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Neglect is embedded in our history. It’s hard to have a conversation without someone mentioning the neglected funding, the doctors who don’t get it. the lack of treatments,  the unheeding friends or family; i.e. the things we as a community don’t have – which so many others do

The financial crisis fund is about providing basic needs for those with ME/CFS

That neglect meant that when someone with ME/CFS fell on really hard times they were mostly on their own. As you’ll see that didn’t sit right with Erica Verillo. She wasn’t sure what to do – but felt she had to do something – and so she did. She created the American ME and CFS Society and its Financial Crisis fund for M.E..

That fund – supported entirely by donors – is about giving people with ME/CFS in need small or big things that can make such a difference: some new clothing, a medical bill paid, the means to keep the heat or phone on, a wheelchair to get around, a security deposit to get into an apartment.  As much as the physical help AAMES provides, the recognition that someone cares is probably just as important. The sense of aloneness and isolation that so afflicts people with this disease is lifted.

As Erica and AAMES do their spring fundraiser I asked Erica about her motivation for starting AMMES and it’s Financial Crisis Fund. I loved her refreshing honesty. What do the vast majority of us do when facing something that seems too overwhelming to take on? We retreat! And she did! And then at some point she moved forward and because of that people with ME/CFS in need are being helped.

What was your motivation for starting AMMES?

Erica Verillo

The very first email I received when I launched the website for my book seven years ago was from a woman in dire straits. She was severely ill with ME/CFS and had lost her job. And she was about to lose her husband. She ended her email with a plea, “Help me, please help me, dear god, someone please help me.” It was a cry of utter desperation.

I had three choices: 1) Answer the letter with sympathy and understanding; 2) Try to find some help for this woman; 3) Ignore the email.

I chose option number three.

When faced with a crisis, especially someone else’s, for which we feel wholly inadequate, the most common response is to do exactly what I did – namely nothing. What can we say? What can we do? How many of us are trained in crisis management? I certainly wasn’t.

That email has stuck with me throughout the years. I have repeatedly come back to the thought that perhaps I could have done something, anything, to help her. It turns out there was something I could have done. I couldn’t solve this woman’s problems, but I could have listened and responded. The next incoherent desperate email that came my way (there have been many), I had learned my lesson. I responded with sympathy and understanding. The woman replied, no longer incoherent and rambling, and said, “Thank you for listening.”

It was so simple! All I had to do was listen! But there was another step. People started asking me concrete questions: “Where can I find a doctor?” “What treatments should I take?” “Where can I get reliable information?” So, I began referring people to various helpful sites, and expanding my own site. After a few years, with these requests continually streaming in, I realized that it was time to set up an organization for patients – one that would address their on-the-ground needs.

The American ME and CFS Society (AMMES) was founded as a way to answer some of the questions patients had been asking me through the years. It helped that I had already written a couple of books on the subject, so I was able to adapt a lot of information from what I had already written. My six years of experience as a ProHealth editor also served me well. I uploaded over 3,000 abstracts from the PubMed database, set up interactive databases for doctors and treatments, and wrote 60,000 words to cover all the basics. I designed a logo and a website, and hired (and fired) quite a few graphic artists, web developers, and designers. I worked with lawyers to get nonprofit status. It took two years. When the site was launched in 2016 I thought I was finished!

I wasn’t.

How did you come up with the idea of a financial crisis fund?

I got an email from an advocate in 2018 telling me about a fundraising competition, and asking if I would enter AMMES. Of course! But there was no category for anything we had on the site. I had to think of something practical. So, I posted a clip of an interview I had done with Llewellyn King in which I talked about homelessness among severely ill patients. The next logical step was to design an aid program for destitute patients. Before I fell ill, I’d run a nonprofit for Central American refugees, so I already had a good idea how to form a crisis fund. And that is how the AMMES financial crisis fund was born – like most births, quite by accident, but to a uniquely qualified mother.

A year has gone by since the inauguration of the AMMES financial crisis fund. In the course of a year, we have raised, and spent, $46,490. Most of that money has been dedicated to preventing evictions. In one case, a person who contacted us had already been evicted and was facing a night in his car, which would have killed him. (That is not an exaggeration. He was evicted on December 31st, in Illinois.) AMMES has also paid medical bills, including the co-pay for a wheelchair, food bills, utility bills (usually overdue, and in danger of being cut off). We helped purchase a bed for a patient who was sleeping on a couch, a microwave, and shoes for a patient who only had flip-flops to wear.

In short, we are attending to basic needs, things nobody in this country should go without. Nobody should be homeless, or hungry, or not have adequate clothing. These are the basics of survival.

So why is it so difficult to raise money for this cause?

To put it bluntly, helping sick people stay in their homes is not “sexy.” Nonprofit grants that get funded are for things like playgrounds for inner city kids, music programs, animal shelters, urban gardens. All of these provide a sense of accomplishment for those who donate. There is no feeling that a problem has been solved when people donate to help with an ongoing crisis. In fact, when I asked why something similar to what I was doing had never been done for the ME/CFS community, the answer was: “It would be a bottomless pit.”

The person who made that statement wasn’t wrong. Dealing with poverty is a bottomless pit. As long as there are poor people there will always be a need. But looking at the problem realistically, everything is a bottomless pit. Research into ME/CFS is a bottomless pit. Over the decades, research into ME/CFS has absorbed millions upon millions of dollars. Yet, for all the assurances that there will soon be a cure, that day has not come. More millions are needed. But nobody feels that research is a bottomless pit that does not deserve funding.

The fact that a need is ongoing does not mean it is not worth supporting. If we can save one person’s life – as AMMES has – that alone is cause for celebration. It means that there is one fewer death from ME/CFS. And I am absolutely positive that given the desperation of some of the people who have come to AMMES for help, we have prevented suicides as well.

When it comes to saving lives, there is no number that makes a project not worthwhile. Every life counts.

AMMES is currently running a Crowdrise fundraiser. Please DONATE. We spend every penny on patients in need.

https://www.crowdrise.com/o/en/campaign/american-me-and-cfs-society

What do you envision for AMMES in the future?

For starters, I would like to see every ME/CFS organization in the country make a substantial yearly contribution to the AMMES financial aid project. We all know how devastating this disease is, yet the devastation of poverty-stricken patients gets short shrift. Each organization that even mentions the fate of severely ill patients should earmark funds for ensuring that those patients do not die in the streets, or go hungry, or suffer from lack of heat in winter, or clothing. It doesn’t matter that we cannot help every single one of the patients who find themselves in desperate straits, we have a moral obligation to help as many as we can.

Another project that we are in the process of launching is a Craigslist-type of service, where people can connect online to offer free goods and services, post jobs, rides needed, and sign up to be Buddies. The buddy system is something we badly need as a community. We can make friends on Facebook and connect through other social media, but there is nothing like one-to-one contact. Buddies are people with ME/CFS who correspond with their ME/CFS “pen pals” via email. It’s personal, it’s warm, and it’s the next best thing to having a supportive friend over for tea.

Finally, I would really like to see some healthy relatives and friends of ME/CFS patients step up to the mat and join the AMMES board. So far, I have worked on AMMES alone. I need help, preferably from someone who is a social worker and can provide long-term solutions for our applicants. AMMES could also use a person who can raise funds for us. All nonprofits face a perpetual battle for funding, but in our case, we are forced to turn away sick people who are about to lose their homes when we run out of funds. Which is now.

Melinda Gates, if you are listening, please donate a couple hundred thousand dollars to AMMES. Everybody else, ten bucks will do.

Please DONATE. We spend every penny on patients in need….

___________________________________________________________________

I just added my little bit of  support.  Got to the AAMES Financial Crisis Crowdrise Fund to add yours

Read more about the Financial Crisis Fund here and here.

The post Saving Lives: Erica Verillo and the AAMES Financial Crisis Fund for ME/CFS appeared first on Health Rising.

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I can hardly believe it myself. My ME is in remission. Jen Brea

Steps per day – Jen Brea – before and after surgery (see blue line) (From https://forums.phoenixrising.me/threads/my-me-is-in-remission.76324/)

She ditched her wheelchair seven weeks ago. Her POTS disappeared in March.  The sensitivities to sound, light, vibration and touch are gone. So is the muscle twitching, the air hunger, the restless legs, the brain fog, the short-term memory issues and the flu-like symptoms,  For the first time in eight years, she’s walking for exercise and, well, for the thrill and joy of walking. She’s lifting light weights for 30-90 minutes. She recently did an hour of water aerobics. She knew her PEM was gone immediately after the CCI/AAI surgery.

Her spine is still healing but it seems it’s just a matter of time before Jen Brea’s ME/CFS is totally gone.

All it took was a series of spinal surgeries done over several weeks about six months ago. That sounds like a lot and it is – neither craniocervical instability (CCI) and tethered cord syndrome are easy to diagnose and are even more difficult to get treated – but her rapid recovery after 8 years of moderate to severe illness is amazing. She’s been in a wheelchair almost her entire time with this disease.

Just six months ago, following a thyroid surgery which exacerbated her then undiagnosed case of CCI, Jen Brea was arguably at her lowest point ever. Besides all her ME symptoms, she was having trouble breathing, had flaccid limbs, numb, painful and weak legs, and was experiencing difficulty speaking and thinking.

That all rather quickly disappeared.

Recovery

We know Jen Brea and her husband’s story on an intimate level through Unrest. Jen may be the only person some people feel they know with ME/CFS. She doesn’t appear to have ME/CFS anymore, though, and in six months, she may be completely healthy.

We’re complex beings and even a remarkable story like hers can bring up a mix of emotions. Happiness that someone who has been so ill may no longer be suffering. Hope that it could happen to us. There’s a potential dark side as well which Jen Brea alludes to – the survivor’s guilt for her of getting better while others continue to suffer – and possibly a feeling of getting left behind by those who haven’t recovered.

If I could, for the good of the community, pick one person to get well, it would be Jen Brea.

The Recovery/Recovering Stories section of Health Rising often triggers differing emotions – some people love them, others hate them. It’s not hard to see how someone else’s recovery story could trigger some issues.  The losses raise their heads to be counted again. Conversations, once vanquished, about the unfairness of it – a tunnel down which no cheese exists – show up again.  The problem is not someone becoming well but the shadow that recovery casts on our current situation.

I’m luckily rather immune to that. After 40 years of ME/CFS, I can hardly remember the healthy Cort. He’s not a problem anymore. Besides, if I could pick one person to get well – one person who, if healthy, could advance our cause the most – it would undoubtedly be Jen Brea. Her new health – she says she will stay involved – is a gift not just to her but to all of us.

The story of remission makes it even more clear to me than ever that we must fight for research to better understand the mechanisms underlying all of our cases.

I will never forget the experiences that I have gone through over the last eight years of illness. With my improved health, I will continue to fight alongside each of you for equality, dignity and better care; to challenge stigma and advocate for research dollars and medical education. I will not give up. I am in this fight until every person living with ME, no matter the cause, has access to diagnosis and care. Jen Brea

The Craniocervical Instability Subset in ME/CFS – Just How Big is It (and How Big Do We Want it to Be?)

