This was Dr. Montoya’s chance to highlight the ME/CFS work being done at Stanford and it was impressive. Most of the researchers presenting today are brand spanking new to the field and they are producing results and they are excited. The research being done at Stanford, one of the top medical schools in the country, brings a rigor to the field that’s sometimes been missing in the past.
It hasn’t been easy for Dr. Montoya – one researcher told Montoya was told by several of his peers that focusing on Chronic Fatigue Syndrome would ruin his career, but he’s courageously moved forward and with several potential legitimate breakthroughs being presented at this meeting, it appears to be working.
Dr. Unger (CDC)
Dr. Unger’s presentation gave us nothing new, but the facts she presented about the epidemiology of Chronic Fatigue Syndrome were nonetheless impactful and bear repeating.
#meCFS#CFS Stanford – room is packed to overflowing, standing room only – we have to move to another room, several 100 people present
#meCFS#CFS Stanford – Unger shows fatigue, sleep even pain worse in ME/CFS than in chronic pelvic pain, spinal cord injury, muscular dystrophy
#meCFS#CFS Stanford – Unger shows yearly dollar losses due to ME/CFS range from 18 billion to 51 billion – incredible!
#meCFS#CFS Stanford – when a young person gets ME/CFS their chance of graduating from colleges drops in half
#meCFS#CFS Stanford – Unger adamant ME/CFS – very heterogeneous; all study results confounded by the presence of the different illnesses (Unger is not a big fan of a new definition, neither is Mark Zinn – Unger thinks we should subgroup first, Zinn states you would have to throw away so much evidence from past studies if you switched to new definition. He was quite taken by the MRI studies already done in ME/CFS…
#meCFS#CFS Stanford – heterogeneity makes it much more difficult to study this illness
#meCFS#CFS Stanford – says increased prevalence (1-4 million) from Empirical Definition mostly due not to definition but to study parameters (and we always thought it was due to a lax definition….)
Jarred Younger – Leptin, Leptin, Leptin
Could leptin really be it in ME/CFS?
We’ve hardly heard of leptin, but after Dr. Younger is through we might become very familiar with it. A younger researcher, Dr. Younger’s (::) dynamic and enthusiastic presentation was a highlight of the conference.
Dr. Klimas was very excited by his work. Lot’s of things appear to be coming together for leptin and ME/CFS.
#CFS#ME/CFS Stanford – Younger believes microglial in brain are key, (Van Elzakker is sure microglial in body play a role as well, and that glutamate is key also)
#meCFS#CFS Stanford – Younger’s good day/bad study examines no less than 75 immune factors (!) and finds leptin is the only one that is correlated with fatigue (!)
#meCFS#CFS Stanford – high fatigue = high leptin and vice versa in 6/10 CFS patients, he’s now waiting on news re: a 200 person NIH grant to study Leptin further in ME/CFS
#meCFS#CFS Stanford – Then a startling network analysis shows that leptin affects maybe 25-30 immune factors in ME/CFS. Could leptin be the key? (He also found it in FM. I asked Dr. Fletcher if she’d ever found it in her studies; she said she never looked :))
#meCFS#CFS Stanford – Leptin is a pro-inflammatory agent that reduces the threshold for the microglia in the brain to firep; i.e., they become more sensitive to negative events in the body … ( Younger believes the microglia cause central sensitization in the brain.)
#meCFS#CFS Stanford – … until they can fire with the smallest stressor such as exercise or any time something bad is happening in the body
#meCFS#CFS Stanford – if you pretreat microglia with leptin and then add a pathogen – the microglia go bananas
#meCFS#CFS Stanford – add leptin to microglia and then add a pathogen = huge increases of very powerful pro-inflammatory agent, TNF-a
#meCFS#CFS Stanford – what increases leptin? aging, chronic stress, toxins, immune activation (and VanElzakker says the microglia itself)
#meCFS#CFS Stanford – If microglia and leptin play a key role then lots of treatment options are available (very encouraging)
#meCFS#CFS Stanford – unfortunately none of them have been studied :)). Nonetheless – they include low dose naltrexone
#meCFS#CFS Stanford – Younger – Idibulast another microglial inhibitor that VanElzakker has high hopes for, which is undergoing trials for pain in the US.
