A consensus means that everyone agrees to say collectively what no one believes individually.
~ Abba Eban

At the end of the comments from the last blog, the conversation turned to the new International Consensus Criteria for ME: Myalgic Encephalomyelitis: International Consensus Criteria. Carruthers et al. I’m glad that this is becoming a place where we can consider the issues together. My personal reaction to the paper was mixed. While I found it immediately useful for sending to uninformed doctors who might recognize their patient in it, it excludes a lot of patients who will therefore be hurt by it, if anyone pays any attention to it, which they probably won’t. In particular, it excludes a large subset of patients who had gradual onset or recovered to a great extent following a first crash. I didn’t meet criteria for the first decade of my illness. I certainly do now, but if this had been the case definition, the same things would still have happened to me with respect to disability coverage, disbelief and misinformed treatment by physicians.

For the first ten years of my illness, I had no PEM. I could bench press over a hundred pounds, rode on the back of a tandem for an hour or more a couple of times a week, played tennis, could scuba dive and ski. But if I worked a full, normally intense day, I’d get a headache and a hypertensive crisis (up to 220/140). So I was forced to circumscribe my life in ways that didn’t trigger it. I worked in a clinic attached to my home to keep the day short and reduce stress. Ken Wilber’s functional bubble: link to letter and check out his very cool website I had episodes of severe anxiety, autonomic dysfunction (cyclic vomiting, not OI or POTS) and bizarre sensory symptoms (dysgeusia, globus hystericus, hyperesthesia, hypoesthesia in a dermatomal distribution). Also flu-like malaise. I didn’t meet the new ICC criteria during any of that time. I now have or have had literally everything on the list, except, for some peculiar reason, I’m still sharp, never “foggy”, and my memory is pretty good, as good as it ever was anyway. I wonder why I’m different in that respect, when otherwise I’m classic, and the only thing I can come up with is lots and lots of exposure to high dose oxygen.

The problem with this newest case definition is that it allows minimization of the huge number of affected people by looking only at the tip of the iceberg. In the past, I haven’t been too interested in what they call it; it seemed like little more than semantics to me. I thought that case definitions would surely take a backseat to viral load measures. But it hasn’t happened yet. When I read the Science paper, one of my first thoughts was, thank God, my daughter will be able to walk into any doctor’s office and say, I have XMRV, without being subjected to ridicule, but that hasn’t happened yet either. We are forced back to case definitions, the search for markers to prove a biological basis and fiddling around the edges with respect to treatment. Now in practice again, I can’t bring myself to use CFS as a diagnosis, because it’s a perjorative and will be used to deny my patients treatment. There is no code for ME, but all the components of the illness can be coded separately.

Ali went out with us for lunch yesterday for the first time since the fall, and still feels well after. She seems ready to cross that line again. She said that the things we’ve done with her have been real quality of life improvements, especially if you use hours of suffering as a meter. Glycemic control, hormone balancing, recently high dose oxygen and Meyer’s cocktail plus glutathione infusions, are the things she listed. There is no way to know how much antiretrovirals may be contributing at this point. We’ve considered going off, especially in light of the money involved, but have decided not to rock the boat. In my case, I think it’s worth taking for prophylaxis now that I’m exposed to patients, and they to me.  The trend in HIV is moving towards the use of antiretrovirals for prophylaxis and earlier treatment of infected individuals to prevent spread. The findings of Zhang et al that XMLV’s are highly infectious in a laboratory setting, as well as the isolation of XMRV from tracheal secretions, Xenotropic Murine Leukemia Virus–related Gammaretrovirus in Respiratory Tract. Fischer, suggest that HGRV’s may be spread by casual contact. The cluster outbreaks support this as well. Since many spouses and children are clinically well, host susceptibility is a bigger factor than presence of virus. Like HTLV, most infected people don’t become ill. 

