Archive for April, 2013

Your Brain on Viruses: Study Finds Even Common Viruses Cause Cognitive Declines

The ‘Manhattan Project’

The Northern Manhattan Study is an immense project that’s taking a deep look at health in Northern Manhattan, New York . The project consists of  analyzing basic health characteristics of several  thousand people over time and it’s spinning out studies at a dizzying rate.  The project is not on chronic fatigue syndrome, but because it’s  looking at factors that have shown up in ME/CFS it may shed  some  light on what’s happening there.  In fact it may shed a lot of light.

Manhattan

The ‘Manhattan Project’ is examining health issues in a wide swath of the population. Several findings may have relevance to ME/CFS/FM

For instance, each of the studies below looked at a factor that’s been found (in at least some studies) in ME/CFS and  each of the findings seemed to make sense what we know of ME/CFS.

Increased IL-6 levels were associated with cognitive declines in one study, and increased  soluble tumour necrosis factor receptor 1 (sTNFR1) levels were associated with increased  mortality in another.  Increased levels of daytime sleepiness in the elderly were associated with increased risk of stroke, heart attack and vascular events in another.   Metabolic syndrome was associated with cognitive declines in another. Eating a Mediterranean diet was associated with  reduced ‘white matter hyperintensity volume’ a marker of small blood vessel breakage in the brain and reduced vascular events such as stroke.

Infectious Burden

Neurology. 2013 Mar 26;80(13):1209-15. doi: 10.1212/WNL.0b013e3182896e79.Infectious burden and cognitive function: The Northern Manhattan Study. Katan MMoon YPPaik MCSacco RLWright CBElkind MS.

The most applicable study to ME/CFS, however, is clearly the latest one which determined if infectious disease burden was associated with cognitive declines.  In this study the researchers tested  blood from a broad swath of the population in New York  for antibodies to common bacteria and viruses (three of them herpes viruses) and gave the participants  cognitive tests.  Then they created an index of infectious burden (IB) and determined if more infections meant more problems with cognition…and found they did; the more active infections present, the  worse the cognitive impairment.

Infections

This study suggested that having more infections, active or latent, are associated with reduced cognition.

No ME/CFS studies have attempted to associate pathogen load with cognitive declines but given the increased  rate of infections Dr. Peterson and other immunologically oriented ME/CFS  doctors have found and the documented cognitive impairment in ME/CFS, the finding made sense. Cognitive impairment is  associated with brain issues but the researchers didn’t zero in on the brain; instead they focused on cardiovascular problems which interfered with blood flows to the brain.

It turns out that studies have linked common infectious agents to inflammation, coronary artery disease and stroke and a past ‘Manhattan project’ study found  that high infectious burdens  were associated with an increased risk of stroke and increased carotid plaque buildup.

Many viral pathogens in the herpesviridae family, characterized by latent or persistent infection, were implicated in increased stroke risk.

It appears that chronic infections often play havoc with cardiovascular functioning. Infectious organisms can impact cardiovascular functioning in various ways. They can directly invade the vascular walls. C. pneumoniae and H. pylori DNA was found in aetherosclerotic lesions in 26%  and 37% of cardiac bypass patients in one study.  With regards to pathogens commonly found in ME/CFS, high rates of active HHV6 infection  found in Italian cardiac patients who did not have aetherosclerosis suggested the virus may play a role in heart patients who have idiopathic heart disease.

Cardiovascular Issues

At the 2008 HHV6 Symposium in Baltimore, a German researcher, Dr. Lassner reported that heart biopsies he’d done in German heart patients commonly revealed parvovirus B-19, HHV-6, enterovirus and/or Epstein-Barr Virus infections.  He noted that HHV-6 infection of the blood vessel walls results in the production pro-inflammatory cytokines which can constrict the blood vessels, impair capillary production and reduce heart blood flows. HHV6’s ability to trigger blood vessel wall constriction is intriguing given studies suggesting it may play a key role in ME/CFS.

Blood vessels

Pathogens can affect the cardiovascular system and cardiovascular problems appear to be rife in ME/CFS.

Lassner, interestingly, found antivirals (IVIG-parvovirus, interferon-enterovirus) to be effective in virus infected heart patients, but reported much the same treatment response  pattern found in many ME/CFS patients; improvement while on antivirals followed by relapse when off them.

Infections can also turn on the macrophages which help create the dangerous plaques, they can confuse the immune system into attacking parts of the body and they can help an inflammatory state that is damaging, etc.

These observations, along with the results of this current study lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, may be an important etiologic factor of atherosclerosis.

Simply the presence of active herpesvirus or other infections  can contribute to an inflammatory mileu that can be detrimental.  Katan reported that an inflammatory state could lead to aetherosclerosis, ‘subclinical stroke’ and dementia. Subclinical strokes (ie transient ischemic attacks from which patients recover) primarily effect executive functioning, one of the cognitive processes known to be impaired in ME/CFS.  Changes in mood and  the ability to organize and take on multiple tasks could be a sign of a ‘subclinical stroke‘.  Other symptoms can include feelings of numbness or weakness, double vision, dizziness/vertigo, confusion, inability to speak, loss of balance or coordination.