Jen Brea makes two people with severe, apparently classic cases of “ME/CFS” who have recovered or are recovering after being treated for craniocervical instability (and in Jen’s case, tethered cord syndrome). Two more people on PR, @mattie and @StarChild56 have recently had fusion surgeries to correct CCI.  Another’s surgery is on tap. (An interview with Mattie is coming up on Jeff’s website.)

Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Brainstem Series

The fact that 20 people on the Phoenix Rising Forums have been diagnosed with craniocervical instability/atlantoaxial instability (CCI/AAI) over the past 8 months or so is remarkable, and suggests that the condition may not be as uncommon as one might think.

Difficult Diagnosis and Treatment

There’s no doubt this is not the easy way out for ME/CFS. If I could choose a way to recover – which I obviously can’t – neurosurgery would be one of the last options on my list. I think I would rather swallow a toxic chemotherapy drug than have a neurosurgeon fuse my head to the top of my spinal column. That procedure sounds about as spine-tinglingly scary as anything I can imagine. (Brain surgery would probably be worse.) The fact that only four neurosurgeons in the world can be trusted to do this procedure doesn’t help.

Among the first thoughts I had upon learning of Jen’s recovery was that if this is what it takes – a rare diagnosis and neurosurgery – if that’s what it really takes to recover, I don’t know that that’s ever going to happen.

After some reflection, I don’t think it’s as bad as that. Jeff and Jen and two other people have found a way and a remarkable 20 people on Phoenix RIsing have gotten a diagnosis. While diagnosis isn’t a piece of cake, it can and is being done. Be sure to check out Jeff’s recommendations on his website. Plus, other less invasive treatment options are available (see below).

Focus on the Spine

Jeff and Jen’s stories does bring a new focus to the spine and brainstem.  Hip, on the Phoenix Rising Forums, pointed to five structural conditions which can cause brain stem or spinal cord compression – and ME/CFS-like symptoms:

  • cervical spinal stenosis — spinal canal becomes too narrow, which can put pressure on the nerves
  • syringomyelia — fluid-filled cyst in the spinal cord which compresses the spinal nerves
  • Chiari malformation — where brain tissue is pushed into the spinal canal due to a skull which is too small
  • tethered cord — where spinal cord is “stuck” to a structure within the spine such as scar tissue
  • craniocervical instability — instability of head & neck bones compressing the brain stem or upper spinal cord.

Other spinal conditions that could cause or contribute to ME/CFS/FM/POTS include cerebral spinal fluid leaks and intracranial hypertension.

Even if you don’t have CCI/AAI, the search for it may help uncover other problems. One person on the Phoenix Rising forums reported that she didn’t have CCI but that the search for it turned up “severe stenosis, edema, compression fractures, and other issues causing my spinal cord to be affected” and that treatments for those conditions were helping.

Still, I’m hoping that: a) CCI/AAI is not a common diagnosis; or b) if it is, that non-surgical treatments can be as helpful as surgery. What I’m really hoping, though, is that Jeff and Jen’s stories are pointing to a problem area that can be helped with other means.

Focus on the Brainstem

Jen and Jeff’s stories place a new emphasis on the brainstem in ME/CFS.

Jen and Jeff’s experiences are shining a bright light on a potentially very important, and until recently, little explored area of the brain – the brainstem. Structural issues aren’t the only way to potentially tweak the brainstem in ME/CFS; inflammation, infection or autoimmunity would probably do quite nicely, and some evidence suggests at least one of these may be happening in ME/CFS.  Each of these could trigger a different (and less invasive) treatment approach.

Van Elzakker pointed to four ways the brainstem may be involved in ME/CFS:

  • via the dysregulation of immune signals traveling from the vagus nerve to the brain
  • via activation of the many mast cells found in it
  • via problems with its regulation of the autonomic nervous system
  • via a stunting of the anti-inflammatory response.

See – The Brainstem, Vagus Nerve, Neuroinflammation and Chronic Fatigue Syndrome: The VanElzakker Way

Some evidence directly implicates the brainstem in ME/CFS. Reduced brainstem grey matter volume suggests that the neurons in the brainstem may have been damaged. The fact that the damage correlated with autonomic nervous system problems suggested brainstem problems could be affecting exercise, sleep, the gut and cognition. A communication breakdown from the brainstem nuclei to other nuclei in the brain suggested brainstem problems could even be contributing to the motor cortex, i.e. movement problems in ME/CFS. Barnden proposed problems in the brainstem could be inhibiting the flow of signals from the motor cortex in the brain to the muscles.

The Japanese have echoed that general idea. A 2003 study suggested that reduced motor cortex output was reducing muscle recruitment in ME/CFS and causing fatigue.  Given the recent brainstem findings, though, stopping at the motor cortex would seem foolhardy. Given the extreme disability sometimes found in ME/CFS, it’s possible that two of the crucial brain organs involved in movement – the motor cortex and the brainstem – may have both taken a hit.

Studying the brainstem requires special techniques not usually used in brain imaging.  Both VanElzakker and Barnden are employing those techniques as they continue their brainstem studies in ME/CFS.

HIP on the Phoenix Rising Forums suggested an intriguing pathogen connection. Enteroviruses (the first viruses associated with ME) produce enzymes called matrix metalloproteinases (MMPs) that destroy connective tissue proteins like collagen, elastin and gelatin. It’s possible that an enteroviral infection could be causing the ligament laxity issues in CCI.

Jeff and Jen’s Atypically Typical Recovery

The only things we really know about recovery is that: a) it’s not common; and b) it occurs in a variety of ways. When it occurs, it often occurs using nontraditional approaches found teetering on the skinny branches of the medical system.  Just yesterday someone reported that getting treated for pyroluria – a condition many doctors don’t know about or believe in – made a huge difference.

I was recently diagnosed with Pyroluria. I had a urine count of 27.5 so I was severe. I am also copper zinc imbalanced. I am one of those rare people that the illness was shutting down physically and crippling me due to brain inflammation. I had constant vertigo, extreme light and sound sensitivity, sensory processing disorder problems that were so uncomfortable I would beg god to let me die. My body aches and couldn’t turn my head without severe symptoms. These are not symptoms that are easy to fake….. The saddest thing is how the healthcare system didn’t help at all. I was incapable of seeing, walking straight, or talking right some days but yea… not serious enough. I tried so hard to get help and they didn’t seem to care. So I was forced to an FMT; my last resort. Once diagnosed with severe pyroluria I started supplementation and had very quick results. I immediately had changed in functioning and energy. I can work now.

Pyroluria – Real Disorder or Figment? A Fibromyalgia and Chronic Fatigue Syndrome Inquiry

Finding an unusual treatment that works is fairly typical in people who recover. While there are certainly cases of gradual recoveries using supplements, pacing, and mind/body practices, many of the recovery stories involve unusual, out-of-the-box treatments.

Jeff and Jen Brea are leading examples. Not only is the CCI/AAI surgery they had unusual but they were unusual CCI/AAI patients as well.  Both were classic ME patients with all that implies (post-exertional malaise (PEM), viral infections, MCAS, POTS, sensory sensitivities).  Jen’s doctor told her he didn’t know how the surgery would go for her because he’d never had a patient like her. Whatever kind of CCI/AAI she had, it was different from that he’d seen before.

So it goes for many people who’ve recovered. Ken Anbender recovered from 26 years of hell using the Pridgen Protocol. After spending over $200K on more traditional treatments, mold avoidance did it for Joey.   Valcyte did the trick for Kate and her 25 year struggle with ME/CFS.  Sinus surgery proved the cure for Diane.  The winner for one recent onset but severely ill patient was desmopressin – something that doesn’t work that well for most. It took a particularly acute practitioner to diagnose the heavy metal poisoning that put one severely ill patient on the road to recovery.

Another remarkable thing is how sick some people can get and still recover. Jeff, Mike Dessin, and the heavy metal poisoning patient were more similar to Whitney Dafoe than your run of the mill (but still incredibly limited) ME/CFS patient – and yet they fully recovered. Prior to her surgeries, Jen Brea was at her lowest point ever – having trouble breathing, unable to speak or think at times – yet six months later is able to exercise.  When given the chance, the body can come back from an amazingly debilitated state.

For me, the recovery stories provide hope and are a sign not to give up, to stay curious, to keep reading and asking questions. Medicine, as Jen Brea noted in her recent blog, is ever-evolving. What was cloudy yesterday may become clear today. It wasn’t that long ago that CCI/AAI surgery wasn’t even considered for Ehlers Danlos Syndrome – it was the province solely of whiplash and trauma patients.

We should also remember how vitally important sharing our stories – both our ME/CFS stories – and our recovery stories. It’s grim, indeed, to think where Jen Brea might be right now if Jeff hadn’t shared his story on the web. Please share your improvement or recovery story (and if Health Rising asks you to respond to a questionnaire on how you improved please fill it out!)

Our goal has to be to assist the medical system in its evolution, to keep the hope alive, to keep sharing, to have the courage to keep knocking on closed doors, and eventually getting the light to shine through.

____________________________________________________________________________

Getting Diagnosed and Treated for CCI/AAI – a Review Symptoms

An X-ray of an neck being flexed back and forth to check for instability. (X-rays are not sufficient to test for this condition, however.)

The Zebra Network and other websites report three central symptoms of craniocervical instability (CCI):

  • “Heavy” headaches (feeling like the head is too heavy for the neck) and a bobble-head feeling.
  • Pressure headaches generated by things like yawning, laughing, crying, coughing, sneezing or straining.
  • Symptoms of autonomic nervous system functioning problems such as tachycardia (rapid heartbeat, heat intolerance, problems standing (orthostatic intolerance), gut motility problems, thirst and chronic fatigue.

Other symptoms can include neck pain, central or mixed sleep apnea, facial pain or numbness, balance and coordination problems and vertigo, dizziness, fainting, vision issues, difficulty swallowing, choking, tinnitus, nausea, vomiting, paralysis, downward nystagmus (irregular eye movements).

    Jeff reported that, for most of his ME/CFS, his vague headaches and neck symptoms provided no clues that his head and neck were the cause of his ME/CFS. Jen reported that turning her head to the side did cause strange symptoms and that she had been averse to running when healthy.

    Diagnosis Quickie Diagnostics

    Two methods can provide an indication that CCI/AAI might be present.

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    I can hardly believe it myself. My ME is in remission. Jen Brea

    Steps per day – Jen Brea – before and after surgery (see blue line) (From https://forums.phoenixrising.me/threads/my-me-is-in-remission.76324/)

    She ditched her wheelchair seven weeks ago. Her POTS disappeared in March.  The sensitivities to sound, light, vibration and touch are gone. So is the muscle twitching, the air hunger, the restless legs, the brain fog, the short-term memory issues and the flu-like symptoms,  For the first time in eight years she’s walking for exercise and, well, for the thrill and joy of walking. She’s lifting light weights for 30-90 minutes. She recently did an hour of water aerobics. She knew her PEM was gone immediately after the CCI/AAI surgery.

    Her spine is still healing but it seems it’s just a matter of time before Jen Brea’s ME/CFS is totally gone.

