Health Rising - Finding Answers for Chronic Fatigue Syndrome/ME and..
Cort Johnson founded Phoenix Rising and Health Rising to support people with chronic fatigue syndrome and fibromyalgia. Health Rising provides the latest treatment and research information for people with fibromyalgia and chronic fatigue syndrome. Follow to get frequent and up-to-date information.
We also hypothesize that migraine may be attributable to a reactivation
of a latent HSV residing within the trigeminal ganglion. The authors
She was a healthy 21-year-old white college student who woke up one morning to a “scintillating scotoma”, a visual aura of writhing dots. That was followed about an hour later by a severe, throbbing headache and nausea; i.e. she had a migraine – her first ever.
First came the visual aura – then the headache and all the rest
The scotoma disappeared in an hour, the headaches lasted for a day, the nausea for three days and the cognitive problems for over a week. Two days later it happened again and she was diagnosed with an acute migraine.
During the next three months, none of the treatments she tried (NSAIDS, triptans, beta blockers, prednisone and botulinum toxin) helped much. Problems with cognitive functioning forced her to take a semester off from college. Plus she was having trouble with sleep.
She appeared trapped in a classic ME/CFS/FM/migraine/POTS multi-symptom nightmare. Her problems didn’t just include pain – she also experienced significant cognitive issues and sleep problems and her disease was becoming all encompassing – causing her to drop out of school.
The Pridgen Protocol, Herpes Simplex Virus and Migraine
“On the basis of the current understanding of the pathophysiology of migraine headaches, specifically the role of HSV-mediated trigeminal inflammation in migraine symptomatology and the antiviral characteristics of famciclovir and celecoxib, we believe these medications may work synergistically to treat migraine disorder.” The authors
Seven months later her doctor tried something different, something very different – an anti-herpes virus protocol. Despite the fact that herpes simplex virus hangs out in the trigeminal nerve and the trigeminal nerve is where migraines originate, almost no work has been done to determine whether HSV is involved in migraine. If you look up antivirals and migraine there’s almost nothing on it. Migraines are just not treated with antivirals.
But neither is fibromyalgia. Nor have pathogens been looked for. Dr. Skip Pridgen, though, looked at his FM patients and thought that a herpes virus attacking the nerve ganglion might just do the trick. He went on to develop a two drug (Famvir-Celexicob) combination to get after the herpes simplex viruses he believes are causing fibromyalgia and similar disorders.
An otolaryngologist (retired) – who clearly knows intimately what’s going on in the head – named Bradford Na Pier decided that herpes simplex virus might be involved and that Dr. Pridgen’s protocol for fibromyalgia was worth a try. (Pridgen’s protocol is not specifically stated in the case report – it’s referred to in a citation. Doses – still proprietary information as Pridgen tries to get funding for the fibromyalgia phase III trials – are not reported – another indication the Pridgen protocol was used. .)
Five days later the college student reported major improvements in her symptoms including much improved sleep. After two months she was experiencing only mild symptoms and was able to return to full-time college work. She stopped Famvir/Celexicob after about a year. Fifteen months after starting Famvir/Celexicob she has only mild symptoms.
This is just a case report – we have no idea if other migraine sufferers would have the same experience. The fact, though, that the regular migraine meds failed while a drug combo that migraine-treating doctors probably aren’t aware of (and wouldn’t recommend) over time essentially ended this woman’s problems is something to think about.
Her story demonstrates that drugs out there which no one is currently considering could very well have a significant impact on ME/CFS and FM. The new migraine drugs come to mind. Nobody has assessed the levels of the substance (CGRP) these drugs are blocking in ME/CFS and FM. If somebody actually measures them and finds their levels to be high, a boatload of new drug options could suddenly open up for these diseases.
The Pridgen Connection, Fibromyalgia, Chronic Fatigue Syndrome and Migraine
Dr. Pridgen is probably not surprised by this finding. He’s long said that he thinks disorders associated with FM such as ME/CFS and IBS might be able to benefit from his protocol. Logically that could include migraine given its high comorbidity, particularly with fibromyalgia, and the close association of the herpes simplex virus with the trigeminal nerve.
Pridgen looked for herpes simplex virus in the guts of FM patients and found it but has said that he believes it’s causing trouble in other places in the body. These viruses are known for the cold and genital sores they can produce, but they probably hang out on in nerve ganglions across the body and could interrupt the signaling between these and many of our organs, glands, skin, blood vessels, and muscles. Van Elzakker has proposed that ME/CFS is caused by viral activity in the nerve cell ganglion found around the vagus nerve. Work is underway now to assess this hypothesis.
Check out more on herpes simplex virus including the many places it may be able to hide out in the body in Albert Chang’s Health Rising blog.
If Pridgen is right about FM, it makes sense that his protocol might work for migraine as well. This is as noted, just a case report – something Na Pier felt they wanted to get out in the medical literature in hopes that it will draw more interest. Let’s hope it does.
Pridgen is still looking for funding for his big phase III FM trials. Let’s hope he gets it and we can get a clear sense of how effective his protocol is in FM. If it’s successful it will open up both a new window on treatments for fibromyalgia and a new understanding of the disease – and perhaps provide a springboard for more trials in other diseases.
In many ways migraine is in the same basket as fibromyalgia (FM) and chronic fatigue syndrome (ME/CFS). The disease is common, mostly strikes women, is invisible, causes massive amounts of suffering and gets little support at the NIH. In fact migraine, with its 2-3 million severe sufferers and 30 million plus occasional sufferers, gets considerably less funding per patient per year (from $1-10) than ME/CFS. This is despite the fact that migraine is considered one of the top ten causes of disability in the world.
Migraine sufferers may soon experience a explosion of new treatment options
Migraine, fibromyalgia, ME/CFS, interstitial cystitis, IBS, and vulvodynia are some of the mostly women dominated, pain and fatigue causing diseases which cause massive suffering and are virtually ignored by the NIH. The results of a survey of migraine patients by the nonprofit Institute for Clinical and Economic Review could have just as easily been referring to ME/CFS or FM patients. It reported that migraine sufferers “frequently reported feeling frustrated, depressed, defeated, isolated, or a burden to society”. Some patients expressed suicidal thoughts and many complained of “not being take seriously”.
Patients had typically “tried extensive lists of preventive and acute treatments (including drug and non-drug therapies and lifestyle changes).” When treatments did work they either tended to stop working or the side effects were too much.
Migraine, which is notoriously hard to treat, was long thought to be psychological and has a long history of discrimination at the doctor’s office. Finding doctors willing or knowledgeable enough to treat it is difficult. Decades after being shown to be a physiological illness, migraine is still so misunderstood that two years ago the New York Times ran an article titled “Women’s Emotions Do Not Cause Their Migraines“.
Yet migraine has had a real breakthrough in treatment. The FDA just approved the first drug, a monthly injectable called erenaumab, designed specifically for migraine, and several more of its ilk will probably be approved over the next few years.
How did the big disease with little funding make good? Migraine researchers may not be getting much money or respect, but decades ago they uncovered a specific pathway involving a peptide (a peptide is a short string of amino acids – smaller than a protein) called CGRP (calcitonin gene-related peptide) that seemed to play a role.
CGRP is a potent vasodilator which enhances pain signal transmission and affects blood vessel functioning. In migraine, sensory neurons in the trigeminal system release CGRP. The trigeminal nerve – the largest and most complex nerve in the head – regulates sensations to the head, neck, sinuses and jaw and controls chewing. Any activation of the neurons in this trigeminal vascular system – which originates in the brain stem – can cause CGRP release, vasodilation (blood vessel swelling) and mast cell degranulation (inflammation).
It’s this overactivation of the trigeminal vascular system that causes migraine sufferers to retreat to dark places with low stimuli during migraine attacks.
New Possibilities for Migraine Sufferers
The new drug is not a panacea. It won’t help everyone. The studies done to date in about 3,000 patients suggest it will reduce migraine attacks by more than 50% in about 50% of migraine sufferers. A third of chronic migraine sufferers will see reductions in migraine of about 75%. One good note – in contrast to current migraine drugs which most migraine sufferers discontinue within a year, side effects are minimal.
By the end of next year migraine sufferers could quickly go from having no migraine specific drugs to being awash in them. The drug just approved should be available as early as next week. Decisions on Eli Lilly’s galcanezumab and Teva’s fremanezumab are expected by the end of this year. Allergen (ubrogepant) and Biohaven (rimegepant) are expected to file for FDA approval next year. It’s possible that by the end of next year five new drugs specifically designed to treat migraine may be on the market.