#CFS#ME/CFS Stanford – Younger – other microglial inhibitors – dextrometorphan, Rifampin, Propertyline (???) and more
#CFS#ME/CFS Stanford – Younger – other microglial inhibitors – Chinese herbs – luteolin, panax ginsenng, resveratol. piperinne, many more – lots of possibilities
Komaroff and VanElzakker
#CFS#ME/CFS Stanford – Komaroff says he was convinced early that inflammation in the brain was key, is sending patients to VE for testing
#CFS#ME/CFS Stanford – Komaroff was convinced of vagus nerve theory by evidence showing vagus nerve infection can spark CNS inflammation in animals
Ron Davis and the IOM
Davis thinks the IOM could help – a lot
Ron Davis, one of the top geneticists in the country, is on the IOM definition panel and works with Dr. Montoya and Dr. Kogelnik. His son, Whitney, is very, very ill with ME/CFS. He and his wife both believe people with Chronic Fatigue Syndrome have been done a great wrong by the scientific community.
Davis is telling the Stanford brass that ME/CFS must be studied. It’s notable, though, that even the top echelon of researchers in the medical field such as Ron Davis and Ian Lipkin receive push-back when they talk about ME/CFS.
Things are changing, though, as the Stanford Symposium and it’s new slate of ME/CFS researchers indicate. ME/CFS is making inroads and who knows what the next couple of years will bring…
#CFS#ME/CFS Stanford – Davis is highly lauded geneticist, runs huge lab; believes IOM panel will finally give ME/CFS legitimacy
#CFS #ME/CFS Stanford – Davis is talking to everyone he can at Stanford -saying ME/CFS is last the big disease to make your name in!
#CFS#ME/CFS Stanford – Davis hopes IOM will give ME/CFS access to top researchers, says panel is working hard, reviewing 1,000’s studies.
Gene Expression Results Indicate Pro-Inflammatory State is Present
“there is genomic evidence of a chronic inflammatory state in the blood of ME/CFS patients”
#CFS#ME/CFS Stanford – Mark Davis’s lab does gene expression on 200 patients and 400 healthy controls, 25 million data points!
#CFS#ME/CFS Stanford – finds hundreds of genes differentially expressed in ME/CFS vs healthy controls
#CFS#ME/CFS Stanford – then they compare the gene signature found in hundreds of other disorders to see which disease MECFS is closest to
#CFS#ME/CFS Stanford – ME/CFS scores a close match to ‘systemic inflammatory syndrome’ – it’s an inflammatory disorder
#CFS#ME/CFS Stanford – other diseases the MECFS gene expression results are similar to are a parasitic disorder, disorders caused by
#CFS#ME/CFS Stanford – … gram-negative bacteria and lentoviruses, etc.; all inflammatory disorders
#CFS#ME/CFS Stanford – many genes highlighted, notes high ubiquitin and interestingly, gene associated with Sjogens Syndrome and lupus.
MRI Findings in ME/CFS – Michael Zeineh, MD, PhD
#CFS#ME/CFS Stanford -Zeinich finds significantly less white matter bilaterally in ME/’CFS vs controls (n=29)
#CFS#ME/CFS Stanford – reduced volume of thalamus found, basal ganglia not different but basal ganglia ends up being correlated with fatigue on MFI.
#CFS#ME/CFS Stanford – once again with basal ganglia we see a seemingly normal result that is possibly not normal
#CFS#ME/CFS Stanford -also finds five locations where cortex thickness is increased in ME/CFS; usually thickness is decreased in disease
#CFS#ME/CFS Stanford – Finds stronger connection in one brain pathway – Right Acturate – plus at both ends of the pathway finds …..
#CFS#ME/CFS Stanford – increased thickness at points at both ends of the pathway – rather unusual finding…Van Elzakker suggests increased thickness in one area of the brain is a compensatory response for the damage in the other side of the brain.
