*Patient Stories: Illustrative Examples

In this section, we share our thoughts and examples of patients. To protect their privacy, we ensure that these medical histories are described so they cannot be traced back to existing patients.

The effect of beta-hydroxybutyrate (BHB).

BHB is a ketone. Ketones are the backup system for carbohydrates. When carbohydrate is not available, the body makes ketones from fats. A corresponding system exists for fats. When fat is insufficiently available, the body uses more proteins.

Ketones are not converted in multiple steps like carbohydrates. In several steps in the anaerobic glycolysis, glucose is made suitable for uptake in the citric acid cycle, the primary energy generator. During the conversion of glucose to pyruvate and the end product acetyl-CoA in anaerobic glycolysis, energy is generated, but also lactate. Therefore, it is limited.

At several points, the conversion process can be uncoupled. Then, no Acetyl-CoA is formed, but other products that are more needed. No energy to the muscles, but to other processes.

BHB is the best-known ketone. We use it in our measurements because it is directly absorbed into the citric acid cycle without the possible uncouplings in the anaerobic glycolysis that can block carbohydrate metabolism. So, strength with BHB, but not without BHB, indicates a problem in the anaerobic glycolysis.

Patient 10

Patient 10 is a 27-year-old woman who did not recover after contracting mononucleosis (Epstein-Barr virus) at the age of 15. She was severely physically limited. She was capable of short activities, but after a few minutes, her energy was depleted.

In examinations at other centers, no explanation was found, and she was advised to work with a psychologist to find ways to live with her limitations.

In our examination, we found orthostatic intolerance in the form of neuropathic POTS, meaning her heart rate increased by more than 30 beats per minute upon standing, with indications of blood pooling in the lower half of the body.

In the hand dynamometer test, her grip strength was normal in the first two measurements, but the strength quickly decreased. The (red) curve had a logarithmic progression, with the decline being rapid initially and then slowing down as the measurement continued. The value approached the 5 kg limit. We agreed to repeat the test with BHB. In the measurement before taking BHB, a pattern similar to the first test was observed (green line), but the strength stabilized at 10 kg. After BHB, the strength normalized to an average value for women in our reference (purple line). No further decline was observed.

This patient has clear evidence of a disorder in anaerobic glycolysis. Interestingly, the patient did have energy available for a very short period, probably from the 10-second reserve of phosphocreatine. The BHB completely overtook the anaerobic glycolysis’s energy and acetyl-CoA production. This indicates a blockade of the pyruvate dehydrogenase, the enzyme system that regulates carbohydrate supply to the citric acid cycle.

Patient 9

Patient 9 is a 33-year-old woman who has always had insufficient energy. Her mother and a sister have the same complaint. The patient did not meet our criteria to diagnose ME/CFS. Laboratory tests indicated chronic activity of the immune system. In our examination, it was noted that her grip strength was low, at the 10th percentile. This means that 90% of healthy women her age have more strength. The graph of the patient’s strength in red ran parallel to the blue reference line. After taking 2.5 grams of BHB, her strength increased by 57% (the grey line).

In patient 9, a flat graph was found. There was no energy available for a short period. After BHB, the energy production doubled. This suggests a problem in the anaerobic glycolysis, which explains half of her physical limitation. However, a decoupling of the energy production process elsewhere also seems likely.

Patient 8

Patient 8 is a 30-year-old woman who did not recover after two infections.

A hand grip test was conducted during the first phase of the examination. The result was well below the expected value for her age. The maximum strength was 10 kg (normal average 31 kg), and the strength quickly dropped to 5 kilograms (the red line in the figure). We decided to repeat the measurement without and after 2.5 g of BHB. The test was repeated several weeks after the first test. Initially, we found some strength in the test, but it quickly diminished to the minimum value measured in the first test (the grey line). After BHB, similar values were found (the yellow line).