Why is migraine treatment moving forward so quickly? For one, migraine advocates made diagnostic clarity a chief goal in their search for treatments – something that has not happened in ME/CFS. That diagnostic clarity gives drugs companies a clear patient group to target. For another, a clear biological pathway was established which made so much sense that when one version of a CGRP antagonist bombed, drug companies simply readjusted and took another tack.
The Role of CGRP as Targeted Treatment for Migraine - Introduction - YouTube
The Fibromyalgia / Chronic Fatigue Syndrome (ME/CFS) / Migraine Connection
“Similar patterns of gray and white matter abnormalities and altered brain energetics in GWI, CFS, FM, and migraine suggest that common central mechanisms may contribute to the type of headaches and cognitive impairments perceived as ‘brain fog’. Baraniuk
Migraine, ME/CFS and FM may be more alike than we tend to think. Migraines are believed to be greatly under diagnosed in ME/CFS and the population at large. In one study, migraines were present in 64% of Gulf War Illness (GWI) and in an astonishing 82% of ME/CFS patients vs. 13% of the healthy controls. Over half of the ME/CFS participants (56%) also meet the criteria for fibromyalgia.
A large study (n=1700) found that no less than 56% of fibromyalgia patients met the criteria for migraine. The “penalty” for having both fibromyalgia and migraine was steep. Women with FM and migraines had significantly higher chances of also having been diagnosed with hypertension (p<.004), asthma (p<.01), irritable bowel syndrome (p<.02), depression (p<.0002), anxiety ( p<.001), PTSD (p<.005) and finally (and most of all) chronic fatigue syndrome (p<.0001).
Migraine, ME/CFS, FM and irritable bowel syndrome are among the eight pain conditions a 2015 NIH report proposed “share common underlying disease mechanisms”.
In migraine, ME/CFS and FM, exertion and exposure to stimuli often must be curtailed dramatically. Whether in the midst of an ME/CFS crash, fibro flare or migraine attack, hypersensitivity to lights, sounds and odors is common. Plus the fatigue and cognitive problems often found in the days after a migraine look very much like ME/CFS/FM. Migraine and ME/CFS symptoms are often substantially reduced during pregnancy.
Brain blood flow problems appear to play a role in both migraine and chronic fatigue syndrome
Baraniuk and Rayhan proposed a similar model to migraine may be happening in ME/CFS. They noted that the cortical spreading depression (CSD) found in migraine typically leaves in its wake a hypoxic environment (low blood oxygen levels) and an emphasis, not surprisingly, on anaerobic metabolism with a corresponding increase in lactate levels. CSD is usually a time-limited event, but Baraniuk and Rayhan propose that it’s become chronic in ME/CFS and contributes to the anxiety, fear, fatigue, pain, allodynia and cognitive problems in ME/CFS and similar disorders.
Whether a CGRP connection is present in FM and ME/CFS is unclear. Despite CGRP’s strong links to pain and stimuli sensitivity, only one study – in 1998 – has assessed CGRP levels in fibromyalgia. (That study found CGRP in FM patients’ cerebral spinal fluid.) CGRP levels in ME/CFS have not been assessed, but Donald Staines of Griffiths University has long championed the idea that vasoactive (blood vessel affecting) neuropeptides such as CGRP may play a role in ME/CFS. The blood vessels CGRP affects occur all over the body.
Besides migraine, increased levels of CGRP have been found in temporomandibular joint disorder, cardiac failure, hypertension, and, interestingly enough, sepsis.
Missing Diagnosis and Treatment Options?
In Baraniuk’s 2011 study, only forty percent of migraine sufferers had been diagnosed, and only a third were being treated with drugs. That thirteen out of the fourteen ME/CFS patients with migraines reportedly were responding well to sumatriptan (Imitrex) suggested that many people with ME/CFS may be missing out on a valuable treatment option.
Given the similar central nervous system processes Baraniuk and Rayhan believe are behind ME/CFS, migraine, GWI and FM, they proposed anti-migraine drugs could be helpful in ME/CFS/FM patients who do not experience migraines.
The new drugs coming on the market are biologics which are probably going to very expensive (~$7,000/year). It’s not clear what will happen with insurance companies, but they may require that recipients have tried other migraine drugs first before they will pay for these new drugs.
Could you be experiencing migraine without knowing it? With powerful new drugs for migraine that possibly could affect ME/CFS/FM coming on the market, now might be a good time to find out.
Check out two self-tests for migraine here and here.
We clearly need more research into the intersections between migraine, ME/CFS, FM and other diseases. If CGRP levels are increased in ME/CFS and FM, clinical trials of the new migraine drugs would obviously be a possibility.
Whether the new migraine drugs apply to ME/CFS and FM or not, the migraine drug saga indicates that even in a disease with low funding (migraine = $21 million/year – NIH) if a clear pathophysiological pathway is found treatments can follow.
We often look at the decades of seemingly fruitless work done on multiple sclerosis with despair. How will ME/CFS and FM make out, when MS, with all its money, has made so little progress? But that comparison is faulty. Migraine, a sensitivity disorder often found in ME/CFS and FM patients is a much closer match to ME/CFS than multiple sclerosis is. Fibromyalgia, another common comorbidity, has three FDA approved drugs while receiving pitiful research funding and seemed to be on the brink of two more last year.
At the Montreal ME/CFS conference Dr. Nancy Klimas noted that the $40 million the Department of Defense has been giving Gulf War Illness annually has resulted in 10 clinical trials currently underway. That suggests that in several diseases which have similarities to ME/CFS, even moderate levels of funding can have a significant impact.
The Montreal Chronic Fatigue Syndrome / Myalgic Encephalomyelitis Conference Pt I
I thought I was in Paris, so much French was being spoken. The conversations in the cafes, on the streets, in the subways – everywhere – were in French. It turns out that with its 4,000,000 plus residents, Montreal is the second largest French speaking city in the world. I couldn’t understand a word anyone was saying but the beauty of the language was evident. (Thankfully they quickly switch to English when needed.)
My Parisian uber driver told me, however, that Canadian French is not correct French at all – it is, he sniffed, anglicized French which he had trouble understanding at first. French, he assured me, is the easiest language to learn because, in contrast to English, it actually has rules that it follows. Plus in French you actually say all the letters. He demonstrated that by pronouncing Toronto the way it should be pronounced (Tor-on-To) and then the way Torontoan’s pronounce it (Tor -an – do). He also informed me that because the French was first on the green and gentle isle that is England, that English is actually French spoken poorly.
The conference took place in auditoriums in a French hospital – the Chu-Justaine (there are French and English hospitals in Montreal) – home to one of the four most important pediatric centers in North America. The auditoriums, which tended to be packed (Ron Davis’s talk was standing room only), were a step up from the usual hotel conference room. Having the conference off-site from the hotel, on the other hand, required some extra work and expense. The food, which was generous, included the most interesting aperitifs I’ve ever seen. The only real miss was the “rest room” which consisted of a very small room with a pad on the floor and chair.
The Chu Sainte-Justaine is one of four important pediatric centers in North America
Canada has recovered nicely from the weird rejection a couple of years ago of all grant applications for federally funded research studies on the grounds that chronic fatigue syndrome (ME/CFS) is not a real disease. The conference was funded by the second grant, plus Canadian and U.S. groups (Solve ME/CFS Initiative, Open Medicine Foundation). Plus Canada is going to fund a small research center that will collaborate with the NIH funded research centers in the U.S.
The conference came about from a few key actions. I was told that Christian Godhut, a Montreal patient who was too ill to attend but whose father was present (and regularly attends ME/CFS conferences) pressed an influential doctor to get Montreal to do more. The doctor got in touch with the best researcher he knew of – Alain Moreau – and asked him to produce an overview of ME/CFS research with the idea of identifying research needs.
As Moreau worked his way through the overview he became intrigued with the disease and applied for the grant which helped pay for the conference. The NIH funding of the ME/CFS centers prompted Canada to provide funds towards a small research center that will collaborate with the U.S. ones. Plus I was told Canadian officials have promised to be more pro-active about getting the word out about ME/CFS.
This is just to show that individuals can make a difference and that you never know the impact your actions may end up having.