#CFS#ME/CFS Stanford – The fact that the MFI score correlates with the Right Acturate findings suggests it is contributing to fatigue
#CFS#ME/CFS Stanford – researcher notes they weren’t able to access limbic/deep brain regions, VanElzakker says come to Mass General and we’ll do it there. Montoya says give me your number 🙂
#CFS#ME/CFS Stanford – did not find differences in blood perfusion; i.e, blood flows through the brain
#CFS#ME/CFS Stanford – notes that twin study in ME/CFS did also not find differences in perfusion either
#CFS#ME/CFS Stanford – Byron Hyde stands up and says this is the most amazing presentation of MRI findings he’s ever seen…(!)
Quantitative EEG Studies Suggest Subcortical Pathology in ME/CFS – Marcie Zinn, PhD, Mark Zinn, MM
“CFS is going to teach us a lot about the brain”
Zinn – “We are going to learn a lot about the brain from ME/CFS”
One of the highlights of the conference, one had the feeling this could end up being a seminal paper in ME/CFS. The researcher is jazzed. He believes it explains a lot about ME/CFS and that it should hearten patients. One note – delta waves should only appear during sleep, but hey’re showing up in spades in ME/CFS patients while they’re awake.
#CFS#ME/CFS Stanford – can we detect brain-fog with EEG? And find a biomarker for ME/CFS
#CFS#ME/CFS Stanford – Measured peak alpha frequency; height of the peak of electrical signals. Peak alpha frequency is associated with cognition
#CFS#ME/CFS Stanford – finds 5/7 places in frontal lobe, 3 sites in sensory lobes and three others with reduced peak alpha frequency in ME/CFS
#CFS#ME/CFS Stanford – ‘that’s a lot of brain area!” that’s most of the cortex…these areas are mostly controlled by the thalamus
#CFS#ME/CFS Stanford – reduced peak alpha frequency hugely predicted amount of fatigue result..P<.000, a very strong result!
#CFS#ME/CFS Stanford – that means interruptions in goal directed behavior (boy, is that right on), and problems with alertness, attention …
#CFS#ME/CFS Stanford – and memory performance. “Patients are having trouble organizing and conducting behavior’..
“That’s a lot of brain area!” (Zinn)
#CFS#ME/CFS Stanford – then they went further. Used Electromagnetic tomography to try to understand brain-fog. Found that compared to controls
#CFS#ME/CFS Stanford – CFS patients had widespread delta sources mainly in the frontal and limbic areas…prefrontal-limbic connection
#CFS#ME/CFS Stanford – orbitofrontal gyrus is particularly important as well as insula, anterior cingulate, other parts of frontal gyrus
#CFS#ME/CFS Stanford – also destabilization in ‘ascending arousal mechanism’; highlight problems in the brainstem that ascend in brain
#CFS#ME/CFS Stanford – delta wave increases appear to block faster brain rhythms thus causing problems in speaking, word finding, etc.
#CFS#ME/CFS Stanford – abnormal delta results in disruptions in information transfer across the brain, cannot process information well
#CFS#ME/CFS Stanford – grey/white lesion, brainstem lesions, cerebral inflammatory and metabolic disorders found in this type of problem
#CFS#ME/CFS Stanford – also finds decreased beta brain waves in part of brain that effects motor deficits, slower motor performance, muscle weakness
#CFS#ME/CFS Stanford – problems with somatosensory cortex could result in more pain, problems with stimuli (bingo!)
#CFS#ME/CFS Stanford – suggests ME/CFS is synonymous with ‘limbic encephalitis’ (these were all in patients without psychiatric co-morbidity :))
#CFS#ME/CFS Stanford – ‘a global expression of CNS hypoactivaton was found in CFS”
#CFS#ME/CFS Stanford – Zinn says he can go into a severely ill ME/CFS patients bedroom and capture her/his EEG
#CFS#ME/CFS Stanford – Zinn says study will provide much relief to ME/CFS patients. I bet it will be a landmark study 🙂
Circulating Cytokines in ME/CFS PatientsReveal a Novel Inflammatory and Autoimmune Profile” Jose G. Montoya, MD
“The Perfect Storm”
#CFS#ME/CFS Stanford – Montoya Cytokine study – big study 180 patients! very robust – says hard to find data of this sample size anywhere
#CFS#ME/CFS Stanford – Montoya Cytokines – Females across groups had higher levels leptin, ENA78, IL1RA, resistin…Leptin again!
