Is Post-exertional Malaise (PEM) a Mast Cell Activation Syndrome (MCAS) ?
This clinical study evaluated the effectiveness of ketotifen, a mast cell stabilizer, in the treatment of post-exertional malaise (PEM) in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID. PEM, a symptom characterized by excessive worsening of symptoms after activity, significantly impacts the quality of life of individuals with these conditions. PEM blocks recovery because it is a negative consequence of activity, and increasing energy through treatment is pointless due to PEM because it makes the patient sicker for days after activity, negating the result.
This retrospective study in our medical center included patients prescribed ketotifen. Before treatment, patients underwent a comprehensive assessment, including medical history, standardized questionnaires (DePaul Questionnaire, Orthostatic Grading Scale, Epworth Sleepiness Scale, Convergence Insufficiency Symptom Survey), and functional tests (Stroop Test, Handgrip Strength Test, NASA 10-Minute Lean Test) to document their diagnosis and symptom severity.
Treatment consisted of a weekly escalating dose of ketotifen, from 1 mg per day to a maximum of 6 mg per day based on individual tolerance and response. Improvement in PEM was assessed on a 4-point Patient-Rated Global Impression of Change (PGIC) scale. Additionally, during monthly check-ups, patients were asked about their experience and a description of changes, if any.
Ketotifen is a histamine receptor 1 antagonist, a leukotriene receptor antagonist, and a mast cell wall stabilizer. Ketotifen has been known for 45 years for the treatment of allergies. It is used off-label in the treatment of mast cell activation syndrome.
For this retrospective analysis, the data of 134 patients (84 ME/CFS, 50 Long COVID) were examined. After an initial dose, 30% of participants discontinued ketotifen treatment due to side effects, mainly fatigue, drowsiness, and negative emotional experiences. A significant reduction in PEM (PGIC>1) was observed in 77% of ME/CFS patients and 91% of Long COVID patients who continued treatment.
These findings suggest a link between PEM and mast cell activation syndrome (MCAS), a condition characterized by excessive mast cell activity and a wide range of symptoms. With its ability to stabilize mast cells and block the effect of histamine and leukotriene release, ketotifen may offer a therapeutic option for treating PEM in both ME/CFS and Long COVID patients. The similar response rates observed in both patient groups further support the hypothesis that shared underlying mechanisms, possibly related to mast cell dysfunction, contribute to PEM in these conditions.
While promising, these results are based on clinical data and warrant further investigation through rigorous scientific research. Future studies should focus on confirming the efficacy and safety of ketotifen for PEM, exploring the underlying mechanisms of mast cell activation in PEM, and determining the optimal dosing strategies for this patient population.
Treatment of Long COVID and ME/CFS: Bridging the Gap Between Science and Clinical Practice
Why are there no approved medications yet?
Introduction
Thirty years after the widely accepted definition of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), initiatives are emerging in the Netherlands to establish a scientific basis for drug treatment. However, the challenges involved are not yet widely known.
Over the past 35 years, our center has made various contributions to scientific knowledge about ME/CFS and treated thousands of patients. We consider it our responsibility to formulate recommendations that can increase the likelihood of effective treatments. This can be achieved through close integration of clinical practice and scientific research.
This call is directed at scientists to contribute to the preparation and execution of research into drug treatments. Collaboration between scientists and clinicians is essential to making progress and evaluating the impact of potential therapies.
The Problem
The criteria for ME/CFS are established based on consensus. This means that only the observations and opinions of experts were used in formulating these criteria. Although these consensus criteria are valuable, they lack a scientific basis.
Each new group of experts brought additional insights, causing the criteria to change over time. A good example of this is the Fukuda criteria for CFS in 1999 and the Canadian criteria for ME/CFS in 2003. Both represent significant progress in diagnostics and demonstrate the ongoing evolution of diagnostic guidelines.