Our conclusion from the first test was that the energy production was insufficient for activity but sufficient for survival. In the second test, some energy production seemed possible, but not for more than a few minutes, and pain occurred.

In patient 8, no energy was found; the strength was at the level of a toddler of 5. In the follow-up tests, energy was available for a few minutes, but with a ketone, it was not possible to produce energy for longer, and pain occurred due to acidification. In patient 8, there seems to be no decoupling in the first phase of carbohydrate conversions from glucose to pyruvate. Further research is needed to determine the role of the citric acid cycle. The most likely is an itaconate shunt, which stops the citric acid cycle after cis-aconitate or a decoupling in the electron transport system in complex 3.

Patient 6

“The Woman with the Hammer”

A 23-year-old woman presented at the Long COVID clinic with severe physical and cognitive symptoms following COVID-19 in the spring of 2020.
Before her illness, the patient was active. She regularly participated in sports and had a rich social life. There were no relevant medical issues.

The patient worked as a nurse in a department of a regional hospital. The department was deployed for COVID patients. The staff’s protection with surgical masks was inadequate.
The patient was moderately ill at home. After the acute illness period, she remained physically and cognitively very limited.
A psychologist and a physiotherapist treated the patient. The physiotherapy consisted of exercising on a stationary bike twice a week.
The patient’s symptoms were sufficient for the diagnosis of Long COVID and ME/CFS.
Fatigue was described as an empty battery with periods of flu-like feeling.
The patient was hypersensitive to light and sound, had slow thinking, and was easily irritated. She often had colds, and herpes labialis (cold sores) recurred more frequently. Post-exertional malaise (PEM) lasted one to four days.
Walking was limited to a maximum of one kilometer. She often had to be carried up the stairs at home. Concentration was limited to a maximum of 45 minutes.
The patient had orthostatic complaints that occurred after standing for 15 minutes.
During the NASA 10-minute lean test, the maximum increase in heart rate was 27/min, and the pulse pressure ratio dropped to 26%.
The Stroop word color test confirmed her complaint of slowness.
The reason for this presentation is the result of the hand dynamometer tests. We measured the grip strength thirty times for 3 seconds with a ten-second pause.
The maximum grip strength at the first measurement was 15 kilograms, the average for a 90-year-old woman. The strength quickly decreased and remained at a level of 4 kg. In our reference group, it is 27 kg and 23 kg, respectively.
The measurement was repeated after 2.5 g of the ketone beta-hydroxybutyrate (BHB). The grip strength increased to a maximum of 33 kg. The strength gradually decreased to 7.5 kg (see graph)

Discussion

The graph shows that the patient had some energy for a very short period but quickly dropped to a level where no carbohydrates were used. During the first measurements, she still had energy in the form of creatine phosphate, but then only enough energy for survival remained. The energy was temporarily at a normal level after a ketone. This fits with a blockage of anaerobic glycolysis, particularly of pyruvate dehydrogenase and phosphofructokinase, as a ketone follows a parallel route past anaerobic glycolysis to the citric acid cycle. The short duration of the effect suggests that more impediments to energy production are present.

Figure: Vertical is the strength in kilograms, horizontal is the 30 measurements. The blue line is the grip strength of healthy women in our reference group. The red line is the result of the first 30 measurements. The gray line depicts the 30 measurements 45 minutes after intake of 2.5 g of beta-hydroxybutyrate.

Patient 5:

A Leading Role for the Immune System

This patient was 41 years old when she presented herself in 2018.

Medical History

In her childhood, the patient repeatedly suffered from throat infections with inflamed tonsils. Her condition improved twice after treatments by an ENT specialist. Afterward, she experienced a period of good health.
At the age of 26, joint problems began, eventually leading to a diagnosis of rheumatoid arthritis by a rheumatologist. These symptoms limited her ability to work, but in 2015, the symptoms disappeared, and she was considered cured. However, she continued to experience persistent fatigue.
In 2017, her fatigue significantly increased, and her physical condition rapidly deteriorated. She could barely walk for half an hour, and even climbing stairs at home was too much. The patient was unable to work and spent most of the day in bed. At the first visit, she used L-carnitine at a dose of 1.5 grams daily and antihistamines for hay fever.