As with every conference the talks were a jumble of snoozers, moderately exciting ones and positively scintillating ones Alain Moreau and his counterparts did a good job highlighting Canadian researchers and doctors while bringing in some excellent outside researchers.
It was particularly good to see Carmen Scheibenbogen show up. Scheibenbogen, a German researcher with her fingers in many pies, was there attending her first (but hopefully not her last) North American ME/CFS conference. Roland Staud, one of the rare researchers to cross over from fibromyalgia to ME/CFS, made, I believe, his first appearance at an ME/CFS conference as well. I missed several presentations but Maureen Hanson, Betsy Keller and Nancy Klimas provided particularly thought-provoking presentations.
Maureen Hanson – The One Problem to Rule Them All?
Hanson headed off the Metabolic section and as she did so she noted Canada’s excellent, free Human Metabolite Database (HMDB) which contains detailed information about 114,100 metabolites. It wasn’t a groundbreaking new study result that made Maureen Hanson’s talk so interesting – it was her conclusions.
Hanson’s – known to be a rigorous researcher – has been comparing the results of past metabolome studies to see if the results match up. Are we getting more or less consistent results or are the results all over the map?
Could the metabolism be ground zero for chronic fatigue syndrome (ME/CFS?)
Whether we’re getting consistent results or getting a jumble of results from metabolomics studies is a very important question given the amount of interest and effort that has gone into the field recently. Ian Lipkin is adding metabolomic studies to his portfolio. After finding some darn interesting cytokine findings, the Simmaron Research Foundation is exploring the metabolomics of spinal fluid.
I still go back to Ron Davis’s findings with his son; after doing test after test after test, it was only the metabolomics results that impressed him. This field needs to replicate those results, though, for them to be considered solid.
It wasn’t looking good early on as Hanson noted the different platforms used, the different sample types used (serum vs plasma), the different extraction methods, the different ways samples were stored, etc. All these possible confounding factors in a rather finicky field seemed to presage disaster, but in the end the news was good. Except for the studies which used plasma vs. serum, the findings were actually very consistent and even in the plasma vs. serum studies the numbers weren’t that far off.
As to the applicability of metabolomics to ME/CFS, Hanson reported she was able to identify 95% of ME/CFS patients correctly using 41 metabolites. Her search for metabolomic subsets failed – suggesting perhaps that metabolic problems are at the core of ME/CFS; that they may be THE central driver which gives rise to the subsets that are probably found in ME/CFS.
Hanson perhaps gave a clue to what she thinks is going on when she noted the 2014 Vermoulen study which suggested low oxygen flow to the tissues was causing the problems with exercise in ME/CFS.
Hanson is currently doing or will do a two-day metabolomic and exercise study which I believe is part of her NIH research center grant. If ME/CFS is indeed a hypometabolic state that’s held in place by problems with energy production, the results of the two day exercise study will be fascinating. Will that hypometabolic state – always measured during rest so far – get even more hypometabolic after the two-day exercise trials? This is the kind of big, complex and expensive study that we need the NIH for.
Betsy Keller – The Ever Evolving Exercise Picture in ME/CFS
Keller first thanked the Workwell Foundation for getting her into this field. Most of the patients she sees are there for disability evaluations.
Quite a few groups are doing exercise studies, but it’s the Workwell Foundation – composed of exercise physiologists – which has contributed the most eye opening finding of all: that the ability of ME/CFS patients to generate energy gets whacked by exercise. That finding is all too obvious to anyone with ME/CFS, but it turns out that that finding may be unique to ME/CFS.
Keller stated that people with lung disease, heart disease or sedentary controls are able to replicate their energy production to a surprisingly precise degree (differing by 1-7%) on the second day of a two-day maximal exercise test. Many people with ME/CFS cannot – something happens to them during or after exercise to disturb one of the most fundamental biological processes of all: their ability to turn oxygen into energy goes down, sometimes quite severely. Hanson reported that a former marathon runner’s ability to produce energy went down a staggering 44% after one maximal exercise test.
Ventilation is proving to be a major issue in ME/CFS. (By John Pierce [CC0], from Wikimedia Commons).
As more research is slowly, slowly being done, the field has evolved. VO2 max and anaerobic threshold were the central foci early on but it’s becoming clear that the exercise issues in ME/CFS are more complicated than that.
The ventilatory response – the breathing we do to remove the CO2 waste products and get more oxygen to our tissues – is often deranged in ME/CFS as well. If you can’t remove the excess CO2 produced during exercise, you’re going to be in pain fairly quickly. (Of my two single exercise tests done years ago my ventilatory response was the only measure that was off and it was way off.) Dr. Systrom has said that breathing problems during exercise are almost universally found in ME/CFS.
The heart rate should increase at a certain rate during exercise in order to propel more blood to the tissues. It’s becoming clear that a problem called chronotropic incompetence – or the inability to properly increase the heart rate during exercise – is common in ME/CFS.
After exercise the heart rate should drop at a certain rate as the person recovers. Within six minutes their systolic blood pressure should come down to resting levels. Each of these can also be off in ME/CFS.
One might expect a lot of lactate production in aerobically challenged ME/CFS patients, but sometimes Hanson sees little lactate production. (Lactate – a toxin – is a function of anaerobic energy production). This odd situation is probably occurring not because the patients aren’t energetically impaired but because they’re so lousy at producing energy anaerobically. Their tests, Dr. Hanson said, are over very quickly – too quickly to produce a lot of lactate. Ventilation is a better measure in these patients.
Dr. Keller has a paper in review. It’s great to see Dr. Keller digging deeper into this oh so fundamental problem in ME/CFS.
Cara Tomas – Energy Production Sagging in ME/CFS Patients Immune Cells
Cara Tomas – from Julia Newton’s group in the U.K – noted some of the different results we’re getting in mitochondrial studies. Every study is finding something wrong, but at times quite different things wrong. As Maureen Hanson did, Cara went over some of the possible confounding factors.
She used the Seahorse machine in the Newton group’s latest study – that machine, at least, shows some consistency. The Seahorse is currently being used in several studies (Hanson, Barao, Newton ). She was surprised to find that mitochondrial function was not worse in the severely ill ME/CFS patients compared to moderately ill patients. That finding, which needs to be replicated, could suggest that factors other than the ability to produce energy are needed to produce more severe ME/CFS.
Because Tomas used PBMC’s isolated from whole blood, no factors in the blood could have contributed to the results. Tomas first assessed the ability of ME/CFS and healthy controls’ immune cells to create energy in low and high glucose concentrations. Adding glucose should boost up glycolysis – the anaerobic portion of the energy cycle – and it did – but only in the healthy controls. The inability of the ME/CFS patients’ cells to utilize the extra glucose seemed to suggest that something had gone wrong with glycolysis in ME/CFS, but then came a twist: a glycolysis stress test indicated that glycolysis was operating normally.
The ME/CFS patients immune cells couldn’t generate nearly as much energy as the healthy controls
As Tomas went through her tests and found that ME/CFS patients’ immune cells under performed in every situation she put them in, suggesting they were stuck in a kind of low energy model. When given extra glucose they weren’t able to use it. When deprived of glucose they weren’t able to increase their mitochondrial energy production.
The fact that ME/CFS patients’ cells had lower reserve capacity suggested they may have already been operating near their maximum level. The low coupling efficiency suggested that when pushed, they simply didn’t have the resources to respond. When asked to respond the ME/CFS cells were able to generate only about a quarter of the energy of the healthy controls.
The study was on immune cells, not muscle cells, but each finding seemed to make sense given ME/CFS patients’ inability to mount the energy to engage in exercise.
The healthy controls’ cells, on the other hand, demonstrated the flexibility and adaptability healthy cells need to have to respond to the different situations they will inevitably face.
All in all it was a remarkable set of findings which made several of the Ramsay Award studies the SMCI has funded of double interest. A couple of years ago the SMCI made investigating the energy production of immune cells a top priority. Ramsay award winner Chris Armstrong is studying the metabolism of B-cells under a variety of conditions. Isabel Barao is using the Seahorse machine to see if problems with energy production are hampering NK cells’ notorious problems killing other cells in ME/CFS, and Brupesh Prusty is determining if HHV-6 infections are hampering mitochondrial functioning in ME/CFS. Those studies should be finished or finishing up soon.