Clinical Practice
In clinical practice, questionnaires and tests that focus on symptoms, complaints, and perceived limitations are used to diagnose ME/CFS. However, these questionnaires are internally validated but not based on scientifically established causes and processes.
The questions and results of these questionnaires refer to consensus criteria, leading to circular reasoning without a solid scientific basis. This makes it difficult to use these questionnaires to measure treatments’ effectiveness in a widely accepted way.
Furthermore, objective tests have not yet been validated. This is a major bottleneck in clinical practice, as the results do not provide sufficient certainty about the relevance of the outcomes. Proper validation depends on acceptance by pharmaceutical companies and insurers.
Scientific Research
Science has advanced techniques to investigate complex clinical problems such as ME/CFS and Long COVID. Each study contributes to a better understanding of these conditions.
While these discoveries are valuable, they are not yet applicable in daily clinical practice. There is still much room for collaboration between the scientific and clinical worlds. Close collaboration between both disciplines is essential for validating clinical measurements and answering practical questions.
Examples of Future Collaboration
We provide some examples of future collaboration to construct endpoints in clinical research. As mentioned, clinical scientific research is only possible with validated endpoints.
Energy:
Measurement of energy production limitations was previously performed with an ergospirometry test. A hand dynamometer test has replaced this method, but different protocols exist. Our protocol seems suitable in practice for objective measurements of causes and for determining the effect of interventions on energy production. Formal validation has not yet taken place.
In ME/CFS, energy production has shifted from a system that supports activity to a system that focuses on survival. The mechanisms that control this change are largely unknown. We know that the functions of enzymes in carbohydrate conversion are limited, but how this works exactly is unclear. There must also be regulatory mechanisms in oxidative phosphorylation, the final steps in energy production, in patients with Long COVID and ME/CFS, but where and how these intervene is not yet known. To develop effective treatments, more insight into these processes is necessary. Science has the techniques for that.
Cognition:
Although clinical observations of the effects of high plasma concentrations of vitamin B12, posture, hyperbaric oxygen, acetyl-L-carnitine, and other factors on cognitive functions exist, scientific evidence is lacking.
Measurement methods exist to objectively determine cognitive limitations, and sufficient research exists into the nature of these limitations. However, validation is still lacking, which limits the reliability of measurements and conclusions.
PEM:
Post-exertional malaise (PEM) is the core symptom of Long COVID and ME/CFS. Without PEM, there is no Long COVID or ME/CFS. Yet a definition that goes beyond consensus on symptoms is lacking.
Now that patients indicate that this symptom decreases after our targeted drug interventions, this is the right time to determine together with them what exactly changes and what remains. This can contribute to a sharper definition of PEM. Based on this, a measurement method can be developed to quantify this subjective experience objectively. Without validation, the quality of scientific research remains insufficient.
POTS:
The control and regulation of autonomic processes do not function optimally in patients with Long COVID and ME/CFS. There are many descriptions of this dysfunction, but objective measurements are limited to the influence of postural changes on blood circulation. When sitting or standing, pressure changes in the body must be compensated. This often does not work well in Long COVID and ME/CFS. If the reaction is insufficient, blood pools in the legs. The blood vessels constrict if the response is too strong, and resistance increases. The heart responds to this with an accelerated heart rate. In Long COVID and ME/CFS, these reactions deviate from the norm, and the results of measurements in these patients do not match existing questionnaires. As a result, questionnaires are not yet usable in this group, while no alternative is available.
Overstimulation:
Hypersensitivity to stimuli is a significant problem in both Long COVID and ME/CFS. Many patients have to live in a dark and quiet environment, with shielded eyes and ears. Even everyday activities, such as washing, are often barely possible. This serious problem cannot serve as an endpoint for research because there are no reliable measurement methods for it yet.
Patients indicate that light and sound are particularly difficult to tolerate. The intensity of stimuli and response must be quantifiable, especially for light. Validating such measurements is an additional challenge that still needs to be investigated.