Examination

The combination of symptoms met both the Canadian criteria and the SEID criteria for ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome).
The response was significantly delayed, and tilt table testing did not explain the regularly observed high heart rate during minimal activity.
A cardiopulmonary exercise test revealed a significantly reduced maximum exercise capacity, low oxygen extraction, and normal heart and lung functions. The observed values did not align with hyperventilation.
Our diagnosis was mitochondrial dysfunction following a history of rheumatoid arthritis without evidence of organ damage.
The second phase of our research involved treatment, where we investigated the best chances of improvement based on the response to medications and supplements. In this patient’s case, we chose to inhibit the influence of the immune system with low-dose naltrexone (LDN), a substance presumed to stabilize microglia cells.
The patient showed significant improvement at a daily dose of 3 mg LDN. She was able to get out of bed and take short walks outside.After trying various antihistamines, it was found that a dose of 10 mg of Montelukast improved her physical condition to an estimated 85% of a healthy person. This level of improvement was acceptable to the patient.

Conclusion

The patient did not fully recover after a phase of an autoimmune disease diagnosed as rheumatoid arthritis. Following this phase, increased immune activity persisted. Her treatment included L-carnitine, LDN, and Montelukast. L-carnitine optimizes the availability of fatty acids and carbohydrates for energy production in the form of ATP. L-carnitine is also an amino acid that can be used as fuel alongside fatty acids. The combination of LDN and Montelukast suppressed the influence of the immune system on energy production.

Patient 4

A 30-Year-Old Woman with Long COVID: A Case of Energy Production and Orthostatic Intolerance

Summary:

A previously healthy and active 30-year-old woman faced persistent and severe physical and cognitive limitations after contracting COVID-19 in October 2021. Despite undergoing conventional recovery methods such as physical therapy and psychological support, she grappled with extreme fatigue and limited mobility and relied on a wheelchair for outdoor activities. A comprehensive evaluation conducted via video revealed an absence of post-exertional malaise (PEM), but it did show positive indications of orthostatic intolerance and significantly reduced handgrip strength, pointing towards an energy production problem. The diagnostic process also involved a NASA 10-minute tilt test and the Stroop color-word test, ultimately resulting in a diagnosis of Long COVID without PEM. Treatment began with the patient increasing her hydration through Oral Rehydration Solution (ORS), leading to gradual improvement. Over several months, her condition improved to the extent that she could walk longer distances and gradually reintegrate into the workforce. This case highlights Long COVID’s intricate and diverse manifestations, emphasizing that an accurate diagnosis and tailored treatment approach can play a crucial role in aiding recovery and enhancing the patient’s well-being.

Medical History:

The patient had never encountered any notable health problems and maintained a 32-hour workweek while consistently participating in sports activities. However, following a COVID-19 infection in October 2021, her health did not recover as expected. Subsequently, she sought evaluation from an internist and received treatment from both physiotherapy and psychology. Despite these interventions, she exhibited severe physical and cognitive limitations.

Examination:

The examination took place through a video consultation. The patient reported that she could only walk a distance of 100 meters and depended on a wheelchair for outdoor mobility. She encountered a physical constraint at the beginning of any activity, lacking an initial surge of energy. Her capacity to focus on tasks was restricted to 30 minutes. The fatigue she experienced felt like an ongoing drain, without the sensation of being unwell. Notably, no post-exertional malaise (PEM) was observed following physical activity.