Careful history taking suggests  that HGRV’s can turn on and off, in a minor way, for a very long time without becoming a big problem. My history suggests this, with intermittent symptoms that went back to childhood, yet I considered myself healthy and had no medical record at all, except for pregnancies, until I became ill at 41. My husband has lots of symptoms, but doesn’t have ME or CFS by anyone’s criteria. I was intrigued by this paper about nail changes in CFS: Secondary structural changes of proteins in fingernails of chronic fatigue syndrome patients from Fourier-transform infrared spectra. Sakudo. I had nail changes that started maybe a decade before I knew I was sick, so over 25 years ago. I wore acrylic nails to hide it for a few years. I couldn’t find an explanation, except a little bit in Chinese medicine which is concerned with such things, but knew it meant that something wasn’t quite right. I have no lunulas now. Nail beds are short, not wide like clubbing. Nail plates curl at the end. I have Raynaud’s, subclinical for years, occasionally visible in the last few years. I think that the changes are probably due to cellular hypoxia at the periphery exacerbated by vascular instability.

There is one anecdotal report of a young patient who improved dramatically on AZT/raltegravir, stopped the drugs after 6 months and has maintained the improvement. Our assumption that the drugs would need to be taken forever, because that’s how we treat HIV, may be completely erroneous. After following a small group of patients informally for a year and a half, my impression remains that the drugs move the illness, but we don’t know how to use them. Dr. Snyderman’s data is certainly compelling, posted last April here in Another Perspective. HIV doses may be wrong for us. There is one report of someone who has improved on very low dose AZT alone. CFS doctors have long known, start low, go slow, but because that is a no no for HIV, there is no experience so far. AZT has been used for HTLV:

The last two papers suggest that low dose AZT may be useful. AZT works for Adult T-cell leukemia/lymphoma (ATLL), a lymphoproliferative malignancy that develops in a subset of HTLV–infected individuals after a long period of latency. Mahieux suggests that in this setting, it works not through antiviral effect, but through an anti-proliferative effect, requiring long term treatment to activate tumor suppressor genes. An explanation is offered for why some patients with ATLL respond to AZT and some don’t, response to treatment being dependent upon an intact tumor suppressor gene. AZT shortens telomeres in fresh ATLL cells, eventually inducing senescence and death of infected cells. Patients with mutated tumor suppressor genes don’t respond. The relative contribution of proliferation versus viral replication likely varies between infected people, possibly determining in which direction the disease progresses, ATLL or HAM/TSP, cancer vs neurodegenerative outcome.

In the meantime, Simon Wessley wonders why people are angry with him when he says that we’d rather have an incurable retrovirus than admit that we are mentally ill: BBC news (audio). Dr. Wessely, it’s because a psychiatrist without compassion is a terrifying thing indeed. Meaningful psychiatric care, safe rehab, disability coverage, the simplest supportive interventions have been denied us for decades, but we’re supposed to thank Dr. Wessely for taking an interest in us. Go push your worthless theories in some other arena, or suffer the reaction. We’ve had enough of your “help”. Enough of your blame. When I first became ill, any real doctor could tell that there was nothing wrong with me. And I was a real doctor… The nephrologist who fancied himself an astute diagnostician was sure I had a pheochromocytoma or carcinoid tumor, but after he did all his fancy tests and couldn’t find anything, he concluded, “You’ve lost your nerve.” My hypertensive crises were diagnosed as “white coat hypertension”. How right he was, though my fear of white coats certainly turned out to be justified.

Life Goes On

In three words I can sum up everything I’ve learned about life. It goes on.  ~ Robert Frost

The week before I left to come to Hawaii was a difficult one for me. I took a series of emotional hits in quick succession, then had to leave home to take care of patients here, alone with no support. I arrived feeling sicker than I had in many months. My first patient was a well known advocate in our community, and I will always remember that she was there when I got off the plane, as well as her caring in the first difficult days. She knows who she is, a very special woman.

Childbirth was the initial trigger for my illness, and a concussion once, but sustained emotional stress was involved in my worst declines. So I was a little concerned, as was my family. I did dip a little, predictably, but I’ve been able to function throughout and am feeling better again. More resilient than expected. Able to weather some difficult stuff without going down, a degree of stability necessary for the patients who are choosing to put their trust in me. At least they can be sure they are sitting with a doctor who cherishes every encounter, whatever the future may hold. I know what it’s like to be unable to work. Actually, I know what it’s like to be unable to roll over. I get a little frustrated sometimes at having to pace myself pretty extremely when I’m at risk, like now, but if I stick to very restricted hours and activities, particularly when I don’t have help, I can do the things I need to get done in the physical world. The medicine is the easy part. A reflex. So far caring for my own patients is sustaining me. As always, I work diligently to stay focused on what I can do, rather than what I can’t, and I don’t allow myself to sweat the small stuff.

