Copyright 2017, All Rights Reserved
4) What Will it Take to Solve ME?
Upon receiving an anonymously donated $5 million for his Stanford ME/CFS Initiative in 2009, Jose Montoya moved forward on several fronts at his institution. These collaborations have resulted in published studies on the brain and immune system, as well as the publication of an additional anti-viral drug trial. Early in 2015 Montoya talked about some of these studies as the sole guest on a Centers for Disease Control conference call. His participation in the call occurred just days after the Institute of Medicine published its now-historic report claiming that ME was not merely "real" but urgently in need of money and research.
Montoya reported that faculty in Stanford's neuroradiology department had focused on white matter in the brain. As others have done, the Stanford team noted white matter atrophy in the disease. A finding of white matter atrophy indicates, essentially, shrinkage and is a presumed result of inflammation. Like several other researchers, Montoya hypothesizes that in the case of ME, inflammation is occurring due to an immunological challenge from an infection. In his CDC call, he postulated that suppressing herpes viruses in ME "may be an important component in a holistic approach to treating ME."
The Stanford neuro-radiologists employed a sophisticated MRI technique called "diffusion tensor imaging," or "DTI," however, the first time anyone had used the technology to study ME brains, Montoya noted. DTI is, according to one definition, "highly sensitive to changes at the cellular and microstructural level." Researchers increasingly are using DTI to measure microscopic brain changes and injuries.
White matter atrophy has been documented in Alzheimer's disease, MS, AIDS and other degenerative neurological diseases and has also been associated with old age. Significantly, white matter atrophy in MS has been linked to cognition difficulties identical to those long-identified in ME: mental processing speed and working memory.
In addition to reduced white matter, Stanford neuro-radiologists made an unexpected finding of a damaged or abnormal nerve tract in the right hemisphere: the Latinesque-named "arcuate fasciculus," which connects the frontal and temporal lobes. They also discovered that the greater the abnormality, the more severe the patient's disease. The Stanford collaboration resulted in a publication in Radiology, called "Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome."
Unfortunately, more is understood about the left arcuate fasciculus, which plays a critical role in speech, than the right. Additional research is required to understand the implication of the finding but the discovery is yet another worrisome brain abnormality arising after more than 30 years of abnormal brain findings in ME. Perhaps the earliest and most important was a 1992 study published in the Annals of Internal Medicine. Harvard's Anthony Komaroff coordinated the massive study of 259 patients, more than 80 percent of whom were found to have multiple small, ischemic white matter lesions. The finding that should have set off alarm bells in the public health establishment but was instead trashed in a vehement letter to the Annals by staff at the Centers for Disease Control after Komaroff's paper was published.
As an aside, Paul Cheney is the first doctor I am aware of who sought an MRI brain scan in an ME patient. The patient was twelve years old, the star ballerina in her ballet class and among the epidemic victims in Nevada. One morning in 1985 she awoke and could not balance on two legs, much less one. Cheney ordered an MRI and to his surprise, discovered the child had small white matter brain lesions. As a result, Cheney and his partner Dan Peterson began ordering brain scans on more epidemic patients and discovered the finding was common. During that era, a period when MRI technology was relatively new, the only other patients in whom neuro-radiologists saw the identical abnormality were patients suffering from AIDS dementia or bi-polar disease.
Another area of study Montoya described in his 2015 CDC conference call was continued experimentation at Stanford with the anti-herpes drug Valcyte. In order to counter skepticism about Valcyte as an ME treatment, in 2012 his group published the results of a third Valcyte study that demonstrated treatment duration--in the case of this study, six months--was critical to the drug's good effects. But for some patients, Montoya suggests, the timeline may be considerably longer.