    All it took was a series of spinal surgeries done over several weeks about six months ago. That sounds like a lot and it is – neither cervicocranial instability and tethered cord syndrome are easy to diagnose and are even more difficult to get treated – but her rapid recovery after 8 years of moderate to severe illness is amazing. She’s been in a wheelchair almost her entire time with this disease.

    Just six months ago, following a thyroid surgery which exacerbated her then undiagnosed case of CII, Jen Brea was at arguably at her lowest point ever. Besides all her M.E. symptoms she was having trouble breathing, had flaccid limbs, numb, painful and weak legs, and was experiencing difficulty speaking and thinking.

    That all rather quickly disappeared.

    Recovery

    We know Jen Brea and her husband’s story on an intimate level through Unrest. Jen may be the only person some people feel they know with ME/CFS. She doesn’t appear to have ME/CFS anymore, though, and In six months she may be completely healthy.

    We’re complex beings and even a remarkable story like hers can bring up a mix of emotions. Happiness that someone who has been so ill may no longer be suffering. Hope that it could happen to us. There’s a potential dark side as well which Jen Brea alludes to – the survivor’s guilt for her of getting better while others continue to suffer – and possibly a feel of getting left behind by those who haven’t recovered.

    If I could, for the good of the community, pick one person to get well, it would be Jen Brea.

    It’s not hard to see how someone else’s recovery story could trigger some issues.  The losses raise their heads to be counted again. Conversations, once vanquished, about the unfairness of it – a tunnel down which no cheese exists – show up again.  The problem is not someone becoming well but the light that recovery casts on our current situation.

    I’m luckily rather immune to that. After 40 years of ME/CFS I can hardly remember the healthy Cort. He’s not a problem anymore. Besides, if I could pick one person to get well – one person who, if healthy, could advance our cause the most  – it would undoubtedly be Jen Brea. Her new health – she says she will stay involved – is a gift not just to her but to all of us.

    The story of remission makes it even more clear to me than ever that we must fight for research to better understand the mechanisms underlying all of our cases.

     I will never forget the experiences that I have gone through over the last eight years of illness. With my improved health, I will continue to fight alongside each of you for equality, dignity and better care; to challenge stigma and advocate for research dollars and medical education. I will not give up. I am in this fight until every person living with ME, no matter the cause, has access to diagnosis and care. Jen Brea

    The Craniocervical Instability Subset in ME/CFS – Just How Big is It (and How Big Do We Want it to Be?)

    Jen Brea makes two people with severe, apparently classic cases of “ME/CFS” who have recovered or are recovering after being treated for craniocervical instability (and in Jen’s case tethered cord syndrome). Two more people on PR, @mattie and @StarChild56 have recently had fusion surgeries to correct CCI.  Another’s surgery is on tap. (An interview with Mattie is coming up on Jeff’s website.)

    Could Craniocervical Instability Be Causing ME/CFS, Fibromyalgia & POTS? Pt I – The Brainstem Series

    The fact that 20 people on the Phoenix Rising Forums have been diagnosed with craniocervical instability/atlanto-axial instability (CCI/AAI) over the past 8 months or so is remarkable, and suggests that  condition may not be as uncommon as one might think.

    Difficult Diagnosis and Treatment

    There’s no doubt this is not the easy way out for ME/CFS. If  I could choose a way to recover – which I obviously can’t – neurosurgery would be one of the last options on my list. I think I would rather swallow a toxic chemotherapy drug than have a neurosurgeon fuse my head to the top of my spinal column. That procedure sounds about as spine-tinglingly scary as anything I can imagine. (Brain surgery would probably be worse.) The fact that only four neurosurgeons in the world  can be trusted to do this procedure doesn’t help.

    Among first thoughts I had upon learning of Jen’s recovery was that if this is what it takes – a rare diagnosis and neurosurgery – if that’s what it really takes to recover, I don’t know that that’s ever going to happen.

    After some reflection I don’t think it’s as bad as that. Jeff and Jen and two other people have found a way and a remarkable 20 people on Phoenix RIsing have gotten a diagnosis. While diagnosis isn’t a piece of cake it can and is being done. Be sure to check out Jeff’s recommendations on his website.. Plus other less invasive treatment options are available (see below).

    Focus on the Spine

    Jeff and Jen’s stories does bring a new focus to the spine and brainstem.  Hip, on the Phoenix Rising Forums, pointed to five structural conditions which can cause brain stem or spinal cord compression – and ME/CFS-like symptoms:

    • cervical spinal stenosis — spinal canal becomes too narrow, which can put pressure on the nerves
    • syringomyelia — fluid-filled cyst in the spinal cord which compresses the spinal nerves
    • Chiari malformation — where brain tissue is pushed into the spinal canal due to a skull which is too small
    • tethered cord — where spinal cord is “stuck” to a structure within the spine such as scar tissue
    • craniocervical instability — instability of head & neck bones compressing the brain stem or upper spinal cord.

    Other spinal conditions that could cause or contribute to ME/CFS/FM/POTS include cerebral spinal fluid leaks and intracranial hypertension.

    Even if you don’t have CCI/AAI the search for it may help uncover other problems. One person on the Phoenix Rising forums reported that she didn’t have CCI but that the search for it turned up “severe stenosis, edema, compression fractures, and other issues causing my spinal cord to be affected” and that treatments for those conditions were helping.

    Still, I’m hoping that a) CCI/AAI is not a common diagnosis ,or if it is that non-surgical treatments can be as helpful as surgery. What I’m really hoping, though, is that Jeff and Jen’s stories are pointing to a problem area that can be helped with other means.

    Focus on the Brainstem

    Jen and Jeff’s stories place a renewed emphasis on the brainstem in ME/CFS.

    Jen and Jeff’s experiences are shining a bright light on a potentially very important, and until recently, little explored area of the brain – the brain stem. Structural issues aren’t the only way to potentially tweak the brainstem in ME/CFS; inflammation, infection or autoimmunity would probably do quite nicely, and some evidence suggests at least one of these may be happening  in ME/CFS.  Each of these could trigger a different (and less invasive) treatment approach.

    Van Elzakker pointed four ways the brain stem may be involved in ME/CFS:

    • via the dysregulation of immune signals traveling from the vagus nerve to the brain
    • via activation of the many mast cells found in it
    • via it problems with its regulation of the autonomic nervous system
    • via a stunting of the anti-inflammatory response.

    See – The Brainstem, Vagus Nerve, Neuroinflammation and Chronic Fatigue Syndrome: The VanElzakker Way

    Some evidence directly implicates the brainstem in ME/CFS. Reduced brainstem grey matter volume suggests that the neurons in the brainstem may have been damaged. The fact that the damage correlated with autonomic nervous system problems suggested brainstemp problems could be  effecting exercise, sleep, the gut and cognition. A communication breakdown from the brainstem nuclei to other nuclei in the brain suggested brainstem problems could even be contributing to the motor, i.e. movement problems in ME/CFS. Barnden proposed problems in the brainstem could be inhibiting the flow of signals from the motor cortex in the brain to the muscles.

    The Japanese have echoed that general idea. A 2003 study suggested that reduced motor cortex output  was reducing muscle recruitment in ME/CFS and causing fatigue.  Given the recent brainstem findings, though, stopping at the motor cortex would seem foolhardy. Given the extreme disability sometimes found in ME/CFS, it’s possible that two of the crucial brain organs involved in movement – the motor cortex and the brainstem – ,may have both taken a hit.

    Studying the brainstem requires special techniques not usually used in brain imaging.  Both VanElzakker and Barnden are employing those techniques as they continue their brainstem studies in ME/CFS.

    HIP on the Phoenix Rising Forums suggested an intriguing pathogen connection. Enteroviruses (the first viruses associated with M.E.) produce enzymes called matrix metalloproteinases (MMPs) that destroy connective tissue proteins like collagen, elastin and gelatin. It’s possible that an enteroviral infection could be causing the ligament laxity issues in CCI.

    Jeff and Jen’s Atypically Typical Recovery

    The only things we really know about recovery is that a) it’s not common and b) it occurs in a variety of ways. When it occurs it often occurs using nontraditional approaches found teetering on the skinny branches of the medical system.   Just yesterday someone reported that getting treated for pyroluria – a condition many doctors don’t know about or believe in – made a huge difference.

    I was recently diagnosed with Pyroluria. I had a urine count of 27.5 so I was severe. I am also copper zinc imbalanced. I am one of those rare people that the illness was shutting down physically and crippling me due to brain inflammation. I had constant vertigo, extreme light and sound sensitivity, sensory processing disorder problems that were so uncomfortable I would beg god to let me die. My body aches and couldn’t turn my head without severe symptoms. These are not symptoms that are easy to fake….. The saddest thing is how the healthcare system didn’t help at all. I was incapable of seeing, walking straight, or talking right some days but yea… not serious enough. I tried so hard to get help and they didn’t seem to care. So I was forced to an FMT; my last resort. Once diagnosed with severe pyroluria I started supplementation and had very quick results. I immediately had changed in functioning and energy. I can work now.

    Finding an unusual treatment that works is fairly typical. While there are certainly cases of gradual recoveries using supplements, pacing, mind/body practices, etc. many of the recovery stories involve unusual, out of the box treatments.

    Jeff and Jen Brea are leading examples. Not only is the CCI/AAI surgery they had unusual but they were unusual CCI/AAI patients. Both were classic ME patients with all that implies – they experienced, post-exertional malaise (PEM), viral infections, MCAS, POTS and sensory sensitivities.  Jen’s doctor told her he didn’t know how the surgery would go for her because he’d never had a patient like her. Whatever kind of CCI/AAI she had, it was different from that he’d seen before.

    So it goes for many people who have recovered. Ken Anbender recovered from 26 years of hell using the Pridgen Protocol. After spending over 200K on more traditional treatments mold avoidance did it for Joey.   Valcyte did the trick for Kate and her 25 year struggle with ME/CFS.  Sinus surgery proved the cure for Diane.  The winner for one recent onset but severely ill patient was desmopressin  – – something that doesn’t work  that well for most. It took a particularly acute practitioner to get heavy metal poisoning diagnosed in another person who has mostly recovered.

    Another thing to remember – particularly if you are very sick – is how sick some people can get and yet recover. Jeff, Mike Dessin, and the heavy metal poisoning patient were more similar to Whitney Dafoe than your run of the mill  (but still incredibly limited) ME/CFS patient – and yet they fully recovered. Prior to her surgeries Jen Brea was at her lowest point ever – having trouble breathing, unable to speak or think at times –  yet six months later is able to exercise.  When given the chance the body can come back from an amazingly debilitating state.

    For me the recovery stories provide hope and are a sign not to give up, to stay curious, to keep reading and asking questions. Medicine, as Jen Brea, noted is ever evolving. What was cloudy yesterday may become clear today. Jen Brea noted that it wasn’t that long ago that CCI/AAI surgery wasn’t even considered for Ehlers Danlos Syndrome – it was the province solely of whiplash and trauma patients.

    Our goal has to be to assist the medical system in its evolution, to keep the hope alive, to keep sharing, to have the courage to keep knocking on closed doors, and eventually getting the light to shine through.