A few people wrote that they were disturbed that I said I didn’t expect a cure. I should have said in my lifetime or in the foreseeable future. In the same way that HIV patients are incurable, yet attain functional cures for long periods of time with treatment, I expect that a similar degree of successful management of the disease will be possible for ME/CFS patients. The politics and regulatory issues are a nightmare, as I’ve learned firsthand through my association with the WPI. Coming here to see patients one-on-one feels like respite compared to that. The hardest thing for me to absorb is that a giant hand came down and hit the pause button on the science, and therefore the search for appropriate specific treatments, until Lipkin opens the envelope and declares a winner. We have the technology! It’s just money and priorities. If everybody would wake up and recognize it for the public health disaster that it is, it would take a couple of years to get a handle on what’s there from an infectious disease standpoint, a couple more to figure out the basic pathophysiology and a couple more for compassionate use treatments to be available. But it doesn’t look like that is what is going to happen. The psychiatrists will have their way for a while longer. We will have a new diagnosis, CSSD, Complex Somatic Symptom Disorder. New name for Munchausen’s.

The best news is that my Munchausen’s by proxy is in remission:). Ali is doing very well again, with large amounts of supplemental oxygen. We put the concentrator in the middle of the house with a long hose allowing her to be wherever she wants to be. She has been using it at 10 L/min for about an hour a day, more if she has breakthrough symptoms. She has needed no prompting, but wants to do it, because it makes her feel better. She has also had a few Meyer’s Cocktail plus glutathione infusions that seemed helpful, supportive, but she hasn’t had any for 4 weeks now and continues to improve with oxygen being the only new treatment. Her MCS symptoms, or hyperosmia, have almost resolved. She was able to go to a party for a few hours at a neighbor’s house last week where she was exposed to perfumes without problems. She hasn’t tried the chamber yet, but I have asked her to figure out if pressure adds anything for her, since she is much more sensitive than I am. As for me, I do think I benefit from the effect of coming to sea level from altitude (my house in Santa Fe is at 7000 ft). It most likely would be short-lived if I stayed, but should happen each time I come here, planning to use oxygen when I return to elevation. The travel really doesn’t bother me much anymore. I use the wheel chair service and am grateful for it. Supplemental oxygen during flight would protect against adverse effects of hypobaria and hypoxemia, but it is very expensive and a hassle. If I just pretend I’m home on the sofa, play with my iPhone and let them transport my body, the travel doesn’t seem to be a problem for me.

And lest anyone think that mouse retroviruses are not part of the picture whilst we are waiting for Dr. Lipkin, reminiscent of Waiting for Godot:), take a look at this important paper: Frequent detection of infectious xenotropic murine leukemia virus (XMLV) in human cultures established from mouse xenografts. Zhang/Gazdar. It’s reads like science fiction if one considers the consequences of this wee oversight, realizing that mouse xenografts have been used since at least the 40’s, though I still think the early yellow fever vaccine work was probably the beginning of human assistance in the natural process. Or it may have begun even further back, with the selective breeding of mice in the early 20th century, mice that were unable to survive in the wild, producing infectious viruses to which they are not susceptible due to receptor mutations. The use of animals, including mice, for the production of vaccines started in the early 30’s or before. Yellow fever was attenuated in mice and injected into monkeys and humans. See previous blogs here, here and here. Also there must have been lots of experiments at the time that didn’t make it into print. The records from the Rockefeller Institute would probably shed a lot of light. This paper was published in 1932 and the first documented outbreak of Epidemic Neuromyasthenia at LA County Hospital was in 1934: Vaccination Against Yellow Fever With Immune Serum And Virus Fixed For Mice. Sawyer/Lloyd. J Exp Med. 1932 May 31;55(6):945-69. Infectious mouse retroviruses probably infected humans before that, but at very low levels, since the sick mice died like they were supposed to. 