Beginning in the mid-1990s, the Centers for Disease Control began emphasizing the importance of early intervention. Unfortunately, no one has actually proven early intervention makes any difference in disease progression. Recovery and improvement seem to be, more often than not, random. In addition, efficacious therapies are vanishingly rare. Ampligen is one, anti-herpes drugs are another, although in both cases, some portion of patients fail to respond. One Los Angeles doctor told me in 1986, "You could rub chicken fat on these patients' foreheads and for a little while they will feel better," implying there was a high placebo response rate in the disease. Interestingly, Simon Wessely published a study in 2005 that indicated the placebo response rate in ME is quite low.
I ask Montoya how important he considers early intervention.
"Well, I come from two perspectives," Montoya says. "I have had experiences of patients who have been sick for thirty years and who have gotten better. Just like I have had patients who've been sick for two years, and they get better. But they are very likely to be different patients.
"But the other thing that has not been given enough attention is that the immune system of an ME patient is dysregulated, it's dysfunctional. And I think we're finding more and more data that it's hyperactivated. But, it has a wisdom of its own. It has a wisdom and equilibrium that allows the patient to stay alive for years, that allows the patient not to succumb to horrible infections.
"The immune system of a transplant patient is so bad that they die from CMV (cytomegalovirus), HHV6, fungals, aspergillus (mold), any of a dozen areas of my expertise. But their immune systems are so badly dysregulated that if you don't give them the right medications, they die.
"The immune system of an ME patient allows that patient to go on for years in a bad situation and state, but that means that there is an inherent wisdom there," Montoya continues. "And so when we try to disrupt that wisdom, it resists. And I think that that's why certain interventions make the patients worse, but it also argues that the intervention has to be sustained so there is a re-teaching or re-setting of the immune system. I think the length of that intervention now will be important. (The issue will be) not only what intervention but how long?"
But, no surprise given the variance in severity and duration, it gets more complicated, Montoya says:
"It's possible that interventions will be different for the short duration (patients) and the long duration (patients). Just like I'm convinced the interventions will be different between the mild and the severe. But to disrupt something that has been going on for so long, you have to do it in a sustained way."
A year after his CDC conference call, in 2016, Montoya published his ME Initiative annual report. He wrote that he was planning "to launch comprehensive pathogen discovery research in the disease....We will take samples of blood, cerebrospinal fluid, lymph nodes, bone marrow and NK cell compartments...this study will be the first comprehensive effort to search for pathogens in sites never attempted before." His primary collaborator, Montoya reported, will be bioengineer and physicist Stephen Quake, Ph.D., a Howard Hughes investigator, an inventor and esteemed faculty member in the Stanford School of Engineering.
"There are several reasons explaining why today, in 2017, we don't ultimately know what ME is, why we don't understand completely what is wrong with patients and why we don't have a biomarker and why we don't have more targeted, effective therapies that have been proven to work in seventy to eighty percent of patients," Montoya says.
"It took only three years, from 1981 when first reports came out of something killing young people--only three years from that to discover there was HIV behind it. Then ten years to find the cocktails by 1995. That timeline has not been the case for ME, and as you laid out in your book one reason was that the CDC and NIH took a position of this being a psychological disease."
But, Montoya continues, there are other reasons ME continues to languish.
"When one does research into biological specimens, the lower hanging fruit, the specimen that is easiest to tap into, is the blood...It's not easy to find the pathogen in the most obvious compartment, the blood. It's harder to reach deeper compartments. And so I think that another potential factor, among many, as to why we're where we are and why we're not where we should be has to do with failing to go after certain compartments, such as bone marrow and NK cells."
Unfortunately, as reported in Part One of this series, Montoya has yet to get full funding for this innovative work.
"We have everything set up but are waiting to get the funding," Montoya says. "To do research these days is a whole coordinated work of many pieces. What people outside of medical school don't know is that our own personal salaries have to be brought by us in the form of grants, patients we bill, or gifts."
Montoya's ME/CFS Initiative at Stanford is one of the groups applying for a center grant from the NIH. The deadline for applications was May 2. Reportedly, NIH study groups chosen to review applications will make their decisions in September. Since NIH has never had a standing review committee for ME, but instead routinely pulls together ad hoc panels, the identity of the reviewers who may have varying levels of expertise and even political opinions about the disease is critical and beyond applicants' control. Nevertheless, the $29 million, a small sum by NIH standards, is the largest commitment to ME the agency has made.