    ____________________________________________________________________________

    Getting Diagnosed and Treated for CCI/AAI – a Review Symptoms

    The Zebra Network and other websites report three central symptoms of craniocervical Instability (CCI):

    • “Heavy” headaches (feeling like the head is too heavy for the neck) and a bobble-head feeling.
    • Pressure headaches generated by things like yawning, laughing, crying, coughing, sneezing or straining.
    • Symptoms of autonomic nervous system functioning problems such as tachycardia (rapid heartbeat, heat intolerance, problems standing (orthostatic intolerance), gut motility problems, thirst and chronic fatigue.

    Other symptoms can include neck pain, central or mixed sleep apnea, facial pain or numbness, balance and coordination problems and vertigo, dizziness, fainting, vision issues, difficulty swallowing, choking, tinnitus, nausea, vomiting, paralysis, downward nystagmus (irregular eye movements).

      Jeff reported that, for most of his ME/CFS, his vague headaches and neck symptoms provided no clues that his head and neck were the cause of his ME/CFS. Jen reported that turning her head to the side did cause strange symptoms and hat she had been adverse to running when healthy.

      Wearing a Philadelphia Cervical brace can help with self-diagnosis. The improvement Jeff and Jen experienced helped them self-diagnose themselves. (As Jeff’s condition worsened, though, the collar didn’t help at all; i.e. it may not help everyone).

      Diagnosis

      Merck reported that symptom improvement during a procedure called Invasive Cervical Traction (ICT) where one’s head is pulled upward by a pulley system can help diagnose CCI/AAI. Or a physical therapist can apply cervical traction. Dr. Bolognese told one potential patient on Phoenix Rising to “Try cervical traction with your local physical therapist. If you obtain dramatically positive results with the traction, then email me back about your feedback, and we will select you for a visit or a videoconference.”

      Lacking that, a doctor can simply pull the patient’s head up off the spine in the doctor’s office, and see if that helps!

      On his Mechanicalbasis website, Jeff provides crucial advice for getting tested and fully diagnosed including how to get your scans into the right hands. Most neurosurgeons aren’t trained to recognize craniocervical instability and finding an imaging facility that does the right kind of scans can take time. Different neurosurgeons will employ different scans.

      Upright MRIs with flexion, extension, and rotational views, or supine CT scans with flexion, extension, and rotational views or 3Tesla supine MRI’s.  (A patient of Dr. Kaufman’s reports that the extremely strong 3Tesla MRI’s may be the best and are more readily available. Check out the difference between the 3T and 1.5T machines).

      Chiaribridges reported that “the ideal tests to diagnose CCI and AAI are an upright MRI with flexion and extension (bending one’s head forward and backward as far as one can) and a 3D CT with rotational views, respectively. Ventral brainstem compression is not always seen in traditional supine MR imaging but..

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      Which will be the next drug to be FDA-approved for FM or ME/CFS?

      Both fibromyalgia (FM) and chronic fatigue syndrome (ME/CFS) clearly need better treatments. The FDA-approved drugs for these diseases are too often ineffective, come with too many side effects (fibromyalgia) or just aren’t available at all (ME/CFS).

      Too many people remain in pain, unable to work (or work well), be active, get out and visit and do the things they used to love to do.  Alternative health treatments and mind/body techniques can certainly help, but for most of us significant relief or a cure is probably going to take the form of a drug or other FDA-approved treatment that insurance companies will pay for. Hence the focus of these overviews on drugs.

      In part one of this series, we looked at the recent disappointing drug trial failures and one drug that’s managed to revive itself after a near-death experience. In this one, we look to the future – at clinical trials underway or reported to begin shortly.

      This overview doesn’t cover supplements, diets, exercise or mind/body treatments – all of which are undergoing trials in these diseases. If you’re interested in being in one of the trials mentioned, clicking on the link will take you to the trial in the clinialtrials.gov database.

      Fibromyalgia

      At over $3 billion a year in the U.S. alone, the market for FM drugs is a hot one.

      Big Market! – The FM market in the U.S. is estimated at nearly $3 billion annually. According to a recent analysis, at least five pharmaceutical companies/startups (Aptinyx, Inc., Prismic Pharmaceuticals, Inc., Innovative Med Concepts, Inc., Intec Pharma Ltd., Astellas Pharma, Inc.) have drugs in the pipeline for FM.  A Pipeline Report lists 13 companies pursuing drug treatments for FM and covers over 20 drug profiles.

      A cough suppressant for FM? Jarred Younger is trialing dextromethorphan – a possible microglial inhibitor – in fibromyalgia in Alabama. (The microglia are immune cells in the brain that produce neuroinflammation.)

      Vaccine? – Some people with ME/CFS recoil at the idea of getting a vaccine, but a staphylococcus vaccine worked well for a Swedish doctor with ME/CFS for decades. Now the Faustman Lab in Massachusetts is attempting to activate the immune systems of FM patients using the bacillus Calmette-Guérin (BCG) vaccine.

      Carl-Gerhard Gottfries: A Swedish Chronic Fatigue Syndrome Treatment Success Story

      Pain Pathway Modulator? – An interim analysis of Aptinyx’s NYX-2925 fibromyalgia trial showed good results. That’s good news because their big neuropathic pain trial recently tanked.  NYX-2925 is an N-methyl-D-aspartate (NMDA) receptor modulator, and the studies are taking place in Michigan and Ohio.

      The New Naltrexone? Was low dose naltrexone (LDN) just the beginning? Jarred Younger is exploring a potentially more effective and side-effect free version of LDN called dextro-naltrexone. (Not in clinical trials…)

      Jarred Younger III : Treatments – A Better LDN and the Hunt for Microglia Inhibitors

      Stimulating! – seven different magnetic stimulation studies are under way or will soon be recruiting.

      Soft Tissue Manipulation (massage?) – Dr. Liptan has said that massage is the best thing for FM.  If you’re in Madrid, you might be able to check that out for yourself in a “soft tissue manipulation” study which hopes to increase its participants’ heart rate variability levels.

      Tomnya: The Lazarus Drug – If Tomnya (TNX-102) can improve both sleep and pain (and help with PTSD if you have it!) in FM, Tonix Pharmaceuticals will have a real hit on their hands.  Check out a drug that’s come back from a near-death experience and should enter trials soon.

      TNX-102’s Rebirth Could Help With Sleep AND Pain in Fibromyalgia

      Mystery Drug – The Astellas Pharma ASP0819 Phase II study recently finished up, but it’s worth noting because it was large (n=186) and took place in dozens of centers over the past four years. It’s also a complete mystery. Astellas is holding info on ASP0819 close to its chest: I couldn’t find any information – even in the scientific literature – on what the drug does.

      Getting Oxygenated – The first FM hyperbaric oxygen trial went quite well. With the 60 90-minute hyperbaric oxygen sessions (five days every week) in this Israeli study, the FM patients are getting pounded with oxygen.  A French study may be doing them one better, though; it’ll be comparing the results of hyperbaric oxygen with transcranial magnetic stimulation.

      New Age Fluff or Real Treatment? Fibromyalgia Hyperbaric Oxygen Therapy Study Opens Eyes

      Diabetes Drug? – Half the FM patients in one metformin retrospective FM study reportedly recovered quickly. Could it really be so easy? One metformin trial in fibromyalgia has been completed and another is under way.

      Fibromyalgia, Pre-Diabetes and Metformin: Could a Diabetes Drug Help with FM (and ME/CFS?)

      Ear Therapy – FM patients in France will get what appears to be ear acupuncture or auriculotherapy, which the investigators report works in their clinic and has been validated by the World Health Organization (WHO) since 1987.

      Shocking… Shock-wave therapy, the investigators report, has “been used successfully to treat painful skeletal muscle, tendons and fascia” problems. They’ll be trying it in Switzerland if you’re in the neighborhood.

      No less than 10 studies are looking at some form of acupuncture (electroacpuncture, dry needling) in FM and myofascial pain syndrome. (If insurance companies would approve it, I’d give it a shot in a minute…)

      Lyrica generics coming – Pfizer has hauled in $30 billion from Lyrica in the U.S. alone over the past fifteen years, but the drug manufacturer’s cash cow will be ending soon. Fierce Biotech indicated that Lyrica generics from Teva, Mylan, Sandoz and other companies should be hitting the market soon.

      Chronic Fatigue Syndrome (ME/CFS)

      Market? What market? Does Big Pharma care about an untouched million-person market? Apparently not. While they throw money at fibromyalgia, they’re still afraid to stick their toes in the water for ME/CFS. That seems crazy, given that many would probably be tempted to sell their first-born for a chance at a good drug.

      While it’s not coming from Big Pharma, there is hope, though. It’s coming from small drug companies (Cortene) and doctors and researchers (Dr. Klimas and the Institute for Neuroimmune Medicine, Dr. Naviaux and the Open Medicine Foundation, and Dr. Peterson and the Simmaron Research Foundation).

      Let’s not forget the work Ron Davis is doing testing drugs with the nanoneedle, or the Solve ME/CFS Initiative’s Ramsay award to Vincent Lombardi to search for an immune-based drug target.  Either could reap major dividends if they work out.

      Ramsay’s Continue Focus on the Mitochondria in ME/CFS – Plus, the Hunt for a Drug Target is On (!)

      Cortene – The big surprise of last year – the Cortene drug trial – has finished up at the Bateman Horne Center, and we are awaiting results.

      The Cortene Chronic Fatigue Syndrome (ME/CFS) Drug Trial Begins

      Klimas Drug Trial – this most fascinating of trials used supercomputers to come up with its Etanercept (first) and Mifepristone (later) combination. The goal – to reset the systems of Gulf War Illness (GWI) and ME/CFS patients and return them to normal functioning. The Gulf War Illness trial is probably finished or is nearing finishing, and another similar small trial has started or will be starting soon in ME/CFS.

      Klimas Methylfolate Study – talk about a down-in-the-dirt, practical, study.  Dr. Klimas’s methylfolate study to determine if a genetic defect is causing folate problems in ME/CFS and if the proper supplementation will help is reportedly done.  It won’t cure ME/CFS, but any boosts in energy and well-being are certainly welcome.

      “The Great Chronic Fatigue Syndrome Community Gene Study” Breaks New Ground

      Suramin – Can Naviaux turn back the clock, dig patients out of their hypometabolic, hibernation-like, worm-like (that’s the C. elegans worm) dauer state with a drug used for African Sleeping Sickness? The problem has been getting access to the drug – which reports indicate will happen at some point. The small Surinam autism trial went well…

      Treating Autism and ME/CFS: Could One Drug Help Both?

      Younger’s Plants – So the study is on Gulf War Illness, not ME/CFS – but if Dr. Klimas can try to treat GWI and ME/CFS with the same drug combo, we can put Younger’s botanicals study into the ME/CFS category.

      Younger has hinted that some botanicals may actually work better than LDN at reducing neuroinflammation. The data analysis of his large botanicals trial is underway. We should have it by the end of the summer.

      Microglial Inhibiting Drugs and Botanicals to Combat Neuroinflammation

      Mestinon – Some patients have reported doing very well on Mestinon (pyridostigmine bromide) while others haven’t. Dr. Systrom will reportedly be publishing a retrospective study on the effectiveness of Mestinon in treating exercise intolerant patients with ME/CFS, FM, POTS and allied disorders. Several studies are underway in POTS.