In fact, Ramsay award winners were on full display at this conference; they included Carmen Scheibenbogen (2 Ramsay studies), Jonas Bergquist, Chris Armstrong and Maureen Hanson.
Roland Staud – Fatigue and the ME/CFS Brain
Staud was an inspired choice as he’s one of the very few researchers to study both ME/CFS and FM – and we could dearly use researchers who have a foot in both worlds. This is the first time, I believe, that he’s shown up at an ME/CFS conference.
A rheumatologist based in Florida, Staud has for many years focused entirely on FM and pain, but in the last three years this well published researcher has produced no less than six studies on ME/CFS.
Bad Brain Motor?
Could the brain not be activating the muscles in ME/CFS properly?
Staud stated that his recent brain imaging study used a different, more precise kind of brain imaging called spin labeling which provides better imaging of neuronal functioning. His goal was to see whether blood flow to the brain overall was reduced and whether blood flow to brain areas that are associated with fatigue is altered in ME/CFS. Since blood flow is an indirect measure of energy – the brain directs more blood to areas of it that are active – the study measured blood flow during a fatiguing cognitive task.
Staud found that, in contrast to some studies, no differences in overall blood flow to the brains of people with ME/CFS, but a paradoxical result when brain blood flow was looked at in more detail. Increased blood flow to parts of the brain associated with memory and cognition (superior temporal gyri (STG), precuneus, and fusiform gyrus) were associated with decreased fatigue in healthy controls but increased fatigue in the ME/CFS patients during the cognitive task and afterwards.
In other words blood flow to one part of the brain produced exactly opposite fatigue responses in the ME/CFS patients vs. the healthy controls. Patients with the greatest reductions in blood flow to one part of the brain (precuneus, left fusiform gyrus) after the cognitive task experienced the least fatigue. These parts of the brain are believed to affect attention, motor coordination, and sense of self/self-reflection.
That suggests that some sort of flip has occurred in ME/CFS and the fatigue reduction pathways are now responsible for producing fatigue in ME/CFS – a bizarre finding, but then again bizarre findings are not unusual in ME/CFS.
A currently embargoed paper by Staud is expanding on his findings. It found altered “connectivity” i.e. transmission between the precuneus and portions of the brain associated with movement planning and motor function (supplementary motor area, precentral gyrus, basal ganglia), cognitive control (superior frontal gyrus), and sensory function (thalamus) both during resting state and during cognitive tests.
Notice the possible issues with movement planning and “motor functioning” (movement) Staud is finding. He’s not the first – others in the rather distant past uncovered possible issues with engaging the muscles in ME/CFS, but the research mostly lapsed. Miller’s basal ganglia studies of a couple of years ago underlined possible problems with “motor functioning” in ME/CFS. Now Staud is adding to that oh so interesting theme. If the brain is not engaging the muscles properly – they should be sequentially engaged as the need arises – then fatigue is an inevitable result.
A big question is why decreased blood flow to the regions of the brain responsible for movement or motor activities would be associated with more fatigue in ME/CFS. Because some research indicates that the motor system might be left “on” in ME/CFS during the recovery period, perhaps reduced blood flow could ameliorate that (?)
In response to a question, Staud said the brain areas he found that make a difference in ME/CFS highly correlated with those that Dr. Hyde asserts are most relevant. The difficulty in accessing the brain makes it a problematic feature to change, but transcranial magnetic stimulation (TMS) is having some success redirecting the flows from one part of the..
Certainly the nervous system plays a major role in producing pain. The immune system with its inflammatory processes and ability to create sickness behavior is certainly in the discussion, but hormones? Many women are well aware that hormonal fluctuations can boost pain levels, but could the sex hormones play a role in the genesis of the pain women and men with fibromyalgia experience?
The gender imbalance has always suggested something’s up with the female hormones in FM and ME/CFS.
It turns out that the evidence rather strongly suggests that they might. A major gender gap in the incidence of both fibromyalgia and chronic fatigue syndrome (ME/CFS) suggests that sex hormones must play at least something of a role in these diseases. Animal studies indicate not only that females are more sensitive to pain but also that that sensitivity can be altered by changing their hormone levels.
The fact that that gender gap appears only when girls reach puberty strongly suggests something’s up with the hormones in fibromyalgia. Reports abound of improved pain and fatigue during pregnancy for some women with ME/CFS/FM. Plus several studies indicate greatly increased rates of gynecological disorders in ME/CFS.
Studies indicate that sex hormones affect the activity of pain receptors, the central pain-processing pathway in the brain, inflammation in the spinal cord, the microglia in the brain and opioid pain processing. Two sex hormones in particular – testosterone and progesterone – appear to have pain diminishing properties, and progesterone has anti-inflammatory and neuroprotective effects as well.
Given the abundant evidence indicating that sex hormones can indeed affect pain, it was no surprise to see Jarred Younger at the University of Alabama at Birmingham publish on this subject. His recently published study was small but intense. The fact that only eight FM patients participated in the study means we can’t know if their results apply to the FM population as a whole, but that wasn’t the point of the study. The point was to generate enough exciting data to get the next, bigger study funded, and in that Younger surely succeeded.
Younger belongs to a newer generation of researchers and he’s doing different kinds of studies. Instead of taking one measurement and hoping it reflects what’s going on in the body over time, Younger has taken people with ME/CFS or FM and tested them every day for almost a month.
Then he’s correlated their biological data with their symptom data in order to try to understand what’s going right when they’re feeling better, and what’s going wrong when they’re feeling worse. The daily blood draw studies clearly take a lot from both the participants and the staff (no weekends off) but the results have been fascinating. Immune factors, for instance, have popped out which nobody expected to pop out.
In this study Younger measured testosterone, progesterone and estradiol levels as well as cortisol in 8 women with FM for 25 days straight while having them record their pain levels. He found that both progesterone and testosterone were inversely correlated with pain levels; that is, the higher the FM patients’ progesterone and testosterone levels were the lower their pain was.
The green line is progesterone (highest in the luteal phase); the red line is pain. Note how they diverge in these fibromyalgia patients.
Progesterone level fluctuations by themselves altered pain levels by about 25%. By themselves, neither estradiol or cortisol levels had any effect on pain except when progesterone levels were low. Low progesterone in combination with high cortisol produced the highest pain levels. Women will probably not be surprised to hear that pain levels were highest during the menstrual period when sex hormone levels were at their lowest.
Younger noted that this was the first time pain levels and sex hormone levels had ever been tracked on a day-to-day basis in humans, but a very large (@10,000 person study) also found that lowered sex hormone levels (estrogen, testosterone, androstenedione, and 17-hydroxyprogesterone) were associated with an increased prevalence of chronic muscoskeletal pain.
The Stress Pain Connection
What exactly is going on is still a mystery, but some hypotheses exist. Progesterone could be tamping down inflammation or modulating nervous system activity.
Hillary White, PhD notes that stressful situations usually reduce pain levels but that the opposite tends to occur in FM. Pain levels in the body are reduced during stressful situations when a neuropeptide called substance P converts testosterone to estradiol.
Estradiol then upregulates the production of the endogenous (self-produced) opioids which cause pain relief. She believes the lower testosterone levels found in FM (and other pain disorders) prevent this inhibitory pain network from functioning properly. Once that inhibitory pain network goes off the rails, pain sensitivity spikes higher and higher, and instead of stress reducing pain, it provokes it.
The cortisol/progesterone interaction Younger found suggested that high stress (high cortisol) combined with low progesterone was a recipe for more pain in FM. White is not the first to propose that stress enhances pain in FM. Dr. Martinez-Lavin proposes the same thing in his book “Fibromyalgia: When Stress Becomes Real Pain and What to Do About It”. Eighty percent of the FM/ME/CFS patients taking the poll (which is still open) on the blog strongly agreed with the statement “I notice that stress is associated with pain or discomfort”.
Other studies suggest that when estradiol levels are low, higher testosterone levels are needed to engage the inhibitory pain pathways. The study suggested that taking oral contraceptives or hormone replacement therapy may indeed affect pain levels in FM. In his video, Younger noted that men with higher testosterone levels are less likely to come down with fibromyalgia.
The Bigger Picture
The cortisol/progesterone interaction Younger found was fascinating and significant, but Younger believes many more factors probably come into play. He wondered what a study exploring adrenal and thyroid hormone levels, neuropeptides, neurotransmitters, cytokines, and other factors might find and even suggested that “an optimized set of analytes could predict most pain fluctuations in fibromyalgia.”