Hats off to Zhang et al for their vital work, and for calling a spade a spade. Finally someone stating the obvious. 22Rv1 doesn’t explain away all the ruckus, nor was it the incredibly rare event postulated by Paprotka et al. Like XMRV, it is a signpost to a much greater problem. It is the patients that are contaminated, and not by just one virus. Many infectious retroviruses. Just because way back when, Coffin, Stoye, Heneine and the gang all said it couldn’t happen, doesn’t mean that it didn’t. Some choice comments from the Zhang paper:

ERVs represent remnants of ancestral germline infection by exogenous retrovirues and after integration into the genome are transmitted vertically as proviruses. Murine leukemia viruses (MLV) as ERV provirus forms are present at about 60 copies per mouse genome from which up to 15 copies are related to infectious xenotropic murine leukemia viruses (XMLV)… Thus, active mouse ERV provirus present in common inbred mouse tissues can be the origin of XMLV or recombinant polytropic MLVs which are infectious to human tissues implanted in laboratory mice.

Earlier studies have documented that XMLV type-C retrovirus particles were indentified in human xenograft cultures derived after xenografting in immune-compromised mice… NCI-N417 SCLC cell line was established from a mouse xenograft by the Gazdar lab at the National Cancer Institute (NCI) in the early 1980s and this cell line was subse- quently found to contain XMLV a few years later.

Reports of XMLV strains being present in human xenograft cultures appeared in the 1970s…

Our results indicate that human tumor cells frequently become infected with MLV virus after xenografting and subsequent culture. We have observed that mouse stromal cells may persist in culture for lengthy periods. Mouse stromal cells, while they contain abundant provirus forms of MLV, including ecotropic, polytropic and xenotropic strains, seldom spontaneously release large amounts of infectious virus (authors’ unpublished findings). Virus infection of xenografted cells may require activation of XMLV virus by chemical or immunological induction in mouse and by prolonged mouse and human cell contact. Viral transfer may occur in the mouse host or during subsequent xenograft culture. Our findings of infectivity of XMLV-positive supernatant fluids demonstrated that XMLV can readily infect other human cultures without presence of mouse cells or other aiding factors, indicating that these viruses are highly infectious.

In conclusion, our studies demonstrated that several MLV strains were present in over one fourth of xenograft cell lines. Infected cell lines were identified in most laboratories working with or establishing xenograft cultures, indicating that such contamination was widespread. Infected cultures usually release large numbers of infectious virions, and intra-laboratory spread of MLV virus to other cell lines maintained in the same facilities may occur, confirming the highly infectious nature of MLV virus. Retroviruses have been associated with multiple diseases including solid and hematologic malignancies, AIDS as well as with non-malignant diseases. The high susceptibility of human cells to infection with XMLV, the high levels of reverse tran- scriptase activity present in culture supernatant fluids and the demonstrated infectivity of the shed virions suggest that such viruses may present potential biohazards to laboratory person- nel involved in cell culture facilities or to those handling human xenografts. In addition, the effects of the integrated provirus or the released virions on the biology of infected tumor cells are unknown. Provirus integration into the genome is not random, and occurs preferentially at transcription start sites, CpG islands, DNase-hypersensitive sites and gene-dense regions, suggesting that provirus integration may influence transcription in the host cell. Thus laboratories handling or culturing human xenografts should monitor for monitoring personnel for viral antigens or antibodies to them. 

The Treasure Hunt

I was in Reno last week. It was an honor to be there to meet Dr. Lipkin and hear about the study from the horse’s mouth. I also had the rare opportunity to listen to him brainstorm a little with Frank Ruscetti. It had a historically important feel to it. Dr. Lipkin is committed to being the perfect referee, “agnostic”, but I thought I saw the glint of desire to dive in to the discovery process. Dr. Ruscetti is a rare human being who sees his work in the context of the big picture. He is a realist, who never loses site of the patients that are the reason for the work in the first place.