      A Mestinon Miracle: Vagus Nerve Stimulating Drug Helps Long Time ME/CFS Patient Exercise

      Ampligen – Talk about the need for a miracle. ME/CFS’s perennial disappointment, Ampligen, has been in play for over 30 years now without getting approved. The FDA says it wants one more big trial, to which Hemispherx responds it can’t afford it – leaving us in limbo once again.  Only Hemispherx truly knows what’s going on.

      There is some good news, however. Dr. Peterson, the Simmaron Research Foundation, Maureen Hanson and the CDC are working on quantifying Ampligen’s effectiveness and determining why it’s effective when it is. More on that coming up.

      Ampligen Chronic Fatigue Syndrome (ME/CFS) Resource Center

      Pain

      Next generation opioids – we know now that it’s theoretically possible to create opioid drugs which are not addictive, do not lead to tolerance or increased pain sensitivity, etc. Whether industry will be able to create them is another issue. I looked through 200 of the 779 opioid studies underway and found not a single one featuring next-generation opioids. Their time has not yet come. Perhaps the HEAL Initiative will help…

      The Opioid Painkiller Clampdown – Will it Lead to Better Drugs?

      Heal Initiative – the NIH is pumping hundreds of millions of dollars into pain and pain drug research in a very ambitious effort to come up with 15 new pain drugs over the next 5 years.

      The Opioid Painkiller Crackdown’s Silver Lining for Fibromyalgia: The Heal Initiative

      Other Fatiguing Diseases

      Because severe fatigue is a huge issue for other diseases, it’s possible that a drug breakthrough that treats the fatigue in them could bleed over into ME/CFS, FM and related diseases.

      Cancer-Related Fatigue

      Riluzole, dexamethasone, methylphenidate, metformin,

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      It was looking really good for a while!

      It’s been a tough couple of years for drug trials in fibromyalgia (FM) and chronic fatigue syndrome (ME/CFS).  The rapid approval of three drugs (Lyrica, Cymbalta, Savella) in the late 2000’s made FM seem like a good bet.

      Four years ago the future looked bright.  A pharmaceutical source predicted four new drugs (a new Flexeril, a better formulation of Lyrica (mirogabalin), an NSRI (SNRI) called TD-9855, and a time-release formulation of Lyrica) would be approved for fibromyalgia by now. (They were only off by four.)

      Meanwhile ME/CFS had Rituximab and the Synergy trial going for it.  All of the drugs bit the dust – some in spectacular fashion.

      The Future Fibromyalgia Drugs? Pharmaceutical Source Predicts Four Drug Approvals in Coming Years

      First came the TNX-102 failure and then the astounding collapse of mirogabalin.

      Flexeril Reformulation Fails 

      An updated form of Flexeril, TNX-102 looked like a sure bet.  The new sublingual format shot the drug straight into the body, allowing a significant reduction in the dose, and bypassing the problems that were relegating Flexeril to short-term use. Tonix – the drug’s manufacturer – was so confident that it reportedly started its phase III FM trial before the phase II trial had even ended. Refreshing sleep and reduced pain seemed to be on their way for FM patients.

      The phase III trial did show benefits but failed to meet its primary endpoint – reducing pain significantly in at least 30% of the people taking it. Tonix’s stock price plunged by 70% on the news, wiping out $30 million in shareholder value. Its interest in FM apparently over, Tonix reported that it would try again with PTSD.

      Daiichi’s Doomed Effort

      Hubris appeared to have struck again with Daiichi Sankyo. The Japanese pharmaceutical was so confident in its more supposedly more effective, safer and longer-lasting formulation of Lyrica that it embarked on a global series of trials involving over 3,600 patients in 300 centers.  Yen, dollars, Euros and who knows what other denominations were no doubt dancing in the Japanese pharmaceutical giant’s head as it contemplated taking over Pfizer’s $5 billion/year Lyrica market.

      Instead the drug didn’t meet its mark and Daiichi pulled back from fibromyalgia – but not from other pain conditions. (See below.)

      The Big Hurt: Second Major Fibromyalgia Drug in a Year Fails

      Rituximab’s Resounding Failure

      Likewise, the Rituximab trial hopes in ME/CFS ended in spectacular fashion when the ME/CFS community learned to its dismay that substantially more patients benefited from the placebo than from the drug – which also had high rates of side effects to boot. (Then again, so did the placebo group – which shows that bad things are happening all the time to some people with ME/CFS.)

      Synergy Sinks

      Then Synergy ME/CFS trial (methylphenidate+supplements) failed in a different way: response rates were good, but the rates of placebo effectiveness were so high that the drug/supplement combo failed to produce significant results.

      Synergizing Health? The K Pax Chronic Fatigue Syndrome Study Results are In…

      Brindcifovir Bombs

      Just this year Brindcifovir – a new injectable version of Vistide – was supposed to be God’s gift to people with herpes virus infections.  After the initial trial of transplant patients failed to reach its endpoint, the drug was thought to be wounded but not mortally stricken. This year, however, Chimerix, citing an inability to enroll enough patients for its latest trial (!), pulled the plug on Brincidofovir entirely and laid off 40% of its staff.

      Phase III trials are clearly a tough gig! The news was not all gloomy, however. Like Lazarus rising from the dead…

      TNX-102 is Back! Tonix’s Sleep & Pain Drug to Begin Fibromyalgia Trials 

      Ten days ago, Tonix announced that it wasn’t done with fibromyalgia after all. Citing the success of its PTSD trials, a promising re-analysis of its fibromyalgia study data, and the strong support from the FDA, Tonix announced it was back in the fibromyalgia drug creation business. (Thanks to Daniel for the tip :))

      TNX-102 had not failed completely in it’s first phase III trial. It had shown benefits – particularly with sleep – but hadn’t met its crucial primary pain endpoint.  Tonix reported there’s an easy way to fix that problem – simply double the dose. That doubled dose worked just fine in its PTSD trials  – and relieved PTSD patients’ pain to boot. Only minor side effects showed.

      The company couldn’t stop itself from gushing about how on board the FDA was with the drug moving forward.

      “The FDA’s acceptance of the well-established safety information of currently-marketed oral cyclobenzaprine products and their agreement that TNX-102 SL 5.6 mg long-term exposure data from our PTSD studies may support the fibromyalgia indication are very reassuring.

      “We have extensive clinical experience and data collected over the past seven years with TNX-102 SL in fibromyalgia and PTSD studies. In addition to the synergy between these two development programs, we are very pleased with the FDA’s clear guidance and support to help advance our lead product candidate, TNX-102 SL, in fibromyalgia and PTSD toward NDA approvals.”

      With its ability to potentially effect two major symptoms in FM – sleep and pain – TNX-102 certainly is an enticing drug. Tonix said it would be submitting plans for the next trial to the FDA soon.

      Mirogabalin Making Headway as Well

      Nor did Daiichi pour God knows how many yen into mirogabalin just to walk away. It’s drug – called Tarlige  – has been approved for neuropathic pain in Japan, and clinical trials into neuropathic pain and post-herpetic neuralgia have been successfully completed. The drug will probably make its way to the U.S. at some point – not for FM – but perhaps for the neuropathic pain often found in FM.

      Daiichi is also giving Heptares Therapeutics $12 million to discover and develop small-molecule drug candidates that target G protein-coupled receptors (GPCR) for pain. These appear to be the same receptors involved in the new migraine drugs that are hitting the market.

      Synergy Not Necessarily Sunk

      Synergy is not necessarily sunk either. A re-analysis of the data suggested that the drug may have work better than believed  – particularly in the worst off patients. Whether money can be found to mount another trial is another question.

      Pridgen’s Drug Combo Reportedly Still Moving Forward

      Pridgen has apparently failed thus far to convince funders to back the phase III trials needed to push his antiviral drug combo forward. When last heard from, though, Pridgen is moving forward with another phase II trial planned.

      Conclusion

      Despite the failures of the past couple of years the good news is that the drug that people with fibromyalgia most would have wanted to succeed – TNX-102 – which Tonix says should help with both sleep and pain is back on track. Plus, after several strong trials, mirogabalin will probably show up on these shores at some point as well.

      Next up check out a long list of future drug possibilities and a look at the clinical trials underway (or soon to be underway) for ME/CFS/FM/POTS and other fatigue and pain disorders.

      The post TNX-102’s Rebirth Could Help With Sleep AND Pain in Fibromyalgia appeared first on Health Rising.

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      Upon reading Ryan Prior’s story of Ron, Janet and Whitney’s battle with ME/CFS on CNN yesterday Martha penned this moving post on her Facebook site. Thanks for allowing Health Rising to share  how Ron, Janet and Whitney’s story provided an opening for Martha to take a stand to end her own self-doubts and move forward. From Martha’s Facebook site:

      Today, May 12, is International Awareness Day for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): the condition that I have suffered from for 18 years.

      The article attached to my post, here, features one fellow sufferer, Whitney Dafoe; his father, Ron Davis, a Stanford geneticist who is racing the clock to uncover the roots of the illness; and his mother, Janet Dafoe, who, along-side her husband serves as Whitney’s primary care giver.

      Martha describes herself as moderately ill but her losses – career, family, friends, dreams – have been incalculable.

      Like any chronic condition (Multiple Sclerosis, Lupus, Parkinson’s Disease, etc.), ME/CFS affects each person differently, and to varying degrees. Whitney Dafoe is one of the most affected that has ever been brought into the greater spotlight, which makes his story – their story – difficult for even me (or maybe especially for people like me) to read.

      I have never been as gravely ill as Whitney is. I am what is best described in the field as “moderately affected”: not as affected as some, but enough so that I have never been able to work, I have not been able to have a family of my own, and I have lost almost every other opportunity to interact with life in a normal way, due to this condition. And, I have repeatedly sat vigil; holding my breath and waiting, as my system touched down – multiple times over the years – into somewhere too close to the edge of total system collapse and a truly threatening level of dysfunction.

      By the grace of God, or the Universe, or whatever guiding force may look down upon us all, or, perhaps, just by luck alone, I have been fortunate enough to find some treatments over the years that have kept me from getting permanently stuck in that frightening place.

      However, Chronic Fatigue Syndrome has long been surrounded in stigma, confusion, mis-perception, and even mis-appropriation of government funding – a history that’s been defined in many ways by the belittling words in the condition’s very title.

      As a result, I have had to fight our system of health care at every step along the way to receive any care at all. This is highly typical – if not universal – for sufferers of this condition.

      I have also lost many friends and important relationships over the years, due to my inability to adequately sustain them, and, to adequately explain my situation, my condition, my life (and why it looks the way it does), and my-self, to them. (I often still find myself struggling to explain these same things to those of you who are left.)

