritans.org/