Mady Hornig's Research Made Simple

Sudden Onset has produced another excellent video explaining the science of ME/CFS.

In ME/CFS: The Scientific Evidence -Episode 3 - "The SIGNATURE" Mady Hornig's research on immune abnormalities is elegantly explained using images and music. I would encourage everyone to watch this 15-minute video, as you will not find a more concise explanation anywhere.

Mady Hornig's cytokine study, Distinct plasma immune signatures in ME/CFS are present early in the course of illness, made headlines last February for a number of reasons. First, it showed significant immune system alterations between patients and healthy controls. Second, it revealed why many other studies have not found similar abnormalities.

The answer turned out to be something fairly simple. The immune systems of people who had ME/CFS for three years (or less) had a cytokine pattern (a "signature") that was markedly different from controls as well as from patients who had been ill more than three years.

Based on these findings, the researchers concluded that people with short-term ME/CFS have upregulated immune systems indicative of a viral infection, and patients with long-term ME/CFS suffer from "immune exhaustion."

What was remarkable about this study was that not just one, but ALL twenty-four cytokines were altered in both long- and short-term patients compared to controls.

The early phase (blue bars) of ME/CFS showed elevations of nearly all the interleukins (pro-inflammatory cytokines) which is typical of an immune system fighting off an infection. Strikingly, patients who had been ill for less than a year were 100 times more likely to have elevated interferon gamma, which is indicative of a viral infection. Short-term patients were also 50% more likely to have elevated IL-12 P40, which is a pro-inflammatory cytokine produced by microglial cells (among others). The microglia are activated in the brain when there is an infection in the central nervous system. Although an elevation of IL-12 P40 is not definitive proof of neuroinflammation, it supports a study published in 2014 by Nakatomi et al. which found evidence of microglial activation in the brains of patients with ME/CFS.

The chronic phase (red bars) showed elevations in eotaxin CCL11,  GMCSF (granulocyte macrophage colony-stimulating factor receptor), PDGF-BB (platelet-derived growth factor-BB ), and CD40L. Also of note was the depression of IL-17F in both phases. (In 2008, Metgzer et al. found a similar depression of IL-17F. The authors concluded that this cytokine may play a protective role against the disease. )

Because they perform so many roles, it is impossible to make generalizations about the function of individual cytokines. Nonetheless, three of the cytokines related to the chronic phase of ME/CFS stand out.

• Eotaxin CCL 11 recruits eosinophils, white blood cells which are elevated in people with allergies. When administered to mice, eotaxin CCLL decreases their neurogenesis and cognitive performance.

• GMCSF is found in high levels in joints with rheumatoid arthritis, an autoimmune disease.

• CD40L leads to reactive oxygen species production, resulting in oxidative stress.

Oxidative stress, atopy (allergy), and autoimmunity are three immune processes implicated in long-term ME/CFS.

At this point, a replication of this study is crucial. We can only hope that the NIH will undertake funding for similar immune system research.

It would also be enormously helpful if the authors of previous immune system (and other) studies went back over their data to see if there are patterns associated with short- and long-term patients which may have been lost when the results were averaged. Among the 5000+ studies that have been performed on ME/CFS patients there is a wealth of data that have yet to be explored.

Some of those "hiding in plain sight" data may lead to a biomarker.

Mind the Abyss

This video is a powerful description of sudden onset ME/CFS. (Those who had acute onsets will find it achingly familiar.) Unlike most other videos on this subject, it does not rely on speech to get the point across.

Often images and music can do a better job of portraying reality than interviews. The emotive content of abstract representation seems to bypass the skepticism that is aroused in people, particularly physicians, when they hear people speak. Music hits us in a place that has no defenses.

If I could, I would show this video to every physician and medical student - everywhere.

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• Assists patients with chronic disease in learning about the types of new medicines in development that may help them.

Helping Millions of Patients

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Rituximab: A Wonder Drug for Severe ME/CFS?