      And though I have spent my entire adult waking life and “career” trying to understand the condition, trying to understand and assess the potential applicability of various recommended treatment options available (most of which come from well beyond the orderly walls of Mainstream Medicine, and instead must be collected from the various fields of care that make up all of Alternative Medicine)…my collective intellectual knowledge on these matters often outstrips my ability to actively institute them on my own behalf…

      …my system (or psyche) has increasingly grown resistant to my own best efforts to just, stop, and – in the face of all that damaging madness – simply care for myself in the very best way that I know how…

      She has encountered the stigma associated with ME/CFS many times

      Somewhere along the way, the doubt that was cast onto me so repeatedly from the outside, turned to into doubt that now comes from the inside. As the validity of my symptom lists were repeatedly questioned, as my motivations for educating myself were so obviously suspected (and by so many of my physicians), and the topic of conversation around me was repeatedly (and awkwardly) shifted, I began to doubt my own self: my own perceptions, my own ability to assess and understand a situation, let alone any specifics of this complicated condition. And, perhaps most damaging of all, I began to doubt that I was even remotely worth the kind of loving and immaculate care that I must provide my system in order to keep it afloat and above the imperative line of “functionality”.

      But every time that I waver in this way, at least, every time that I can remember to do so, my mind drifts back into the scenes of Whitney Dafoe’s bedroom, where he now lives full-time: intimate, exposing scenes that he and his family have chosen to share in their collective efforts to reveal the true devastation that this disease can, and does, cause…(and, to attract attention and funding to assist in the elucidation of the causes and cures of the condition)….

      …and every time I think of Whitney, lying there in his bed, alone – day after day, week after week, year after every passing year – I think to myself:

      Martha, you are not allowed to doubt the reality of your condition. You cannot question the validity, or importance, of the few things you’ve found to help your own situation (even though meager they may appear). If you allow the doubt that has been cast upon you to turn into and onto yourself, then you are also doubting the very reality of Whitney’s condition…as well as all of the “Whitneys” of this hidden world of illness who will never be featured…and never be seen. And, in so doing, you are throwing away the very gifts that God, or the Universe, or sheer Luck alone, have passed in your direction.

      And I will not do that, I cannot do that: not to any of us. We have all been through too much already, without our own selves to fight.

      Everyone watches Days of Awareness for various medical conditions, along with so many other truly valuable causes, come and go…and I think we all wonder how we can help, what can we do in the face of such varied and ceaseless suffering? And, not seeing any clear or helpful answer to these things, we often just feel more aware and even less hopeful for change…paralyzed, even, by the overwhelming nature of it all…

      …Today, on the day that was designed to bring attention to the – (grossly) under-recognized, (grossly) under-diagnosed, and (grossly) under-funded – condition that I, myself, actually suffer from…I still arrive back at this familiar place of dejection.

      But this year…this year the clouds parted as quickly as they’d arrived, and the answer, for myself and for today, became clear: I must make a post, share a little slice of my life’s truth, and then stop, and commit myself fully to the task of learning to care for, and about, myself again. I need do so for myself, for my loving partner (and primary care-taker) Brian, for my family and friends (all of whom I hope to be in a better place to support someday, and even some, to care for), and, in honor of Whitney Defoe, and his brave and loving family.

      Ron, Janet and Whitney’s story enabled Martha to step out of the stream of disbelief she’s encountered with the medical profession, and take a stand for herself and others.

      To all of you who have ever loved me, I ask that you take the time to read the article about Whitney and his family, and his father’s efforts to fight for his son’s life (along with all of ours that are attached to theirs, though this shared affliction). And then please share it, particularly with any friends or other contacts in the medical profession(s), and/or re-post it here on Facebook.

      And please feel free to pass on my thoughts, here, to anyone you know who may be struggling to re-discover how to care for, and about, themselves, due to a similar experience with the stigma, and insufficiency of social and medical support that affects the sufferers so many chronic medical conditions. Some of you might be surprised how many you might actually know: this experience is surely accentuated in ME/CFS, but unfortunately is not at all unique to it.

      And, take good care of yourselves, take good care of one another, and count your every blessing: every Friend of mine on here, is genuinely one of my own.

      Martha

      The post Kissing Self-Doubt Good-Bye: How Whitney Dafoe’s ME/CFS Story Empowered One Person appeared first on Health Rising.

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      International Awareness day is a day for many things – to push for more awareness, to celebrate the advances we are making, and to remember and honor those fighting to bring an end to ME/CFS.
       
      Remembering Tom
      For me it’s inevitably a day to remember Tom Hennessy. Tom started International Awareness day decades ago, was ahead of his time in many ways, and struggled with a horrendously painful case of ME/CFS. Tom took his life six years ago… 

      Ron Davis – taken from the CNN Story (https://edition.cnn.com/2019/05/12/health/stanford-geneticist-chronic-fatigue-syndrome-trnd/index.html?no-st=1557647877)

      Spreading Our Story

      Tom would have absolutely loved to see Ryan Prior get his powerful and exquisitely shot story on Ron Davis, Janet Dafoe and their ill son Whitney “He pioneered technology that fueled the Human Genome Project. Now his greatest challenge is curing his own son” onto a major media outlet on this day.

       
      Share, share, share this up close look at Ron, Janet and Whitney on social media and with friends and family. You never know who you might touch and what difference they might make.
       
      Advocacy Makes Strides
      Advocacy pays off as ME/CFS takes steps forward in halls of Congress in our long fight to gain better funding. Find out more about that from Emily Taylor and the SMCI
      Millions Missing
      check out live video’s from MEAction’s Millions Missing demonstrations across the world on their Facebook site. 
       
      Faces of ME/CFS
      Finally, check out a slideshow put together of the many faces of ME/CFS put together for International Awareness day by the Open Medicine Foundation. 

      The post Major CNN ME/CFS Article Highlights International Awareness Day appeared first on Health Rising.

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      International Awareness day is a day for many things – to push for more awareness, to celebrate the advances we are making, and to remember and honor those fighting to bring an end to ME/CFS.
       
      Remembering Tom – For me it’s inevitably a day to remember Tom Hennessy. Tom started International Awareness day decades ago, was ahead of his time in many ways, and struggled with a horrendously painful case of ME/CFS. Tom took his life six years ago… 
      https://www.healthrising.org/blog/2013/09/28/my-brother-by-choice-goodbye-tom-hennessy-fierce-advocate-memorial-tomorrow/

      Ron Davis – taken from the CNN Story (https://edition.cnn.com/2019/05/12/health/stanford-geneticist-chronic-fatigue-syndrome-trnd/index.html?no-st=1557647877)

      Spreading Our Story – Tom would have absolutely loved to see Ryan Prior get his powerful and exquisitely shot story on Ron Davis, Janet Dafoe and their ill son Whitney “He pioneered technology that fueled the Human Genome Project. Now his greatest challenge is curing his own son” onto a major media outlet on this day.

       
      Share, share, share this up close look at Ron, Janet and Whitney on social media and with friends and family. You never know who you might touch and what difference they might make.
       
      Advocacy Makes Strides – Advocacy pays off as ME/CFS takes steps forward in halls of Congress in our long fight to gain better funding. Find out more about that from Emily Taylor and the SMCI
       
      Missing Millions – check out live video’s from MEAction’s Missing Million’s demonstrations across the world on their Facebook site. 
       
      Faces of ME/CFS – Finally, check out a slideshow put together of the many faces of ME/CFS put together for International Awareness day by the Open Medicine Foundation. 

      The post Major CNN ME/CFS Article Highlights International Awareness Day appeared first on Health Rising.

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      It says right there in the title – “Is insulin resistance the cause of fibromyalgia? A preliminary report” – it’s a preliminary report, but definitely an interesting one.

      In fact, the authors have stated that if the findings are validated, they could lead to a “revolutionary shift” in the way fibromyalgia and related forms of chronic pain (that includes chronic fatigue syndrome (ME/CFS)) are treated. They stated that the new approach “has the potential to save billions of dollars to the health care system and decrease many people’s dependence on opiates”. (Not to mention improve many people’s health and wellbeing :))

      Someone is excited…

      The study results basically come down to the inability to interpret a rather common lab test correctly.  The findings suggest fibromyalgia could be a form of pre-diabetes that could, in some cases, be treated with readily available diabetes medications. (No wonder they’re excited.)

      The Study

      Is insulin resistance the cause of fibromyalgia? A preliminary report. Miguel A. Pappolla, Laxmaiah Manchikanti, Clark R. Andersen, Nigel H. Greig, Fawad Ahmed, Xiang Fang, Michael A. Seffinger, Andrea M. Trescot, Published: May 6, 2019, https://doi.org/10.1371/journal.pone.0216079

      A small study suggested that metformin – a drug that reduces insulin (pictured here) resistance – might be helpful in fibromyalgia

      This small, rather simple retrospective study analyzed insulin resistance (HbA1c test), the use of metformin – a drug used to treat insulin resistance (IR), and pain levels in 23 patients who’d been referred to a pain clinic for widespread myofascial pain (and met the criteria for fibromyalgia).

      (Because this was a retrospective study, there was no healthy control group. Instead, the researchers used two independent healthy control populations to get normative values for the HbA1c test.)

      Diabetes occurs when the body is unable to metabolize carbohydrates (glucose) properly, leading to high glucose levels in the blood. Insulin, a hormone, allows glucose to enter the cells and produce energy. It also helps break down fats and proteins for energy. When too little insulin is present, or if the insulin receptors on the cells don’t respond to it, glucose will build up in your blood, causing problems.

      Over time, insulin resistance and the high glucose levels in diabetes can have nasty effects including eye (retinopathy), kidney (nephropathy), and nerve (neuropathy) problems. Those neuropathy problems include small fiber neuropathy (which is found in fibromyalgia), ME/CFS, GWI, POTS and diabetes.

      The authors noted that because their clinic aggressively treats pre-diabetic conditions (HbA1c values of 5.7 or higher), they had data on metformin usage. In fact, they had quite a bit of data as many of the people with fibromyalgia in this sample were classified as having pre-diabetes. They used the Numeric Pain Rating Scale (NPRS) to assess pain levels every time a patient visited the clinic.

      Results

      After adapting for age, the HbA1c levels were significantly elevated in the FM patients (green)

      The study found highly significant associations between fibromyalgia and increased HbA1c test scores relative to the two test populations (p < 0.0001 and p < 0.0002). That suggested that, at least in this group, the increased HbA1c findings in FM were real, and that insulin resistance or pre-diabetes was present.

      The group which received standard treatments, but not metformin, did improve – indicating that the clinic’s pain protocol (consisting generally of norepinephrine reuptake inhibitors (amitriptyline, duloxetine or milnacipran) and/or membrane stabilizing agents (gabapentin or pregabalin)) was helping.

      The patients on metformin did much better, though. In fact, the metformin completely resolved the pain of half (8/16) of the FM patients, and some patients only responded to metformin. Plus, the metformin treatment seemed to stick over time.

      Misinterpreting HbA1c – A Common Mistake?

      Pain levels decrease the most when metformin (red) is added to the standard treatment (blue) and compared to baseline (green)

      Why hasn’t this simple, rather common test been linked to fibromyalgia before? Possibly because of a mistake the authors propose labs and doctors are regularly making: not accounting for age when assessing HbA1c levels. They noted that the HbA1c values in many of their patients with FM would be considered to be within the normal range.

      HbA1c levels, however, rise over time, even in healthy people. Because standard HbA1c norms apparently reflect an older population, the higher values used may understate the extent of pre-diabetes in younger patients. Age-stratifying the clinic’s FM patients indicated that many of them actually had high HbA1c levels. (This was not a particularly young group: just 3 were in their mid-30’s and most were in their 40’s and 50’s).