"Having this money by NIH is of huge, positive significance," Montoya says. "However, in my view, [the money] is way lower that what they should have given to this disease given the fact that nothing or very little has been done for thirty-five years. In my view, the center grant money should have been $200 to $250 million per year. You cannot bring people into work on this disease and not cover their salaries, not cover their work.
Nevertheless, Montoya adds, "It's going in the right direction. [The grant opportunity] is making us all talk to each other and look to each other. It's not anymore Stanford, Cornell and Columbia. It's a lot of other groups."
It's Montoya who raises the topic of XMRV. Scientist Judy Mikovits' 2009 discovery of a murine gamma retrovirus in ME patients and a portion of healthy controls sent government scientists at the National Cancer Institute into a barely-controlled panic. They struggled to come to grips with the possibility that an infectious agent that caused cancer had already infected a significant number of Americans. A full-court press ensued at CDC and NIH to try to replicate or disprove the finding and the naysayers won the day: XMRV turned out to be a man-made lab contaminant that was ultimately and innocently sent to hundreds of labs.
However, as Mikovits and others--including Montoya, it turns out--maintain, the "de-discovery" effort, coordinated by Ian Lipkin at his Center for Immunity and Infection in response to a request from NIAID director Anthony Fauci, failed to fully undermine evidence for retroviral infection in ME.
"X-M-R-V did a lot of damage to ME because of the methodology that was involved," Montoya says. "The methodology--the contamination. But the work that was done to de-discover the discovery," he continues, "did not conclude there was not a retrovirus, it just said, 'That's not the one in ME.'"
"I'm immersing further deep down in this illness, in this work," Montoya continues, "I'm immersing myself in deeper and deeper layers. But I want to remain open-minded, I don't want to say 'It's a retrovirus' for sure.
"You have in your book several moments where it's so nerve wracking," Montoya adds, and mentions Elaine DeFreitas, the Wistar Institute immunologist who discovered retroviral fragments in adults and children with ME but who, in effect, was unfairly discredited by the Centers for Disease Control by 1992.
"I wish that her work would have been pursued!" Montoya says, his frustration apparent.
"I want to remain open," he continues. "And back in those days [the late 1980s-early 1990s] they could only go after one thing. But now we have the tools and you can go to everything. You can just throw the samples in the right platform and it tells you everything that is there from fungi to bacteria all the way to parasites, and then you compare to cases and then you see what is different.
"So, I want to remain open. And yes, it could be retrovirus, or retroviruses, but we want to remain open."
I ask Montoya about patients who, based on evidence they were infected with XMRV, began taking anti-retroviral drugs manufactured for AIDS and reported they felt greatly improved.
"Raltegravir is an example," Montoya says, "It's a protease inhibitor against HIV and it's also known to have anti-herpes activity, so that is a possibility. Because I have to confess to you I do have patients who have come to me and said, 'I never felt better than when I was on anti-retrovirals." So, it's possible that this is an issue of cross reactivity--that it's affecting the herpes infections."
At the conclusion of our interview, Montoya says, "Many of the things we've talked about--I have been ruminating on them for years. This one just came to me recently: Given all the things we know about ME and the things that we don't know about ME--and when I say 'given everything,' please understand--everything--I believe we need a clinical czar, the same as was done for Ebola.
"Ebola was going crazy, even the threat to the U.S. was very lethal. Only a few American patients got infected and yet that triggered one billion dollars for Ebola!
"And there was a lot of talk about having a clinical czar for Zika. And why a clinical czar? Because every organization within the U.S. government has its own bureaucracy. But, a clinical czar is the person who will expedite things. But, they have to have a budget. So, one billion dollars and a clinical czar."
Montoya floats a high-profile name, someone he says has the wisdom, age and experience.
I have another suggestion.