Finding out what blend of hormones, neurotransmitters, cytokines, etc. are setting off the pain signals in FM and ME/CFS would, of course, be a huge step forward. Since the body is essentially a set of complex networks which interact with each other, the only way to truly get at the changes that occur is to assess what’s happening in those networks. Younger clearly wants a chance at doing that.
It wasn’t so long ago that we simply didn’t have the computer capacity or statistical methods to do such data intensive studies. The one-off studies which use one data point to try to understand a massively complex body that is changing over time still have their place, but more and more studies which intensively sample patients over time to try and get a grasp of the mechanics behind illness are getting underway.
Dr. Klimas’s intensive sampling regimen during and after exercise is uncovering why exercise is so difficult in ME/CFS and Gulf War Illness. Dr. Systrom is doing a similar protocol using invasive CPETs in ME/CFS. Dr. Lipkin and Dr. Hornig are assessing immune factors over a year in ME/CFS. Lenny Jason is tracking what happens to college students after infectious mononucleosis as some come down with chronic fatigue syndrome (ME/CFS).
The New Normal?
Even though sex hormones appear to play a significant role in producing pain in FM, the levels of these hormones in FM patients were actually “normal”. Perhaps it’s time to redefine what normal is in the context of illness. The research in FM, POTS, ME/CFS and Alzheimer’s suggests that “normal” levels of sex hormones, iron, leptin, cytokines and other factors may not be so normal after all. Cytokine levels were “normal” in the Montoya/Davis immune study which nevertheless strongly implicated them in fatigue severity in ME/CFS.
These findings suggest that when a different biological context such as a disease is present, the rules of normality no longer may apply. A factor which appears to be within the normal range may, in these changed systems, be having unanticipated effects. Within the context of fibromyalgia, “normal” levels of progesterone and testosterone may actually be too low. Higher, but still normal, levels of cortisol in combination with low, but normal, levels of progesterone may cause pain levels to shoot up. Dale Bredesen’s functional medicine approach to Alzheimer’s seeks to create optimal instead of normal levels of many nutrients and metabolic factors.
In two studies, Hillary White PhD used testosterone gel to successfully reduce pain in fibromyalgia. Her testing revealed that blood testosterone levels of the women entering the study were in the lower half of the normal reference range for their ages. Using the gel normalized, and slightly increased, their testosterone levels to just above the reference range. (The gel does not appear to be FDA-approved.)
A third of the women reported a 50%, or greater, decrease in pain. Forty-two percent were reported to have a 33%, or greater, decrease in pain. Tender point sensitivity was significantly reduced. Libido was significantly increased. The treatment had no effect, though, on headache severity, sleep, anxiety or depression. White also found reductions in fatigue and has proposed that her testosterone gel can help with the intractable kind of fatigue found in chronic fatigue syndrome (ME/CFS).
Hormones are tricky. Doctors prescribed progesterone/estrogen in post-menopausal women for years thinking it protected them from heart disease only to have a large study indicate that it actually increased their risk of blood clots and strokes and had no positive effects on heart disease.
Seeking to get a boost, healthy middle-aged and older men have been downing testosterone in the billions of pills. Testosterone supplementation, though, doubled the risk of heart attacks in older men and tripled it in middle-aged men with prior heart problems. Some trials have not found increased risk, but like other hormones, once you get on testosterone, it may not be possible to get off. That said, for people with low testosterone levels, testosterone can be quite helpful.
White reported that the American Society for Reproductive Medicine’s Princeton Consensus Statement recommends treating women with gonadal hormones if clinical symptoms such as diminished sense of well-being and chronic fatigue are present. The North American Menopause Society recommends treatment with gels or creams (not pills) for symptoms of decreased sexual desire, if blood monitoring is done. Several alternative MD’s report using testosterone successfully in some of their FM and ME/CFS patients.
Fibromyalgia, like ME/CFS, might very well be cured by using multiple factors that edge the system back to normal. The good news about both FM and ME/CFS is that, aside from small nerve fiber problems – which may be able to be ameliorated – evidence of tissue destruction is rare. Hopefully, Younger’s study is one step on the path to understanding the multitude of factors that result in FM and finding the right combination of treatments to set them right.
ME/CFS advocacy is growing and growing. We have two groups, ME Action (join it here) and the Solve ME/CFS Initiative working pretty much in lockstep to move forward on ME/CFS.
Central to both groups’ efforts are a Senate Resolution sponsored by Senator Markey which reaffirms the House’s commitment to the end of ME/CFS and asks the NIH to do more, and a House report signed by 44 members which requests, among other things, that the NIH develop a strategic plan to move ME/CFS forward.
ME Action continues to get an “A” in creativity. (Whoever dreamed up the shoes idea should get a medal.) It is organizing events in 100 cities (!) across the globe and has created numerous online opportunities including a 24 hour global virtual meetup on May 12th.
There’s nothing like meeting face to face with figures in power to get your point across, establish relationships and make a difference. Talk about targeted action, the SMCI and 120 advocates are going to get close and personal with their representatives in the Capital on May 15th.
The SMCI’s fantastic Advocacy Toolkit provides the most comprehensive guide to advocacy I’ve ever seen including sample letters and phone calls, links to advocacy training, how to request a city or state proclamation, infographics and more.
If I could pick just one advocacy task to be successful, it would be to get Congress fully involved. Congress is the only Institution with the power to force the NIH to make up for its years of neglect. (Check out some thoughts on that.) It’s simple – Congress controls the purse strings of the NIH – the biggest medical funder on the planet. When the NIH moves, we will move; if it doesn’t move, we won’t move nearly so quickly. Let’s get the NIH to fulfill its mission, get back into integrity, fully support everyone in the U.S. who’s ill, and dramatically increase funding for ME/CFS.
#MEAction’s Congressional Call to Action will ask Congressmen and women to watch Unrest (they’ll send them a free viewing (nice!)), post on social media on May 12th supporting the Millions Missing movement and
Pass a Senate Resolution to raise awareness and support for ME/CFS patients and research, and
request a House hearing on the ME/CFS clinical crisis.
ME Action is making this very easy. Click on both pictures to make a quick difference. It literally took me about a minute to send messages to my reps.
Actually getting out and protesting – meeting people and spreading the word – it’s exciting stuff! This years protest has been years in the making: ME/CFS patients will gather in 100 cities around the globe to tell the world that they demand equal access to research funding and treatments. My how this has grown…
From Jen Brea and the Millions Missing Campaign
This Saturday, May 12th, thousands of us will gather around the world in 100 cities and online to demand equality for people living with Myalgic Encephalomyelitis (ME). Patients, carers, this is our moment to be seen and heard, but also to gather and form the bonds of support and activism that we will need to see this through to the finish line.
For all of our allies, so many have asked “How can we help?” And I said, when the time comes, we will mobilize you. Well, now is the time!
Below is our trailer, a list of every in-person action, and at the very bottom of this email, a graphic to share on social media. Please look at the list below and come out (if you can) to a protest or awareness event near you. Invite anyone you may know and who might living in any of the cities below (cousins, friends from school, old pen pals!) using the linked event pages so that these events might be as big and as diverse as possible, and so that we might continue to build community and grow this movement.
#MillionsMissing May 12, 2018 - YouTube
We welcome everyone – patients, carers, friends, allies, researchers, nurses, doctors – as well as people living with related diseases like POTS, EDS, Fibromyalgia, Endometriosis, Chronic Lyme Disease, and all people with disabilities to join us in support and fellowship.
I am so awed and humbled by how much this movement has grown in just a few short years, thanks to your hard work, courage and creativity. I cannot thank you enough.
Let’s make history this Saturday!
With love and “hell yeah!”,
See the 100 cities at the bottom of the page
Do It Online
BEFORE May 12:
Ask Congress to support people with ME. Using our one-click software, it’ll only take a few seconds. Contact Congress now. (US-only)
ON May 12th
1) Join the #MillionsMissing on Social Media
a) Put your shoes outside with a note
On May 12th, take a pair of shoes (or several) and put them on your doorstep, lawn, or driveway with a note about what these shoes represent now that you are ill with Myalgic Encephalomyelitis. Take a photo and post it on social media (Twitter, Facebook, Instagram, etc). Include these hashtags: #MillionsMissing | #CanYouSeeMENow?