      That’s a pretty important distinction to miss, given that pre-diabetes carries a higher risk for: a) diabetes; b) peripheral neuropathies; c) cardiovascular problems; d) neurological diseases, and, to top it off; e) all-cause mortality…

      Metformin

      Metformin is a first line drug for type II diabetes. It has been suggested for FM before, but for its mitochondrial enhancing effects, not its impact on glucose. Numerous studies suggest that mitochondrial problems exist in FM, and several animal studies suggest that metformin may, by increasing mitochondrial and antioxidant activity, reduce pain. One study suggests that FM patients with mitochondrial problems may fare well on metformin. A Canadian metformin FM study has reportedly been completed.

      “Patients with FM presenting with low levels of phosphorylated AMPK and inflammasome activation in BMCs, subjected to long-term treatment with metformin, improved both pain and FM-associated symptoms.” Bullon

      This same inflammasome, by the way, is found in type 2 diabetes. (Inflammasomes are intracellular immune complexes which respond to pathogens and other stressors by producing inflammatory cytokines.)

      Pre-diabetes, Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS) (???)

      This isn’t the first study to suggest that insulin resistance might be present in FM and/or ME/CFS. A 2003 study found high rates of fibromyalgia in diabetes. High rates of insulin resistance – associated with cognitive issues – were also found in a 2013 FM study.

      The pre-diabetes connection may not be as far out as one might suspect. Neil McGregor in Australia and Chris Armstrong of the Open Medicine Foundation have speculated that insulin resistance might be present in ME/CFS.  Ron Davis has suggested that, depending on how the science ends up, ME/CFS could end up in the National Institute of Diabetes and Digestive and Kidney Diseases at the NIH (NIDDK). If these researchers are right, fibromyalgia will probably get there first.

      Marco, a patient, latched onto the diabetes question in his 2014 Health Rising blog: “The Energy Disorders: Diabetes, ME/CFS and FM – Can Diabetes Tell Us Anything About Chronic Fatigue Syndrome and Fibromyalgia?”

      He pointed out that untreated diabetes is, by definition, “a state of energy deficiency” and that diabetes is a spectrum disorder of which six different types may exist. He related a number of intriguing possible connections between fibromyalgia, ME/CFS and diabetes:

      • People with type II diabetes also suffer from fatigue, early onset of muscle pain, exercise intolerance, and delayed recovery.
      • Similar patterns of reduced oxygen uptake during exercise have been found in ME/CFS patients and in Type II diabetics.
      • Low heart rate variability (HRV) (enhanced sympathetic nervous system activity) has been found in all three diseases.
      • Reduced natural killer cell functioning – a hallmark of ME/CFS – has been found.
      • Cognitively, similar issues of executive functioning are present.
      • Small fiber neuropathy is found in FM, ME/CFS, POTS and diabetes.

      Plus, we can now add two more possible commonalities:

      • Poor microcirculation – because insulin interacts with arterioles and precapillary arterioles to increase blood flow to the tissues, insulin resistance could impair the microcirculation, which studies suggest may be impaired in FM and ME/CFS.
      • Poor red blood cell deformability – insulin resistance is also associated with red blood cell deformability problems and increased blood viscosity (thickness) – both of which may be present in ME/CFS. In order for the red blood cells to get through the tiny capillaries and provide oxygen to the tissues, they have to be able to deform. If they can’t do that and/or the blood is too thick, our microcirculation may suffer, resulting in hypoxia (low oxygen levels), high lactate levels (lactic acidosis), and low energy production.

      The Energy Disorders: Diabetes, ME/CFS and FM – Can Diabetes Tell Us Anything About Chronic Fatigue Syndrome and Fibromyalgia?

      Neil McGregor, an Australian metabolomic’s researcher, reported that while his data suggests that a third of ME/CFS patients have insulin resistance, most actually have a form of hyperinsulinemia, which refers to excess levels of insulin.  While hyperinsulinemia is often found in type II diabetes, it does not cause it, and is more often found in metabolic syndrome. It’s clear that much remains to be learned about the role insulin may play in ME/CFS.

      A FM/Type II Diabetes (and Alzheimer’s) Connection?

      To make one more potential connection: several studies have linked type II diabetes with (ouch) Alzheimer’s. In fact, some call Alzheimer’s “Diabetes of the Brain” or Type III diabetes.

      A 2017 paper hypothesized that problems with red blood cell morphology, deformability, and function and high rates of oxidative stress – that help produce insulin resistance in the brain – tie the two disorders together. That’s an interesting trifecta, given that red blood cell problems and oxidative stress have already been found in ME/CFS and FM, and insulin resistance might be added to the list.  (One study suggests that the rate of dementia may be somewhat increased in FM.)

      Is the Fibro-fog in Fibromyalgia a Prelude to Dementia?

      Intranasal insulin (a spray) to pump up the insulin levels in the brain is another possibility.  Researchers were awarded $1.7 million to see if intranasal insulin helps with cognitive and other ‘multi-symptom’ problems in Gulf War Illness. Intranasal insulin is also being trialed in Alzheimer’s and Parkinson’s disease.

      Caveats

      This was a quite small study and people with ME/CFS, in particular, have become acquainted with the hazards of those. Much larger studies are needed to determine if high levels of age-dependent HbA1c are present in FM (or ME/CFS). Large placebo-controlled, double-blinded studies are needed to assess the effectiveness of metformin in reducing pain.

      Physical inactivity and obesity – both of which can be present in FM and ME/CFS – can lead to insulin resistance. (The authors could have but did not assess if BMI made a difference.) Exercise, by the way, if FM patients can handle it, is highly recommended for IR and can ameliorate it.

      Conclusion

      In a small retrospective study, University of Texas researchers found high rates of age-adjusted HbA1c levels in fibromyalgia, signifying that pre-diabetes may be common, and, if their sample population reflects the population at large, possibly massively underdiagnosed in FM. The authors noted that if the HbA1c values in their patients had not been adjusted for their age, most of them would have been normal.

      Could metformin work in FM? It looked very good in this preliminary study. Bigger studies will hopefully tell us more.

      Treatment with metformin – a first-line drug for type II diabetes – resulted in significant and long term reductions in pain. Half of the cohort (n=16) reportedly completely recovered.  Because metformin also enhances mitochondrial and antioxidant production, it may be helpful in several ways.

      Diabetes, FM and ME/CFS do share some interesting commonalities including problems with energy production, small fiber neuropathy, fatigue, exercise intolerance, cognitive issues, red blood cell deformity and possibly problems with the microcirculation.

      The results are enticing, but much larger studies are needed to assess the incidence of altered HbA1c levels, metformin’s effects on pain, and the role physical inactivity and/or obesity might play in the IR found in FM.

      Have you tried metformin?

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      The post Fibromyalgia, Pre-Diabetes and Metformin: Could a Diabetes Drug Help with FM (and ME/CFS?) appeared first on Health Rising.

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      It’s not pretty! The print is abysmally small, the margins are tiny, long stretches of text are common (it abhors paragraphs), the images are jammed together, and the formatting is designed to make you work and is decades out of date, but the fact is that when you’re one of the top research journals in the world, you can make your own rules.

      PNAS is not pretty but it does get the word out

      PNAS or The Proceedings of the National Academy of Sciences of the United States of America – the official publication of the National Academy of Sciences – has been described as “prestigious”, “renowned”, “high impact” and even “sedate” (which in the research world is not necessarily a pejorative term).

      PNAS, which touts itself as the second most cited scientific journal in the world, publishes a wide variety of scientific content. One statistical analysis concluded that, “Three journals have by far and away the most overall influence on science: Nature, PNAS, and Science, closely followed by the Journal of Biological Chemistry. ” Nobody else was even close.

      PNAS may not be pretty – it’s probably intentionally unpretty – but getting published in it gets the word out. Since Rahim Esfandyarpour (the lead author) and Ron Davis’s nanoneedle paper was published in the most recent edition of PNAS, numerous media outlets have picked up their findings. I got to talk to both of them.

      The paper immediately makes clear two things: the lack of a biomarker makes getting diagnosed with chronic fatigue syndrome (ME/CFS) a “lengthy and costly” affair (which, of course, precludes patients from getting treatments when they may help the most – while the disease is still new). From a research standpoint, the paper noted that lack of a biomarker may have tragic consequences if “heterogenous samples of patients” with “only marginally similar conditions” are being included in studies.

      Obviously, getting a biomarker would fulfill a huge need and other possible biomarkers may yet pan out. None, however, potentially tick off all the boxes (potentially very cheap, easy to use and very accurate) as well as Ron Davis and Rahim Esfandyarpour’s nanoneedle.

      The first nanoneedle papers in 2013 indicated that the needle was originally designed as an “ultra-sensitive, real time” biosensor designed to cheaply detect biomarkers such as proteins inside (or outside) cells at a far more sensitive level than had ever been done before.  One very promising feature of the nanoneedle was its ability to quickly identify biomolecules without needing to label them first (and then use a tool to detect them).

      By 2016, a redesigned and improved nanoneedle was presented as a rapid, inexpensive, high throughput, real-time, label-free, highly sensitive alternative to the expensive or less sensitive devices available.

      Then came chronic fatigue syndrome (ME/CFS). Focusing on the unusual problem of energy depletion following exertion (post-exertional malaise (PEM)) in ME/CFS, Davis and Esfandyarpour added a salt stressor to ME/CFS samples and used the nanoneedle to measure electrical impedance (a measure of electrical resistance). (The salt solution was used because it requires cells to generate a lot of energy (ATP) to maintain the appropriate salt concentrations inside and out.)

      The increasing electrical impedance or resistance seen in the ME/CFS but not in the healthy control samples suggested Davis indeed induced a state of post-exertional malaise in his ME/CFS samples.

      That was not surprising; what was surprisingly was how definitively he had done it. In one of the most evocative images yet to come out of the ME/CFS scientific literature, the graph a dramatic separation between the patients and controls. With the needle packing tens of thousands of biosensors, adding up to millions of data points, Davis had every reason to believe that the finding is robust, indeed.

      Causes

      A major question involves determining what biological process is producing the rise in impedance in the ME/CFS patients’ samples. Esfandyarpour pointed out that while answering this question is obviously biologically important, it’s not critical for diagnostics or drug screening to know what’s going on. Many drugs work, after all, without our knowing exactly why. Similarly, all a good diagnostic test really requires is that it be specific to a disease.

      Ron Davis -senior author – on the left and Rahim Esfandyarpour – lead author on the right

      (Esfandyarpour said “many” different drugs, inhibitors, enzymes, and substrates involved in cellular energy production have been tested to see if they can return ME/CFS samples to normal functioning in the nanoneedle.  Two thus far (he didn’t say which ones) have returned the ME/CFS samples to normal functioning.)

      Still, learning what the nanoneedle is showing should give us an idea of what has gone wrong in ME/CFS. There are several ways to do this – some of which do not require the nanoneedle. Different kits could be used to measure how the cytokines, etc. in the sample change following the introduction of a salt stressor. Adding an inhibitor to the sample that affects certain parts of the cells and assessing how the sample responds could provide clues as well.