Fatigue:
Fatigue, along with the psychologists, has disappeared from the diagnostic criteria. However, this does not mean that it has disappeared from clinical practice. It remains a common complaint but is often underestimated. An open and scientific discussion about its meaning is lacking, making it a blind spot and leading to miscommunication.
Fatigue is a broad concept that refers to signals and motivations that indicate that behavioral adjustment is needed to prevent problems. The causes and manifestations of fatigue vary and require different approaches. Fatigue after sports requires physical rest, while fatigue from prolonged computer use requires sleep. Fatigue in Long COVID and ME/CFS, on the other hand, does not respond to sleep or rest. Using the same word for different phenomena can lead to confusion. As Professor Bleijenberg once said: “One fatigue is not the other.”
A systematic and scientific analysis and definition of fatigue in Long COVID and ME/CFS are necessary. Although fatigue is often used as a primary endpoint in research, its cause and meaning are still insufficiently investigated.
There is no evidence that fatigue is central to the pathophysiology of Long COVID and ME/CFS. Yet, it is regularly used as an endpoint in intervention studies. This is partly because fatigue is a cheap and easy-to-measure symptom.
Conclusion
Scientific research into the causes of symptoms and the effectiveness of interventions is essential for the widespread acceptance of treatments. Scientists who investigate clinical issues play a crucial role in this. This is a challenging scientific task and an urgent need to develop effective treatments.
Through collaboration and bridging the gap between clinical practice and scientific research, we can improve patients’ lives. What we research today can contribute to saving and alleviating lives tomorrow.
Treatment Combinations.
Every treatment we offer comprises a combination of various agents. These agents are always added as a separate component to the treatment, allowing us to assess and adjust the efficacy of each agent individually as needed.
Treatment Selection Based on Anamnesis and Measurements:
The choice of treatment is determined by the patient’s anamnesis and specific measurements:
– For a diagnosis of orthostatic intolerance, as indicated by a deviating NASA 10-minute lean test or an elevated value on the Orthostatic Grading Scale, we initiate the treatment with water, salt, and additional medication if required.
Conversely, the preferred treatment begins with L-carnitine in evident mitochondrial dysfunction without signs of orthostatic intolerance.
Values are mentioned when the numbers were deemed sufficient for assessment.
Overall result: A positive effect of the treatment in 96% of the patients who tested at least three agents.
Conclusion
Thanks to our systematic approach and detailed recording, we can provide tailor-made treatments based on each patient’s unique needs and symptoms.
The video is better.
In the past few months, we have been speaking to more people via video and comparing whether it is better than the old in-person consultations at the center.
Indeed, it is better.
We particularly notice that people do not arrive exhausted from traveling to our location and that there is less stress. You don’t need to ask for help with transportation, and you don’t have to rush home for children or due to traffic.
People can talk to us from their couches or bed, and the tests go smoothly with video guidance.
The transfer of information is improved, and there is no need for more than that.
Especially now, with the increasing number of consultations in Europe, this is a compelling reason for us not to return to the old way of shaking hands in the examination room.
Examination and Treatment with Video Consultations:
Using secure video connections, patients can now receive diagnosis and treatment without traveling to our outpatient clinic. We can now better examine individuals who are bedbound or living in other countries. Necessary tests can be conducted at home with professional guidance.
The involvement of physiotherapists and other healthcare professionals in the treatment, using video meetings to support and coordinate the care, has proven to be a practical approach. We are successfully implementing this method in treating ME/CFS and Long COVID patients in Europe.
In this section, we share our thoughts and examples of patients. We ensure that these medical histories are described so they cannot be traced back to existing patients to protect their privacy.
Low Dose Naltrexone for Long COVID?
We receive many questions about Low Dose Naltrexone (LDN).
Long COVID patients are asking if we prescribe it.
The answer to the first question is: yes, we prescribe it only after an examination and with guidance.