Anyone can participate, whether you are a patient or an ally expressing solidarity. You might pair the shoes with a sign that expresses what the empty shoes mean to you. Some examples: “I cannot walk to the end of my driveway” or “My brother should be here.”
b) Show Your Face
Post a selfie from your bed or home to show that your are one of the millions who are missing due to ME. You can print one of our posters, or create your own poster or sign. Don’t forget to include that hashtag: #MillionsMissing!
c) Turn the camera on yourself.
Say a little bit about yourself, and explain what you are demanding from your government. Keep it short, sweet and to-the-point. Please email firstname.lastname@example.org with a link to your video, or send it to us via WeTransfer.
d)Re-share photos from other protests, and from the #MillionsMissing Instagram with your followers on social media. Include the hashtag #MillionsMissing.
ME Action will have a 24-hour, Auckland to Honolulu Global Meetup you can join on May 12th where you can connect, share experiences, and find out what is happening around the world. On the ground protesters can call in to connect to their local events. (In the public room, they may even ask someone to speak to the crowd!)
Researcher Disinterest Still Hampering Chronic Fatigue Syndrome (ME/CFS) Field
A Freedom of Information Act (FOIA) reveals that during the three grant review panels from July 2017 to April 2018, chronic fatigue syndrome (ME/CFS) researchers applied for a total of 12 grants. It was the lowest number of grant applications to the panel dating back at least 12 years. Despite the increased interest in ME/CFS, the last five years have shown a more or less steady decline in individual grant applications from ME/CFS researchers.
2011 – 20
2012 – 30
2013 – 16
2015 – 26
2016 – 13
2017/18 – 12
In order to get to the next level, researchers will need to apply for more grants – lots more grants.
The explanation for the low number of grant applications used to be that the grant review panels were packed with pain researchers who would not score ME/CFS grants well. That explanation was demolished when the pain researcher panels vanished with no uptick in ME/CFS grant application rates. Another idea has been that the NIH funds a lower percentage of ME/CFS grant applications than in other diseases. An analysis suggested that wasn’t true either – ME/CFS studies appear to be being approved at normal and at times higher than normal rates.
On a positive note, the ME/CFS research community showed up in spades with ten applications for the NIH research centers grant. That was an unexpectedly strong showing; at the just-concluded Montreal Conference, Vicky Whittemore said the proposals were strong and if enough funding had been provided, the NIH could have funded several more centers.
The pattern of ME/CFS researchers responding well to NIH grants which have funding attached (the 2006 RFA, the recent NIH Research Centers Grant), but applying in small numbers for individual grants, goes back years. The problem is that NIH grants with funding already attached are rare. If this field is going to move forward with alacrity, ME/CFS researchers need to apply for individual NIH grants in large numbers. The vast majority of the NIH’s funding goes to individual grant applications.
Next Rounds Critical
The next rounds of grant review panels will tell us much. We know that the seven losers of the NIH research centers contest are sitting on about 20 potential grant applications. We know that Ron Davis got one application in early. The big question is how many of those researchers are going to transform their research center applications into individual study applications.
If most of them do, then we could add 4-6 or more big studies over the next year, boosting funding by several million dollars. If, on the other hand, those applications don’t show up in large numbers, it’s hard to know what will move our researchers to take a stab at this vital source of funds.
Avoid Burnout by Keeping Focus on Year-to-Year Results in ME/CFS
I recently came across a book which suggested that we compare ourselves to others less, and focus more on comparing how each of us does over time. In ME/CFS we regularly, almost reflexively, compare our funding to what other diseases are getting. That’s completely understandable. On a needs basis, we deserve the $75 or $100 million that a disease like MS or lupus is getting.
Rome wasn’t built in a day – and neither will a successful research field – but steady progress will win out.
I believe that we should set benchmarks for funding compared to other diseases, but most of our focus should be on how we’re doing from year to year. To have the discrepancy between the funding for MS and ME/CFS gnaw at one, day after day after day is: a) physically and emotionally draining; and b) unproductive.
Comparing ME/CFS to MS is like comparing apples to oranges in some important ways. MS and similar diseases benefit from large and powerful research foundations, effective advocacy efforts, a huge cadre of researchers who regularly apply for grants, homes in NIH Institutes, and long term recognition of the diseases in medical textbooks. Funding for them at this point is almost a self-fulfilling prophecy.
Consider that in order to get the $100 million in NIH funding (20% grant success rate, average grant funding $500K/year) MS researchers must be pumping in somewhere around 1,000 grant applications every year. If each study contains from 50-100 participants, about 10-20,000 MS patients are participating in MS studies every year.
ME/CFS, on the other hand, a very small research community, finally got one full-time advocate about a year ago, has small research foundations, its researchers typically submit 10-15 grant applications a year, and it’s not taught in most medical schools. It simply cannot at this point compete with diseases like MS. Better comparisons might be to diseases which are in a similar place – which are trying to gain their way in the medical field.
ME/CFS can, however, move forward and move forward rapidly enough that within a relatively brief period we could have a robust and sustainable research effort going.
As small as it is, ME/CFS is making substantial progress. Over the last couple of years, NIH funding for ME/CFS almost tripled, 3 research centers have been funded, and a large intramural NIH study is underway. With the Pineapple Fund kicking in $5 million for the Open Medicine Foundation and the $1 million or so the NIH’s Intramural study costs, plus CDC funding, we’re looking at $25 million plus in research funding for ME/CFS this year from the U.S. A couple of years ago (with the CDC funding), we were at about $10 million. It’s not nearly enough, but it is progress – something we haven’t seen for decades.
We have a long, long way to go to achieve parity. Consider that with the NIH’s grant approval rate at about 20%, getting $50 million in NIH funding (or about 100 studies) would require the ME/CFS field pumping in about 500 individual grant applications a year — or 40-50 times what the field is currently producing. (ME/CFS researchers produced 12 grant applications last year.)
It’s questionable whether this field could successfully handle $50 million in funding if given it tomorrow. The sudden appearance of that much easy money would cause all sorts of researchers to enter this field – many of whom we might not want to enter this field – doing studies on who knows what kind of ME/CFS patient. The backlash that ensued at the wasted money could be horrific.
This field could grow much faster than it is, however, and in a sustainable manner. The research insights gained during that process will draw in good researchers. The NIH has started this process but is not doing nearly what it could.
The $15 million the NIH is now spending is not a lot, but it is a start. Consistently boosting our funding levels by, say, $5 million a year over five years, would have NIH spending $40 million/year on ME/CFS or funding 60-80 studies a year. It’s rare that funding grows so rapidly in a disease but it has happened. Behind a very strong advocacy movement, autism funding, for instance, grew spectacularly.
The Next Big Step for ME/CFS? Growing the Field
That’s not going to happen without help. The NIH has been saying for decades that, ‘if you give us grant applications, we will fund them’. I suspect, the occasional weird rejections aside (e.g. Ron Davis’s grant – which did not go to the CFS SEP), that the NIH will, in fact, provide funding if the grant applications come, but years of the NIH stating, ‘just give us more grant applications’, has made no difference. As a purely practical matter, it just isn’t working.
Research Centers were a step forward. Now the NIH needs to grow the field for individual researchers.
It particularly needs to find a way to entice individual researchers to apply for ME/CFS grants. Several decades of evidence indicate that the ME/CFS research community has trouble responding to unfunded grant opportunities (program announcements) but the response to the Research Centers grant opportunity gave the NIH notice that the ME/CFS research community will respond to funded grant opportunities. It now needs to jump on that insight.
The 2006 ME/CFS RFA was very successful, and one done now would undoubtedly be far more successful. (Maureen Hanson talks about the need for this kind of grant in the recent issue of the Solve ME/CFS Chronicle (not online yet. Sign up for the SMCI’s newsletters here.) This field could handle a $10 million five-year RFA which provided for 20 or so very large studies.
Because of the hypercompetitive nature of the NIH grant funding these days, many new researchers would be attracted into the field were RFA’s for ME/CFS proposals available. Maureen Hanson – Spring 2018 SMCI Chronicle
The NIH is not inclined to fund RFA’s for individual diseases – they rarely do that – but ME/CFS is a special case and the NIH acknowledges that it’s neglected this disease and has a lot of catch up to do. In the SMCI interview, Dr. Hanson noted that funding opportunities are often needed to help fields grow and those provided for HIV/AIDS early on helped that field quickly grow. Plus, because individual grants for RFA’s take place in a less competitive environment, simply the fact that an RFA for ME/CFS is available will tend to draw other researchers into the field.