The study, at a cost of $2.3 million, is designed to answer two questions:
1. Do XMRVs, and/or polytropic MLVs, exist in humans?
2. If so, do they occur at higher rates in CFS patients than healthy non-contact controls?

25 patients and 25 controls are being selected by 6 doctors, Montoya, Kamaroff, Bateman, Klimas, Levine and Peterson. Inclusion criteria are very restrictive to a particular subset of CFS that includes sore throat and lymphadenopathy. Samples will be split in Dr. Lipkin’s lab and two from each patient will be sent to 3 labs, the WPI, Lo/Alter and Switzer, where each lab gets to do their own thing. The study will be concluded to be positive if any lab can find 2 positives from the same patient. Discordant results will be decided with a third specimen.

I think we are OK, that it’s a fair playing field. The most commonly asked question in the patient community right now is with respect to the possibility of specimen tampering at points of inception. Even if that did happen at one or two sites, it would skew the stats, but wouldn’t cause the study to be completely negative. It is wrong that so much rides on one study, that nothing else will go forward until it is completed, and that one man has been made judge, jury and executioner, though I came away with the impression that he was a good choice for a difficult task.

Drs. Mikovits and Lombardi, Max, Shanti and Svetlana, have their work cut out for them, 600 specimens, each needing multiple tests. The best possible outcome for the patient community is that the WPI finds XMRVs/HGRVs at a higher rate in patients than controls, that Lo/Alter find the Ps at a higher rate in patients than controls, and that Switzer finds nothing, as expected. Dr. Lipkin mentioned more than once that, when the study is over, there will be a valuable repository of specimens remaining to look for what is there, should the study be entirely negative. At the end of his public lecture, he said that if anyone in the audience wanted to write a check for a million dollars, he’d find out what’s going on; good news, though the comment caused me pain personally, confirming what we all know, that we have the technology, but it isn’t being applied. He lectured about past virus hunts that only took days, also rather painful for this audience to hear. Almost the best news for me was that he said that CFS “smells viral” to him. He is involved in autism research and said that he suspects thimerosal in vaccines may in fact be implicated, not a popular stance with the vaccine companies. Let us hope that when this exercise is over, “the virus hunter” will be inspired to hunt viruses for us.

I had an opportunity to discuss antiretrovirals with Dr. Lipkin and to share my personal experience. He stated his disapproval vehemently. I told him that we had significant anecdotal experience at this point and it appears to be better than placebo, though disappointing in speed and scope of response. I stated my opinion that prescribing arv’s constitutes the usual and customary off-label use of drugs, a decision to be reached between doctor and patient. We obviously disagree completely in terms of whether or not the prohibition against these particular drugs is justified, but, even though he had strong feelings on the subject in the present tense, he concluded it needs to be studied, though everybody agrees that, in the current economic climate, there’s no money for what will need to be a long, complicated study. I didn’t get the impression that he was in any way discounting the possibility of a family of retroviruses with too much sequence diversity to be found when looking with our current lenses.

It was my 5th trip to Reno in 10 months. It was short, but the most stressful for me so far, maybe because it felt so important, though it was good stress, not bad, while it was happening. I felt “on”, but not anxious or consciously uncomfortable. I returned home still feeling strong. The day after I got home to Santa Fe, the Las Conchas wildfire started, now the largest in the history of the state of NM, over 100,000 acres, threatening the town of Los Alamos and Los Alamos National Labs. The air quality has been extremely poor. Here is a picture taken from our house, the night the fire started. The smoke is pluming all over Santa Fe and environs, making the air quality unacceptable for people with pulmonary disease. Mitochondrial disease too, I’d bet.

Despite lots of oxygen, which helps everything during administration and for a while after, I’ve been in crash mode for six days now. First time I’ve gone down for more than a day since December, when I caught a cold after my second trip. No cold now; just CFS. I don’t like to report bad news if it takes away hope, but my commitment is to reporting the truth. Sleep, always a sentinel symptom for me, was the first to go. Then pain, nausea and orthostatic intolerance have put a serious damper on things. Cognition is the last to go for me, thanking God for the not small favor. Clearly, I am still at risk, despite dramatic improvement over the last year.