This short video demonstrates the action of rituximab, a drug which shows promise for those with severe CFS/ME. Rituximab (trade names: Rituxan, MabThera) was first approved by the FDA in 1997 for the treatment of non-Hodgkin's lymphoma. It is believed that rituximab destroys tumors by attaching to the CD20 receptor on B cells, causing the tumor cells to disintegrate. In some non-Hodgkin's B-cell lymphomas, rituximab prevents the production of more tumor cells.

Rituximab is also used in the treatment of autoimmune disorders, such as rheumatoid arthritis and Wegener's granulomatosis. In these cases, rituximab works by temporarily depleting the total number of B cells, which are important in promoting inflammation. Rich Van Konynenburg proposed that this is why rituximab works for CFS/ME patients – by reducing B cells, rituximab reduces inflammation.

The effect of rituximab on CFS/ME patients was discovered by accident. Two Norwegian doctors, Øystein Fluge and Olav Mella of Haukeland University Hospital, noticed that after treating a CFS/ME patient for Hodgkin's lymphoma with rituximab, she recovered from CFS/ME. This led the doctors to initiate a small study of rituximab on CFS/ME patients.

Three CFS/ME patients were given rituximab in an open-label trial (that is, the patients knew they were receiving the drug). All three patients experienced significant improvement; two of them responded within six weeks and the third had a delayed response, occurring six months after treatment. The positive effects lasted for between 16 and 44 weeks. After relapse, the patients were administered another dose of rituximab, with the same positive results. The investigators hypothesized that B cells of the immune system might play a significant role in CFS, at least for a subset of patients, and that “CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function.”

The positive results of this, as well as a second open-label trial, led Drs. Fluge and Mella to conduct a larger study with a more rigorous design to test the effects of the drug. In 2009 they initiated a double-blind, placebo-controlled phase trial with 30 CFS/ME patients. As in the earlier open-label studies, the responses to rituximab were significant. Sustained overall improvements were noted in 67% of the patients (as opposed to 13% of the control group). Four of the rituximab patients showed improvement past the study period. The authors concluded that the delayed responses starting from 2–7 months after rituximab treatment, in spite of rapid B-cell depletion, “suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses.”

Dr. David Bell, a now retired CFS/ME specialist, says “I've not seen results like this in any medical study in the 25 years that I have been in this field."

Antivirals for Cognitive Dysfunction: Interview with Dr. Jose Montoya

This is a short video of Dr. Jose Montoya of the Stanford Hospital Infectious Disease Clinic, speaking about CFS/ME. Dr. Montoya has completed clinical trials of valganciclovir (Valcyte), an antiviral, on patients with Viral Induced CNS Dysfunction, a subset of patients with Chronic Fatigue Syndrome. The data Dr. Montoya presented at the 2008 International Conference on HHV-6&7 indicated that after taking Valcyte, patients experienced significant cognitive improvement. He is currently collaborating with Ian Lipkin, Professor of Neurology and Pathology at the College of Physicians and Surgeons at Columbia University. Professor Lipkin is also Director of the Center for Infection and Immunity, an academic laboratory for microbe hunting in acute and chronic diseases.

In this interview, Dr. Montoya addresses the onset and treatment of CFS/ME. He states that perhaps 11% of those who have acute infections of any kind may develop CFS/ME. Dr. Montoya believes that CFS/ME is an immune response to an infection. While the initiating infection may vary from patient to patient, he believes that CFS/ME is most likely caused by some common pathway in the immune system, which he characterizes as a “two-edged sword.” On the one hand, the immune system combats the infection, but on the other it may perpetuate an ongoing cycle of symptoms.

Dr. Montoya's primary clinical approach is through the use of antivirals. He has personally seen patients who have been ill for decades make recoveries after antiviral treatment. His main interest is in “brain fog,” the set of cognitive disturbances that inhibits a patient's ability to focus or to perform mental tasks.