While funding obviously helps enormously, it’s important to notice that progress can be made at times without huge funding increases. POTS hasn’t even had a dedicated funding option at the NIH, but the field is moving forward rapidly because of some key discoveries. Those POTS findings, in turn, prompted Carmen Scheibenbogen to look for autoantibodies in ME/CFS — successfully. She recently published an impressive review of autoimmunity in ME/CFS. A possible new drug for ME/CFS – Cortene – popped up out of seemingly nowhere, and the recent discovery of how Epstein-Barr Virus triggers autoimmunity could easily reap major dividends in ME/CFS.
Interact with the NIH that is – not the NIH that isn’t.
For years I railed against the NIH. I thought about the NIH in terms of what I thought it should be and wanted it to be, not what it actually was. Decades of busting my head against the wall, expecting the NIH to finally respond to this disease’s unmet needs, have met, at least until recently, with the same frustrating, heartrending result.
I didn’t get the message because I didn’t want to get it, but I do now. It’s clear to me that the NIH as an institution just doesn’t respond well to disease needs. It’s not that the organization is bad, it’s just not structured that way. I believe that the NIH is primarily structured to respond to researcher interests — not disease needs.
The NIH may not have a way to incorporate a disease’s unmet needs into its funding decisions.
Because everything is scored at the NIH, taking unmet disease needs into account would require a scoring mechanism which incorporates that statistic into funding decisions. My strong guess is that there is no such thing, and until there is, our unmet needs are going to have little sway in the most important area – funding.
Discrepancies in funding, after all, abound. ME/CFS is just one of several diseases that the NIH vastly underfunds. Chronic obstructive pulmonary disorder (COPD), for instance, kills 30 times as many people as HIV/AIDS and gets about 30x less funding ($3 billion vs $100 million/year.) HIV/AIDS’s success is an amazing story of how a maligned group (gay people) managed to capture an out-sized portion of the NIH’s budget. It’s story should give us – another maligned group – hope.)
Controversy over the NIH’s poor response to disease burden lead it to produce a 2015 report. The report showed that migraine and headache cause major illness burdens (they are by themselves on the bottom right) but get few resources, while HIV gets far more resources than its disease burden suggests it should. What was the NIH’s response to this visually obvious and public demonstration of its neglect? Three years later, both migraine and HIV are getting about the same amount of funding they did in 2015.
My guess is that the pull at the NIH is to always respond to researcher interest and the next new hot item. The NIH probably assumes that researchers will naturally incline to diseases with unmet needs, and for the most part, they probably do. They just don’t incline to controversial newer diseases that have large unmet needs.
This is not to say that the NIH cannot respond to unmet disease needs. It can and does at times do that – it just did it with us – but it tends to do so feebly; it’s clearly not its forte.
Newcomers Not Very Welcome
The NIH also appears to be structured in a way that rewards “older” diseases and makes it difficult for “new” diseases such as ME/CFS to make headway. Grant applications from “new” diseases have to be reviewed by people outside the field. New diseases don’t typically have homes at top academic institutions – which lowers their grant scores. They may not have an institutional home at the NIH.
That very same structure, though, provides a very consistent source of funding once a disease does get in. If you’re outside of the traditional power structures, it takes a lot of work to get in, but once you’re in – you’re probably in. Our job is to get in.
The NIH That Is…..
If the NIH usually doesn’t give disease needs much priority, then the burning question becomes what does it respond to? I’m a novice at the interworkings of the NIH, but from what I can tell, it responds strongly to at least three things:
Highly visible public health needs
Researcher Interest – More than anything else, the NIH appears to respond to researcher interest. Seventy-five percent of the NIH’s budget, after all, goes to individual grants. The vast majority of research funding decisions come from its hundreds of review panels which review individual grants. This strong response to researcher interest allows a field, once it has been built and attracted a strong stable of researchers, to keep up its momentum year after year after year, but the overwhelming focus on researcher interest makes it difficult to get a field started.
Highly Visible Public Needs – The NIH also responds at times to highly politicized major public health needs. The NIH, for instance, recently put together a large funding program to fight the opioid epidemic which includes, by the way, understanding pain better. (It took a Presidential campaign to get it to do that.) A couple of years ago, it boosted Alzheimer’s and dementia funding by over $300 million. These are major, well recognized health issues that have gotten a lot of publicity. (ME/CFS does not fit in this category: it’s simply not prevalent enough.)
Congressional Prompting – Because Congress holds the NIH’s purse strings, it can sometimes force the NIH to move. Since 2013, Alzheimer’s advocates working through Congress have tripled funding for Alzheimer’s and dementia (from $500 million to $1.8 billion). The effort began slowly with just 9 Senators signing on in 2016 and 12 in 2017. This year, 38 Senators signed a letter to get the NIH to spend even more on Alzheimer’s.
Although the NIH responds poorly to disease needs, Congressmen and women can and do understand and respond to our needs. They can then put pressure on the NIH and that can make a difference. This is probably our best avenue for a breakthrough.
The general idea is that having a real home at an NIH Institute would give us protection and access to its resources. The NIH is not a fiefdom, though, and it’s questionable whether forcing ME/CFS on an Institute that doesn’t particularly want it would benefit us much. Waiting for the right Institute to show up, on the other hand, could benefit us greatly.
It should be noted that we did have a home at one time – the NIAID – which was funding three research centers which were pumping out quite a few studies. After NIAID decided almost 20 years ago that ME/CFS was probably not at its core an immunological disorder, it dumped us.
Being homeless might be the best option for ME/CFS right now.
That breakup left us wandering in the NIH wilderness for almost 20 years. Our three research centers shut down and funding levels declined and declined. By the time funding levels reached their nadir – shortly before the recent expansion – ME/CFS funding levels in real terms were lower than they had been in about thirty years. That was particularly galling given that most other diseases had ridden a doubling in total NIH funding to new heights of funding.
Finding the right home, then, is clearly important. The two most likely homes right now are NINDS and NIAID. Given our history with NIAID, I would quite frankly rather be homeless than be housed with them again. NINDS is a safer bet, given Dr. Koroshetz’s public support for this disease, but if ME/CFS turns out to be a metabolic disease or a disease of the cardiovascular system, then the NDDK and NHLBI, not NINDS, would be better homes.
As more Institutes provide funding for ME/CFS, the case for a single home loses some of its power because while putting ME/CFS in one Institute might increase funding from that Institute, it could also lose funding from the other Institutes. A better strategy might be to leave ME/CFS where it is and have its true home reveal itself as the research proceeds.
Staying Active, Getting Really Creative
As a smaller disease with low resources which is trying to break into the medical mainstream, we have to be creative. Recently Dr. Bateman told the Brain Science Conference that she believes we know 80% of what we need to know in ME/CFS – we just need to get other specialties involved, but we should acknowledge that, as a disease, we’re lousy at networking. Our researchers hardly interact with fibromyalgia researchers and almost completely ignore POTS, dysautonomia, cancer and multiple sclerosis fatigue research. By doing so, we’re missing major opportunities. It should be noted that Dr. Klimas has moved mountains in ME/CFS by getting it included in GWS funding.
Check out what a recent review of the biological mechanisms of fatigue found. No mention of ME/CFS is made – remarkably enough they didn’t even assess the work being done in our disease (talk about a lack of networking) – but they did come to this conclusion:
Cancer researchers have been in the forefront in investigating the possible biological mechanisms of fatigue, identifying inflammation, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and activation of the autonomic nervous system.
Fatigue Conference? The review missed out on metabolism – a huge area of interest in ME/CFS – but aside from that, it could have described ME/CFS. Carmen Scheibenbogen, who is not just full of ideas but is actually putting them into action, is holding the first Fatigue conference I’ve ever heard of in order to get ME/CFS researchers talking with other fatigue researchers in Germany – the land of no ME/CFS funding – of all places.
If she can do that there, we can do that here. The IACFS/ME did include..
Erica Verillo’s AMMES Crowdrise project fills such a vital need that one wonders why it hasn’t been done before.
After forming a new organization (AAMES) and website, Erica’s first action was to produce a fundraiser to support the most vulnerable among us – the severely ill – in their day to day lives.