Findings:

The patient reported experiencing dizziness, and the Orthostatic Grading Scale yielded a positive score of 13/20 (normal < 5). During the NASA 10-minute tilt test, her heart rate increased by 27 beats per minute upon standing, which was within the normal range. However, her diastolic blood pressure increased more than the systolic blood pressure, resulting in a pulse pressure drop below 25% of the systolic blood pressure. The resting heart rate was slightly elevated at 82 beats per minute.
Handgrip strength measurements conducted with a hand dynamometer consistently indicated significantly reduced strength compared to reference values. Her grip strength was equivalent to that of an average 80-year-old healthy woman. There was minimal variation between these measurements, suggesting their reliability. Notably, there was no decline in strength during the initial measurements, and energy production did not increase after the administration of beta-hydroxybutyrate (BHB), a ketone.
The results of the Stroop color-word test indicated delayed processing but no difficulties in comprehension. Interestingly, reading comprehension was better when the patient was lying down compared to when she was in a standing position. Laboratory tests did not reveal any values that were considered abnormal.

Discussion:

The patient displayed evident indicators of Long COVID, yet she did not experience post-exertional malaise (PEM), nor did she feel unwell. Her symptoms strongly suggested insufficient energy production, even though PEM was not present. The physical limitation was apparent and substantiated by the handgrip test. The repeated handgrip measurements shed light on her energy production, hinting at an underlying circulatory issue as the cause. In situations involving a blockade in anaerobic glycolysis, values typically improve after the administration of beta-hydroxybutyrate (BHB), but this was not the case for this patient. The relatively flat trajectory made a blockade in the citric acid cycle or oxidative phosphorylation less probable.
The initial diagnosis was Long COVID with orthostatic intolerance. Treatment commenced with increased water intake and the use of Oral Rehydration Solution (ORS), gradually improving the patient’s condition. After several months, she regained the capacity to walk longer distances and return to work, eventually allowing for the discontinuation of ORS treatment.

Conclusion:

Long COVID manifests in various forms, and this case highlights the heterogeneity of its presentation. In this patient’s case, the predominant symptoms were linked to orthostatic intolerance, which showed marked improvement through increased vascular filling. This underscores the importance of comprehensive diagnostics and personalized treatment approaches in facilitating the recovery and enhancement of the Long COVID patient’s quality of life.

Patient 3

A 27-year-old man.

In February 2020, he had a Covid-19 infection and was bedridden for two weeks.
After recovering from the acute phase, he remained tired and physically and cognitively impaired.
Upon further inquiry, it was found that he experienced fatigue as “flu without the flu”: a constant feeling of becoming cold, which increased after activity. The fatigue was also described as “the man with the hammer”: a feeling as if the battery was always empty.
He felt that he had become much slower.
He was hypersensitive to light and sound. His sense of smell had returned.
Examination by the internist did not explain the symptoms.
His medical history was free of illnesses, and the laboratory results were normal.

The NASA 10-minute lean test was normal.
The hand dynamometer test showed minimal grip strength. The strength increased by over 100% after beta-hydroxybutyrate (BHB) but remained well below normal.
The provisional diagnosis was Long COVID with indications of immune system activity based on the “flu without the flu” complaint and the multiple blockages of energy production.
Blockages in the process of producing energy from fats and carbohydrates are common when the immune system is active.
In the preparation of glucose, the first two blockages can be bypassed with a ketone, but for what comes after, we try to help energy production with a substance formed after a blockage, or we try to reduce the blockage with LDN.
We combined two treatments for maximum effect by combining LDN with alpha-ketoglutaric acid, a substance formed after a critical blockage.
The effect of LDN can be compared to paracetamol for flu. The flu doesn’t lessen, but you feel less sick; it only reduces the impact.
For Long COVID, the dosage of LDN is more challenging than for ME/CFS. Long COVID patients can react much more strongly to LDN. That’s why we now start with a fraction of a drop in the first few days.
There is no scientific evidence for the treatment of Long COVID. This applies to both paramedical and medical treatments. We search for a combination of substances that reduce symptoms for each patient according to a fixed protocol.