Dr. Montoya's goal is to have a CFS/ME center where patients can recover, away from the stresses of life. “Our dream is to eradicate CFS from the surface of the earth,” he states. He believes that dream is within our reach.

More information:

Stanford Chronic Fatigue Initiative

http://chronicfatigue.stanford.edu/

Brain Injury and Gut Dysbiosis in CFS/ME: Interview with Dr. Byron Hyde and Professor Kenny De Meirleir

Dr. Byron Hyde and Professor Kenny De Meirleir are two of the best-known names in the field of researching CFS/ME. Dr. Hyde is the director of the Nightingale Research Foundation located in Ottawa, Canada. His book, The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome remains the most comprehensive collection of scientific and clinical studies on CFS/ME ever published.

Professor Kenny De Meirleir is a professor of physiology and internal medicine at the Vrije Universiteit Brussel in Belgium.  Professor De Meirleir has co-authored more than 80 studies on CFS/ME. He was also one of the authors of the International Consensus Criteria, the most accurate case definition for evaluating CFS/ME.  Professor De Meirleir's work is based on the premise that the gut wall in CFS/ME is abnormal, and that bacterial pathogens in the gut must be treated in order for antivirals or other treatments to be effective.

In this interview, conducted in 2008 by Öppna Kanalen Göteborgs Webb-TV (a Swedish open-channel station), Dr. Hyde spoke about CNS involvement. His perspective is that CFS/ME is a form of brain injury. He considers it to be a diffuse injury that results in an inability to handle physical or mental stress. Once the brain is injured, the illness affects all body systems. He does not believe there is a general treatment for CFS/ME. However, he believes there is a great deal of collateral damage that must be treated on an individual basis.

Professor De Meirleir spoke about his approach to treating CFS/ME. He performs normal tests to exclude major diseases, then does a series of tests for viruses, immune system and digestive system function. He believes that there is a predisposition to the disease when there is food intolerance or maldigestion. He considers maldigestion to be a major stress on the immune system, 80% of which is in the gut. When another infection occurs, “your bucket flows over and you go into a state where the immune system never comes to rest.”

In CFS/ME, Professor De Meirleir treats food intolerance first (with diet). Then he treats gut dysbiosis (abnormal gut flora) and helps repair the gut barrier (leaky gut). He says it takes a year to recover gut function. Professor De MeirLeir also spoke at length about subgroups.

While this interview was somewhat shortened, there is a wealth of information here about the possible causes, mechanisms, and treatments for CFS/ME. Highly recommended. 

Original interview posted on:

Öppna Kanalen Göteborgs Webb-TV

http://okgplay.no-ip.org/

More information:

Nightingale Research Foundation

http://www.nightingale.ca/

Contact information for Prof. De Meirleir

http://www.pugilator.com/awareness/prof-dr-kenny-de-meirleir-and-himmunitas/

TheClinical and Scientific Basis of Myalgic Encephalomyelitis/ChronicFatigue Syndrome. Byron A. Hyde, Jay A. Goldstein, P.H. Levine, eds. Nightingale Research Foundation (July 1992)

Dr. Derek Enlander's Treatment Protocol for CFS/ME

Dr. Derek Enlander is a native Irishman from Belfast. He came to New York as Assistant Professor of Medicine at Columbia University and then became Associate Director of Nuclear Medicine at New York University. Dr. Enlander is on the faculty of Mount Sinai Medical School and is an attending physician at Mount Sinai Medical Center in New York.

Dr. Enlander's protocol is based on treating the immune system dysfunction that underlies CFS/ME. He has an active research program, including Ampligen and GcMAF, in which his patients are invited to participate. Dr. Enlander is the founder of the ME/CFS Center, an international collaboration which includes virologist Illa Singh, geneticist Eric Schadt, immunologist Dr. Miriam Merad, Dr. Kenny De Meirleir and Dr. David Bell. (Sadly, videos of the 2011 Mount Sinai ME/CFS conference are no longer available.)