Fully one quarter of ME/CFS patients are believed to fit this category. Many are in difficult financial straits which prevent them from obtaining basic necessities. Erica’s Crowdrise project aims to bring some relief to them.
“In order to assist patients in need, AMMES is setting up a crisis fund to provide one-time grants to patients for specific needs. The funds can be used to purchase a wheelchair, pay a medical bill, hire home care, secure adequate housing, and other basic needs. All applicants will be required to provide written medical confirmation of their diagnosis, proof of financial need, and document the specific purpose of the grant.”
This worthy project is in trouble. With the campaign coming to an end soon it’s $500 short of meeting the $3,000 target which could qualify it for $25,000 in extra funds. Let’s get this project over the hump and help those in our community who are in the most need. I just gave. Will you?
It’s not every day that a noted researcher calls a study “the capstone” of his career or asserts that it’s more important than the rest of his 500 studies put together.
That’s pretty amazing but the exciting part for those of us with ME/CFS/FM is that the breakthrough describes how a common trigger of ME/CFS and possibly FM – an Epstein-Barr Virus infection – sets into motion a process that results in nasty autoimmune diseases like M.S. and lupus (and possibly ME/CFS/FM).
The research team’s decision to make their code available to others suggests we could know sooner rather than later if EBV has unleashed a similar disease process in ME/CFS/FM. If it has, then note that the search for a way to fix the damage is already underway. Find out more in a Simmaron Foundation sponsored blog
If you think ME/CFS and FM are behind the eight ball at the NIH, then check out postural orthostatic tachycardia syndrome (POTS), a common comorbidity. The NIH doesn’t even measure POTS funding but then how could it? POTS doesn’t even have a designated funding stream there.
That hasn’t stopped POTS researchers, though, from making huge strides in understanding the disease – strides that appear likely to end in the recognition that POTS is an autoimmune disease.
Check out how a small band of researchers and a young but dynamic support organization are making a major difference in a largely neglected disease – a difference which could have implications for ME/CFS and perhaps even fibromyalgia. Find out more in a Simmaron Research Foundation sponsored blog:
Dr. Bruce Carruthers, a Vancouver specialist in metabolic disorders, and other Canadians (and some Americans) and others made a profound impact worldwide with the development of the Canadian Consensus Criteria which knocked the CDC’s Fukuda and Empirical Definitions out of consideration and re-inserted post-exertional malaise into ME/CFS diagnostic criteria for good.
Besides seeing ME/CFS patients for years, Alison Bested M.D. has penned several well-regarded ME/CFS treatment guides, co-authored the IACFS/ME primer for physicians, and created a diagnostic protocol for physicians. Dr. Peter Rowe, now at Johns Hopkins, who hails from Canada, has been a key figure in ME/CFS pediatric care and understanding the role orthostatic intolerance, Ehlers Danlos Syndrome and others play in ME/CFS. His hypothesis on connective tissue disorders in ME/CFS is fascinating. Eleanor Stein M.D. in Calgary (brr!) has produced treatment and diagnostic guidelines on ME/CFS including one on how to differentiate ME/CFS from psychiatric disorders.
Hailing from Alberta (brr!), Valerie Free’s “Lighting up a Hidden World: CFS and ME” is the best single resource on ME/CFS I’ve seen in years).
Some Canadian researchers who have come to the fore lately include Gordon Broderick (now at Rochester General Health), Travis Craddock (at Nova Southeastern), Patrick McGowan (University of Toronto) and David Patrick (British Columbia Centre for Disease Control). The latest Canadian researcher to join the ME/CFS research community is none other than Dr. Alain Moreau, who attended the OMF’s Stanford ME/CFS Workshop, conceived the Canadian Conference, and received a federal grant to produce it.
Canada is the only country I know of to get chronic fatigue syndrome (ME/CFS) inserted into a national health survey (Canadian Community Health Survey (CCHS)). The 2010 survey, which found near equal numbers of ME/CFS and FM patients, suggested that the number of ME/CFS patients in the U.S. might be much more numerous than suspected. The survey also indicated the disease was causing levels of disability similar to those found in Alzheimer’s and stroke. Last year, an Ontario task force, in a 58 page report to the Minister of Health, presented numerous recommendations needed to provide much needed support for the 550,000 ME/CFS/FM and MCS patients in the province.
Canada’s major advocacy group, the National ME/FM Action Network, has been in action since 1993. Its website provides many resources, including a legal library. It recently provided bilingual translations for many seminal ME/CFS documents including the Consensus Criteria, IACFS/ME Primer, Pediatric Primer, etc.
The ME/CFS Canadian Collaborative Team Conference from May 3-5 Advancing an International Research Agenda to Address ME/CFS Research Priorities: From Basic Research to Clinical Practice
Canadian doctors, researchers, and advocates, then, have played quite a role in ME/CFS — but federal funding for research is sparse, ME/CFS expert doctors are rare and it’s never held a major conference before. (The IACFS/ME held its conference in beautiful Ottawa in 2011.)
For its first try at the conference thing, though, Canada is not starting out small. The March 3-5th conference in Montreal – paid for the Canadian Institutes of Health Research (CIHR) and with support from Canadian and U.S. ME/CFS organizations – is a major ME/CFS conference one hopes will be able to repeat itself, perhaps in the off-years between the IACFS/ME conferences.
The Conference’s goal is a smart and ambitious one – to lay the groundwork for a sustainable Canadian ME/CFS research program by developing an international research agenda that Canada can play a part in. About 250 basic scientists, clinical researchers, physicians and healthcare professionals – as well as patients and policy makers – will be attending.
Ron Davis, who will be speaking several times, welcomed the new international conference stating:
There is an urgent need to get to the bottom of this devastating disease. To do this, we need many
people looking at it from different perspectives and sharing as many ideas as possible so that we are better able to understand ME/CFS at the molecular level. This will impact ME/CFS directly by generating new knowledge as well as awareness about this dreadful disease.
Health professionals will have sessions from May 3rd-5th. The patient day on May 4th will be livestreamed and made available later.
While many Canadian doctors and researchers, including Dr. Alison Bested, Dr. Byron Hyde, Dr. Peter Rowe, Alain Moreau, David Patrick and Patrick McGowan, will present, it truly is an international conference. Ron Davis, Betsy Keller, Maureen Hanson, Derya Unutmaz, Roland Staud, Nancy Klimas and Lucinda Bateman from the U.S., Louis Nacul and Cara Tomas from the U.K., Carmen Scheibenbogen from Germany, Jonas Berquist from Sweden and Chris Armstrong from Australia, will all be presenting.
The Patient Session on Day 2 (May 4th) will include presentations on:
A Short History of ME/CFS – Dr. Byron Hyde
The Future of ME/CFS Research in the Omics Era – Ron Davis
Modeling and Creating Clinical Trials in GWS and ME/CFS – Dr. Klimas
Pathophysiological Mechanisms in ME/CFS – Dr. Alison Bested
Objective Diagnoses – Dr. Lucinda Bateman
ME/CFS: Could Neuroplasticity Play a Role? – Dr. Eleanor Stein
The NIH and the Future of ME/CFS – Vicky Whittemore
The Need for Open Collaboration – Linda Tannenbaum
ME/CFS Research Landscape in Canada: How Can Science/Innovation Address Unmet Needs? – Margaret Parlor, President of the National ME/FM Action Network, Ottawa
Is Heart Rate a Valid Exertional Index in ME/CFS? – Betsy Keller
The Alberta Healthy Living Program: The Role of ME/CFS Education – Eleanor Stein, MD, FRCP(C), Calgary, Canada; Judy-Anne Wilson, representative of Edmonton ME Society; Alison Rae, Board Chair and CEO, Action CIND.
Medication and ME – Kevin Mejo, BPharm
Nutrition and ME – Valérie Marcil, Ph.D., DtP
Genetics and ME – Alexis Goth, M.D., CCFP(C)
The Biobank Experience in Australia – Chris Armstrong.
Plus, an Unrest screening will occur at the conference location on Saturday night with a follow-up panel discussion by Nancy Klimas, Vicky Whiittemore and Scott Simpson. I will be moderating.
The Conference will take place at the CHU Sainte-Justine Hospital (Amphithéâtres 125 et 250, bloc 11), 3175 Chemin de la Côte-Sainte-Catherine, Montréal, Québec, Canada, H3T 1C5.