Ali has been doing better since starting Meyer’s cocktail with Leucovorin, plus glutathione, IV pushes and supplemental oxygen by high flow concentrator (10L/min delivered by non-rebreather mask). She does an hour or so of oxygen a day, and the effects are so immediate and positive that she doesn’t have any resistance to doing it. At this point, we both consider the concentrator a no-brainer. She hasn’t tried the chamber yet. I’ve been going in about twice per week and using normobaric oxygen by mask about twice a week as well, and I haven’t decided yet whether I think the chamber adds enough to justify the expense/trouble or not. Ali had a friend visit her for 10 days recently. She used supplemental oxygen ad lib the whole time, was much more active than she has been able to be since last fall, and didn’t crash afterwards. She remains more resilient, despite the fire. She is wanting to get out of the house and just ordered some protective masks that she hasn’t tried yet, which people are wearing in Santa Fe now anyway.

Ali’s MCS symptoms are subsiding somewhat and, if not triggered, she is doing really well. She can wear clothes from the dryer again, though choice of laundry products is crucial. She and I both believe that her symptoms are not triggered by chemicals per se, but certain strong odors, so hyperosmia, much the way some patients have hyperacusis and photophobia, which are also cranial nerve dysfunctions. I believe these sensory symptoms to be related to dysregulation of the cranial nerve afferants, which are relayed through nuclei in the dorsal brain stem, and then to the thalamus, which integrates sensory information to the cortex, regulates arousal/sleep and organizes/controls the timing of the brain’s circuitry. The heightened signal triggers what can be thought of for practical purposes as a subclinical seizure. For some, the instabilities in the brain stem can progress to observable atypical seizures or even full blown tonic-clonic seizures. Here is a study by Frank Duffy at Harvard showing coherence abnormalities on QEEG (measured on the cortex), in patients with CFS, not seen in depressed patients: EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients. Duffy/Kamaroff. Inability to detox properly is likely a piece too, but in Ali’s case, I think that the reactive dysautonomia is triggered by input from the first cranial nerve, rather than a reaction to a toxic substance.

I leave for Hawaii later this week to see patients, looking forward to sea level and clean air. My patients all know I’m sick. When I hear their histories, I often remember exactly how that symptom felt to me, even though my illness has changed a great deal as it has progressed. They know that I don’t have the answer and that I don’t believe there will be a cure. Healing and curing are not the same thing. What we do have to fight with is a coherent model from which to plan a strategy for each person from where they are now. It will be two years soon since Lombardi et al was published; it has been nearly shot down by politics, not science, and  nothing has changed from a treatment point of view, other than antiretrovirals haven’t turned out to be the slam dunk for anyone, including me, that we needed. Of course there are hundreds or thousands of drugs sitting on pharmaceutical company shelves right now that might work, but so far, nobody is looking.

Despite my disappointment (not surprise) that the science is not keeping up with the medical need, I remain hopeful and determined. It won’t be fast enough, but I do believe they will get it right this time, even if the route is circuitous. The scope of the discovery is spectacular in terms of the impact it will have on our understanding of chronic disease. It will transform many fields of medicine, but especially psychiatry, which still views our symptoms as arising from a defect of character. We are the ultimate mind body experiment, and it’s not about character, or lack thereof, that our psyches are too closely linked to soma, the body. There is a biological basis. Heightened senses come with the territory. The misunderstanding, even derision, from our supposed caregivers has caused great harm. It is one of the most painful truths in my life that should I be forced to seek help from my colleagues in the conventional medical world, they will likely laugh at me, not to mention do the wrong thing. But there is redemption in turning suffering into meaning, in using painful experience to become wiser. The disbelief has caused terrible isolation. Healing, separate from curing, is possible, in connection with the truth, and in connection with other people who understand and care.

*    *    *

We must never forget that we may also find meaning in life even when confronted with a hopeless situation, when facing a fate that cannot be changed.  For what then matters is to bear witness to the uniquely human potential at its best, which is to transform a personal tragedy into triumph, to turn one’s predicament into a human achievement.  When we are no longer able to change a situation- we are challenged to change ourselves…
~ Viktor Frankl in Man’s Search for Meaning