The following are current treatments used by Dr. Enlander (taken from his website). (Please go to Dr. Enlander's website for current treatments.)

Hepapressin Injection: Hepapressin is an amino acid complex similar to Kutapressin, derived from Argentinian bovine liver. Like Kutapressin, it is an immune system adjuvant. As Hepapressin on its own is rarely effective, Dr. Enlander combines the injection with his own specialized formula to produce a more efficient complex.

Immune Resist is an amino acid food additive. It is an oral capsule taken once daily. It is thought to be involved in the immune system and may diminish fatigue and "brain fog," and assist in concentration and short-term memory.

IMMUNOPlus: Immunoplus is given as an adjunct to Immune Resist. It contains folinic acid, along with other amino acids and other components in the methylation cycle. Dr. Enlander believes that the methylation cycle is part of the CFS/ ME dysfunction. 

Catapult contains phosphatidyl serine and cat’s claw. It is a non-prescription OTC supplement used to diminish "brain fog." Dr. Enlander reports quite good results with it. 

Neurontin: Neurontin is a prescription drug used as an anti-epileptic in grand mal seizures. In CFS and fibromyalgia the abnormal impulses that come from the brain are thought to be suppressed by Neurontin, allowing muscle fibers to be less fatigued. The daily dose can be up to 2400 mg per day.

Experimental Treatments

Low Dose Naltrexone (LDN): Opiate receptors are activated by naltrexone, which in low dose produces a cytokine reaction. This is thought to be helpful in CFS. Dr. Enlander states that it is too early to determine the effects.

LECTROLYTE or RECUP (a Spanish Electrolyte mixture) has been successful in fortifying muscles. LECTROLYTE may also reduce muscle pain. It contains 450 mg sodium, 125 mg potassium, 15 mg each of calcium and magnesium. LECTROLYTE does not contain sucrose or fructose (RECUP does contain these sugars).

Valcyte: Valcyte is a prescription antiviral medicine that Dr. Montoya at Stanford University has shown to be effective against the HHV-6 virus. Dr. Enlander collaborated in a study of Valcyte under the auspices of the HHV-6 Foundation. Patients interested in this treatment are encouraged to contact Dr. Enlander's office.

Ampligen: Dr. Enlander is cooperating with Hemispherx Corporation in a study of Ampligen in the treatment of Chronic Fatigue Syndrome.

GcMAF: GcMAF is a naturally occurring substance in the human body which destroys pathogens by activating macrophages. Several CFS physicians, including Dr. Cheney, Dr. De Meirleir, and Dr. Elson (Northampton, MA), have begun using GcMAF for patients who test high in nagalase, the enzyme that destroys naturally occurring GcMAF in the body.

EECP Treatment: EECP (enhanced external counter pulsation) therapy is an outpatient treatment used to improve blood circulation and increase cardiac output. It is normally used for angina and heart failure. In ME/CFS the treatment sessions are 30-45 minutes and are given once a week. During the treatment, the patient lies on a comfortable treatment table with large blood pressure-like cuffs wrapped around the legs and buttocks. These cuffs inflate and deflate continuously at specific times between heartbeats, a continuous electrocardiogram (EKG) set the timing so the cuffs inflate while the heart is at rest, in diastole, when it normally gets its supply of blood and oxygen. The cuffs deflate at the end of that rest period, just before the next heartbeat, systole. When timed correctly, this will decrease the afterload that the heart has to pump against, and increase the preload that fills the heart, increasing the cardiac output.

CONTACT:

Derek Enlander, M.D.
860 5th Avenue, Suite 1C
New York, NY 10065
Phone: (212) 794-2000
Fax: (212) 327-2125
Email: mecfsoffice@enlander.com
Website: http://www.enlander.com/

Dr. Enlander accepts Medicare (not HMO), Medicaid (NOT) managed care, GHI-HealthNet- HMO – POS, PHCS, United Health, Cigna, JJ Newman, Oxford freedom Plan..