#CFS#ME/CFS Stanford – Cytokines – CD40, resistin, IL-1a, Leptin, Rantes, CD40 active in B-cell activation
#CFS#ME/CFS Stanford – then filtered patients – low moderate severe CFS= and results were ‘staggering’
#CFS#ME/CFS Stanford – then find 15 cytokines significantly increased in severely ill vs controls; 13/15 got worse as fatigue increased
#CFS#ME/CFS Stanford – cytokines – in mild CFS cytokines are below healthy controls/just the opposite for severe patient
#CFS#ME/CFS believes in mild CFS cytokines are going into tissues to find pathogens,in severe CFS – tissues are so damaged they start spilling cytokines into blood
#CFS#ME/CFS Stanford – TGF-B is antiinflammatory, low levels in ME/CFS suggest immune system failing to haul in pro-inflammatory state=more pain, etc
#CFS#ME/CFS Stanford – Montoya calls increased pro-inflammatory cytokines, reduced anti-inflammatory cytokines over time “the Perfect Storm”
Lipkin shows how wide-ranging his studies can be. Several big ME/CFS studies are on the way and even Ian Lipkin, virus hunter extraordinaire gets his ME/CFS grant applications slammed.
“I am open to everything other than the idea that Chronic Fatigue Syndrome is psychosomatic”
#CFS#ME/CFS Stanford – Lipkin – Believes IL-17 may be very important in MECFS (IL-17 is associated with autoimmune disorders)
#CFS#ME/CFS Stanford – notes that toxins could be as important as infectious agents in disease
#CFS#ME/CFS Stanford – Lipkin nobody can find infectious agents in Kawaski disease. paper notes shift in wind currents in troposphere
#CFS#ME/CFS Stanford – prior to people coming down with Kawaska disease, so he sent up a plane and collected air samples – found lots of candida!
Will Lipkin Crack Chronic Lyme Disease”?
#MECFS#CFS – LIpkin will look at Chronic Lyme disease patients to see if they are infected with other tick-borne disease
#CFS#MECFS – earlier study of ticks found in Northeast found many more infections in ticks other than borrelia (!)
#CFS#MECFS#Lyme – Lipkin – will Lipkin crack chronic Lyme disease? Other studies suggested antibiotics work to suppress Borellia but some people are still sick. Do they have a different infection?
#CFS#MECFS -CFI study – 486 samples! (plasm, though…) only found a few HHV-6…found retroviral reads in 85% of samples – but is not interested in retroviruses – not going down that hole again.
#CFS#MECFS – finds anelloviruses in 75%samples, but similar percentage in cases and controls
#CFS#MECFS 211 PBMC -HHV-6 – 13% in CFS samples, 11% in controls; no go with HHV-6
#CFS#MECFS – Lipkin – higher IL-17 in people with disease for less than 3 years, Ditto with IFN-7, Reduced eotaxin…calls these ‘dramatic differences‘ in immune functioning
#CFS#ME/CFS Stanford – very open to everything except that ME/CFS is not a psychosomatic disorder
#CFS#ME/CFS Stanford – Autism – GI complaints have excellent predictive value for autism. Lipkin finds reduced bacteria that break down carbs
#CFS#ME/CFS Stanford – this is the kind of systematic approach I think needs to be done in ME/CFS
Big ME/CFS Studies On the Way
#CFS#MECFS – CFI looking for things made in the gut that make it into the blood – metabolomics- will be done in ME/CFS in next three months
#CFS#MECFS – also doing proteomics in place, doing RNA sequencing – all on ME/CFS – lots of work. says ‘all the tools are in place’
#CFS#MECFS – Lipkin-most studies will be done in the next 3 months; that’s three major studies due, plus the cytokine study; lots of work
#CFS#MECFS – Question – why the gut? why not the other tissues? does not think it’s feasible to do tissue biopsies
#CFS#MECFS – Lipkin got fecal samples, would like to do throat samples, PBMC’s – reviews of his grant proposal to do gut work on ME/CFS were horrendous
#CFS#MECFS – though, very difficult to get funding, one reviewer of his grant proposal referred to ‘psychogenic illness’ in ME/CFS
#CFS#MECFS – Montoya ending up – says we need a ‘sense of urgency’ and ends a great Symposium 🙂 Congratulations to Dr. Montoya 🙂