Patient 1 and 2

Long COVID, a Syndrome with Many Faces

Patient 2 is a French woman, nearly 60 years old, who experienced two Sars-COV-2 infections. She recovered after the first, but the second left her tired, with limited sense of smell and brain fog. Four months later, she sought advice from an internist at a university in her city. Extensive testing, including laboratory tests, chest and abdominal X-rays, and ECG, led to a diagnosis of post-COVID syndrome. The recommendation was physiotherapy and psychotherapy. Half a year later, after completing both treatments, her condition remained unchanged. Treatment with amitriptyline and beta-blockers worsened her symptoms.

Patient 1 is a 28-year-old German woman who fell ill multiple times during the coronavirus period. The first time, testing was not available. During the last two illness periods, Sars-COV-2 infection was confirmed. She underwent comprehensive examinations by an internist, cardiologist, neurologist, and rheumatologist. Based on the anamnesis, negative investigation, and symptoms, the diagnosis of Long COVID was made. The patient was advised to recover through physiotherapy and occupational therapy. The physiotherapy was terminated after a few sessions as the exercises were too strenuous. The occupational therapy continued because the patient felt that the advice helped her cope with severe limitations. She attended courses in Germany and Spain but without improvement. Treatment with vitamin B12 twice a week was discontinued after three months due to a lack of improvement.

Both patients registered on our website shortly after each other.

During the anamnesis of patient 2, it was revealed that her primary complaints were fatigue and headache, but headaches and migraines had been present throughout her life. Migraines often occurred after exertion, such as sports. Exertion quickly led to a high heart rate. Attempts to treat this consistently increased symptoms. Besides the headache, brain fog was the main complaint at registration. The physical condition was not the reason for the consultation.

During the reading speed measurement, we found normal values. The hand dynamometer measurements showed values above the 50th percentile of the reference range. We repeated the measurements 30 times to get an impression of energy production. After 2.5 mg of beta-hydroxybutyrate (BHB), the strength did not increase. BHB is a ketone. In blocking anaerobic glycolysis due to reduced enzyme activity, we see a significant increase in energy production when no other blockades are present. This matched the anamnesis in which the patient reported no physical limitations.

Clear abnormalities were found in the NASA 10-minute lean test. In this test, the patient lies down for ten minutes and then leans for ten minutes. Blood pressure and heart rate are measured every minute throughout the test.

In patient 2, the heart rate increased more than the threshold of thirty beats per minute. In addition, the diastolic blood pressure increased more than the systolic blood pressure when standing. The pulse pressure index, pulse pressure divided by systolic blood pressure expressed in percentages, dropped to 16%. This is well below the threshold value of 25% and indicates an excessive reduction in stroke volume due to increased resistance in the body’s vessels. After the test, the patient complained about her well-known headache. On her initiative, she repeated the test with the same result each time.

In patient 1, we found corresponding values. The reading test was optimal, the hand dynamometer test values were at the 35th percentile, and after BHB, there was a minimal increase within the margin of error. In the NASA lean test, the heart rate increased by 47 beats per minute, and the diastolic blood pressure increased more than the systolic blood pressure, with a drop in the pulse pressure index well below 25%.

The drop in the pulse pressure index is an overreaction to the changed pressure ratios when standing or sitting. This drop has been described in Long COVID by Vernon et al. [1]. An inherited form with insufficient activity of the norepinephrine transporter has also been described [2].

Patient 2 has had signs of a poorly functioning system her entire life. For patient 1, the problem began after COVID. We advise patient 1 to seek investigation by a specialized center at an academic hospital. For patient 2, this does not seem necessary for the time being.

Long COVID is a syndrome with many faces. Only good diagnostics and tailored treatment offer chances for help for these patients.

1. Vernon SD, Funk S, Bateman L, Stoddard GJ, Hammer S, Sullivan K, Bell J, Abbaszadeh S, Lipkin WI, Komaroff AL: Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne) 2022, 9:917019.

2. Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, Blakely RD, Robertson D: Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 2000, 342(8):541-549.