      One might think the Seahorse – a commonly used tool in ME/CFS that assesses cellular energy production – would play a key role, but it’s not. Because Seahorse cannot incorporate the potentially ever so important ME/CFS plasma into its testing regimen, if something in the plasma of ME/CFS patients is causing problems with cellular energy production, it will not be able to pick it up.

      Esfandyarpour believes something in the plasma may play a critical role in ME/CFS. Davis’s team has been filtering out substances in an effort to learn what factor that might be. Nothing definitive enough to announce has been found yet, but exosomes– (small extracellular vesicles involved in communication between cells) are a possibility.

      Davis said he was encouraged by the idea that a substance in the blood is causing problems. Given that, so far as we know, this is rare in diseases, if such a substance is present, it may be quite specific to ME/CFS.

      They’ll feel confident about such a substance if a) when they remove it the response returns to normal and b) if adding that substance to healthy cells causes their impedance levels to rise. If the substance turns out to be exosomes, the next step is to determine what in the exosomes is causing problems.

      If something in the plasma is found to be playing a crucial role in the abnormal response of ME/CFS cells, a next step will be to determine which cells it’s affecting.

      A Diagnostic Test for ME/CFS?

      The nanoneedle passed a big hurdle when it was able to so definitively distinguish ME/CFS patients from healthy controls. The forty people in the study may not sound like a lot, but it’s not the quantity that tells the tale – it’s the consistency of the result.

      Probabilities tell the tale in research. The highest probability that is considered significant or meaningful in medical research is a less than one in twenty probability (p<0.05) that a result occurred by chance.

      Studies are designed around the need to hit that probability. Miss it even by a small amount, and your results are worthless. Statistical analyses are done to determine how many participants are needed to hit that probability target .

      Few studies hit the target as squarely as this one did

      There was no need for that in the nanoneedle study. The statistics indicated that the probability that the study results were due to chance ranged in the billions. That kind of probability is more commonly seen when trolling for a  mega lotto win than in biology. Put another way, the nanoneedle study was actually far, far larger statistically than it needed to be to demonstrate that the ME/CFS samples could be differentiated from  the healthy control samples.

      Davis will continue testing samples, but for him and his long, long acquaintance with statistics – the question as to whether the nanoneedle can differentiate ME/CFS patients from healthy controls has surely been answered.

      Differentiating ME/CFS from other diseases is the next step, but the big takeaway is that Davis appears to have produced a test that irrevocably demonstrates that people with ME/CFS have a biological illness. Developing a biological test for MECFS, Davis said, was his biggest goal.

      Davis’s next task is to differentiate people with other fatiguing illnesses, such as multiple sclerosis (MS), from ME/CFS – a trickier project. Davis noted that some of the first symptoms to show up in MS are similar to those seen in ME/CFS, and that some people diagnosed with MS have been shown to have ME/CFS and vice versa.

      It’s also possible that some people with MS will develop ME/CFS at some point. This type of disease convergence is not uncommon with fibromyalgia.  Numerous studies indicate that a significant subset of patients with rheumatoid arthritis or other chronic pain disorders also have fibromyalgia. It’s possible that the same is  true with ME/CFS and some also very fatiguing autoimmune diseases.

      Davis, as Jarred Younger has, brought up the possibility that people with MS and ME/CFS – two illnesses often jumpstarted by an infection (and perhaps the same herpesvirus infection) – may start out on the same pathways but then diverge at some point.

      Notice the stark separation at all levels between the patients and the healthy controls

      Having some people with MS will test similarly to people with ME/CFS on the nanoneedle is not a deal breaker, though. Far from it.  It’s not uncommon for diseases to share diagnostic markers. Doctors get around this by using series of tests to diagnose patients. If some people with MS look like ME/CFS patients using the nanoneedle, then a brain scan which shows neuron damage in the M.S. patients will be able to differentiate the two diseases.  People with MS and ME/CFS will be positive on both tests, while people with ME/CFS without MS will test positive only with the nanoneedle.

      An even better testing regimen would use another anomaly more commonly found in ME/CFS, such as the red blood cell (RBC) deformity work the Open Medicine Foundation is funding.  Since problems with RBC deformity probably do not occur in MS, a positive nanoneedle and RBC deformability result should be enough to differentiate someone with ME/CFS from someone with MS or many other diseases.

      The point is that a diagnosis often does not rely on a single test, a single definitive test isn’t needed to diagnose a disease.

      A handful of tests could enable ME/CFS to be clearly differentiated from other diseases in the fairly near future. It won’t take thousands of patients to show that either. So long as you have well-defined patients  in studies produced by good researchers which produce good results; i.e. good probability stats, neither the number of studies or the number of patients need to be particularly large – the results simply need to be trustworthy.

      Metabolic Trap

      Davis has begun to separate out dendritic cells and test them to see if the metabolic trap is present.  He brought up an interesting possibility –  emphasizing that it was only a possibility – that if the metabolic trap is present, it could lay the groundwork for an autoimmune process to manifest itself. This is because dendritic cells are responsible for shutting down autoimmune producing B-cells.

      If the metabolic trap is present in dendritic cells it’s probably mucking up their ability to knock out bad B-cells. Furthermore, because the IDO1 pathway plays a role in immune system regulation, it wouldn’t be odd at all for pathogens to take a swing at knocking it out in order to evade capture. That plus a possible genetic predisposition to problems with this pathway could tell the tale in ME/CFS. That said – at this point it’s just a possibility – but it’s nice to have possibilities – tangible, ways of potentially explaining this disease.

      The NIH Attempts to Take Credit

      Director Francis Collins immediately jumped on the nanoneedle finding to trumpet the NIH’s role in funding the breakthrough. That was, in part,  true – the NIH did provide funding for the early development of the nanoneedle – but then there is a second part to the story. The NIH later dropped its funding for the needle and it did so just about the time it was starting to be used on ME/CFS.

      In 2016, citing a renewed emphasis on ROI grants, the NIH jerked Davis’s longstanding technology grant, undercutting his nanoneedle and other research. Ironically, for all its emphasis on accelerating ME/CFS research the NIH, inadvertently it must be said, pulled the plug on funding for one of our most important ME/CFS efforts.  In a recent conversation, Davis looked back:

      “I used to have experts in almost all areas. We were on a roll developing all sorts of things. I don’t have that anymore because the NIH terminated my big grant on technology development.” Ron Davis

      It turned out that the NIH no longer shared Davis’s emphasis on developing cost-effective tools that help people and reduce the cost of health care.

      So when Francis Collins himself tweeted the good news that the NIH had funded Davis’s effort to develop a new test for ME/CFS….

      “In @stanfordmed study, researchers developed new blood-based test that positively identified participants w/#MECFS. If findings can be validated in larger study, it may provide a diagnostic tool for clinicians & a target for new ME/CFS Txs. #NIH-funded https://stan.md/2IU7nYN “Francis Collin

      He crossed a line for Janet Dafoe and patients who went on something of a twitter rampage at the director’s gall. One wonders how much further we would be if the NIH had continued their support.  Janet pointed out that that the NIH hadn’t funded any of Davis’s ME/CFS nanoneedle work – which was, of course, what the paper was on; everything was funded through patient donations to the Open Medicine Foundation.

      “That NIH grant was TERMINATED about 2 years ago because NIH said they didn’t want to fund that technology anymore. That grant had funded the initial development of the nanoneedle on cancer cells & bacteria. All the ME/CFS work started AFTER that & was FUNDED BY PATIENTS@OpenMedF.  You don’t get credit for this good news for ME/CFS” Janet Dafoe

      Then she pointed out that the NIH had muffed another opportunity to fund ME/CFS  nanoneedle work when NIH reviewers savaged Davis’s NIH application, in part because they objected to the new technology he was using.

      “In fact, Ron Davis applied to NIH for the nanoneedle work and was turned down! Reviewers were very critical and said it wouldn’t work, in spite of good preliminary data. STOP saying you don’t fund ME/CFS because you don’t get good grant applications! Patients funded this!” @OMF Janet Dafoe

      Attacking the competence of Ron Davis  – who’s been called a “frequent provider of disruptive core technologies“, and played a key role in the Genome project, etc. etc. was probably not the brainiest move by the NIH reviewers, who are now presumably busy wiping the egg off their faces.

      The NIH is soon going to get another opportunity to fund nanoneedle work in ME/CFS. With the PNAS paper under their belts, Ron Davis and Rahim Esfandyarpour will be applying for another NIH funded nanoneedle grant this June. Perhaps the third time will be the charm for the nanoneedle and the NIH.

      Resources, Resources, Resources

      With its potential ability to serve as a diagnostic tool, a drug screening tool, a tool to help determine if something in ME/CFS patients’ plasma is knocking their immune cells for a loop, a tool that could greatly enhance research studies (by ensuring that only ME/CFS patients are in them), the nanoneedle obviously presents immense possibilities.

      The work seemed to be going slowly, though, and I was curious to find out why. Asking if the funding or resources were holding the work back elicited a big laugh from Rahim.  Funding, not technology is the limiting factor, he said.

      In its current iteration the nanoneedle is a tortoise that, Aesop’s fables notwithstanding, really needs to be a hare

      It turns out that as sophisticated as the nanoneedle is, in some ways it’s rather primitive. In its current iteration, the absolute fastest it can work is to test two samples over a couple of hours. That’s not great in an instrument that needs to be involved in testing other diseases, in drug testing, in assessing plasma factors, in assessing the pathophysiology behind the reaction (mitochondria, membrane problems, immune issues, etc.).  The drug testing alone is incredibly complex: Davis needs to test different drugs, different doses of drugs, drugs in combination, etc. in different patient samples.  With its thousands of sensors the nanoneedle may be a technological work of art but it’s a sludge when it comes to processing samples.

      Fortunately, a solution is present. Unfortunately, it will take something the ME/CFS field hasn’t had a lot of – resources.  Developing a high throughput system that’s able to test dozens of samples at once is, Davis said, a top priority.

      There’s apparently no mystery to developing that system.  It’s simply a matter of resources. When asked, Esfandyarpour said that designing a high throughput system presented no technical challenges – the only challenge is funding – and not necessarily that much funding. When I pressed him, Esfandyarpour would not say how much money was needed, but when I asked if it was $1 million, he said no, it’s not nearly that.

      Developing a high throughput system is the first and necessary step to maximizing the potential of the nanoneedle but it’s only the first step. The logical conclusion to all this is the transformation of the lab instrument into a portable one that can be used in doctor’s or medical lab. Davis said that doesn’t present any technical challenges either (!). If everything works out a portable testing unit could be ready within two to three years.

      The fact that’s what is holding us back is a matter of resources makes the NIH’s decision to end Davis’s ongoing technology grant sting all that more. In the end, though, the fact that it’s resources – not some technological breakthrough that’s needed  – is actually very good news.

      The resources are out there. I know of very wealthy people with family members with ME/CFS who could easily fund this or other research efforts and aren’t,  I don’t know why. It doesn’t make sense to me, but the fact is that the more we spread the word, the more we get our story out, the more people we contact, the more people with..

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