Cardiovascular issues have been found in ME/CFS and more and more attention is being given to this area. Cardiovascular control is impaired,  reduced cardiac vagal tone is associated with cognitive declines, impaired blood pressure variability,  reduced cerebral blood flows, reductions in stroke volume and cardiac output (all this in the past year and a half)  provide ample evidence of impaired cardiovascular functioning in this disorder.  Interestingly autonomic nervous system issues similar to those found in ME/CFS were correlated with cognitive declines in fibromyalgia.

All in all the finding of decreased cognitive functioning with increased infectious burden in the  Northern Manhattan Study findings may not be surprising for many people with ME/CFS. At the most recent HHV6 Conference in Paris Dr. Peterson reported on several ME/CFS patients who’s cognitive abilities rebounded remarkably following Vistide infusions for herpesvirus infections and Dr. Lerner has reported similar results in his herpesvirus infected patients.

Conclusions

The latest Manhattan project study should be helpful in highlighting not only the cognitive declines but the cardiovascular risks that are associated with common or  chronic latent or active infections. Since active infections are part and parcel of ME/CFS, this study’s important association of decreased cognitive function with increased infectious burden suggests that measuring both those factors in ME/CFS should be routine, and may offer objective measurements of treatment efficacy.

Report From Paris: Peterson Reports Antiviral (Vistide) Effective in Treating Herpesvirus Infected Chronic Fatigue Syndrome (ME/CFS) Patients

PetersonPhoto right

“These results show objective endpoints, subset selection, and recovery. There were complete responders and partial responders among severely ill CFS patients with HHV6 or CMV. These are encouraging results for this subset and further well-designed trials should be pursued to confirm them.” Dr. Dan Peterson

At the HHV6 Conference in Paris, France today Dr. Peterson reported on the results of a retrospective study following 65 severely ill chronic fatigue syndrome patients given a course of Vistide from 2005-2012 for HHV6 and/or HCMV infections.  Despite the interest in pathogens in ME/CFS, antiviral studies are rare and this is the first one reported for this drug.

Virus from vistide presentation


Dr. Peterson has three decades of experience treating immunologically challenged ME/CFS patients.

Vistide (Cidofovir) gets a lot less press than other antivirals and immunomodulators (Ampligen, Rituximab, Valcyte,  Valtrex) used in this disorder  probably because the drug requires a  complex infusion protocol,  frequent blood tests because of the rare but real possibility of  serious kidney side effects and is expensive  (although it can be covered by insurance).

This combination – infusions, frequent blood tests and expense – requires close physician follow-up. With Dr. Peterson’s specialized focus on patients with dysfunctional natural killer cells, however, he may be most consistent about testing for herpesviruses, which are known to be active in ME/CFS patients.

After three decades of focusing on immunologically challenged ME/CFS patients, Peterson may be more experienced at pathogen detection and treatment than any other practitioner in the field, and so it’s not surprising to find the first Vistide study coming from his office.  In an interview, a former patient of his said, ‘he leaves no stones unturned'; when he finds something he goes after it ‘aggressively’.

In his presentation he stated  almost 30% of  his patients test positive for  active HHV-6 or human cytomegalovirus (HCMV) (PCR, rapid culture, antigenemia), and a whopping 50% test positive for active Epstein-Barr virus (EBNA) infection.

Serious Drug For A Serious Illness

Vistide (Cidofovir) is  FDA approved for the treatment of cytomegalovirus (CMV) in patients with AIDS. (Cytomegalovirus is a member of the herpesvirus family.) and it’s been used off-label to treat  human papillomavirus, BHK virus, herpes simplex virus, vaccinia virus infections. The Black Box warning on Vistide speaks for itself

 ‘Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with  few as one or two doses of Vistide. The “recommended dose, rate, frequency of Vistide injections must not be exceeded.”

The Study

A positive response was denoted by a negative pathogen test, improved fatigue and cognitive functioning determined by an interview with Dr. Peterson and  the patient’s self reports after the trial.

Response

  • Full Responders - Patients were deemed to be full responders if they were able to completely return to work or to work-related activities
  • Partial Responders – demonstrated significant improvement of symptoms but were unable to return to work or work related activities.
  • Non-Responders – Did not demonstrate any measurable improvement post-treatment

Results

Seventy percent patients improved

Seventy percent of ME/CFS patients with HHV6 and/or HCMV infections improved significantly on Vistide

Dr. Peterson reported that seventy percent of patients were full  (able to return to work) or partial (significant increase in functionality) responders; a very high rate of success in a illness characterized by a poor response to treatments.  Only thirty percent of Vistide recipients did not have a significantly positive response to the drug. No serious side effects were seen; ironically the minor side effects seen were attributed to a drug, Probocenid, used to ensure Vistide was safe.

It’s not clear what percentage of ME/CFS patients will test positive for HHV6 or cytomegalovirus in other practices but this type of response suggests the drug may be  being under-used. With the FDA Stakeholder’s meeting  coming up in three weeks and the Chronic Fatigue Initiative’s pathogen discovery study results due to be published later this year, Dr. Peterson’s presentation is timely. (Unfortunately, Dr. Peterson was not invited to present at the FDA Stakeholder’s Meeting.)

Dr. Peterson called for placebo-controlled, double-blinded multi-center studies that address Vistide’s efficacy, examine its effects on the immune system and study the mechanisms of increase in VO2 max scores in ME/CFS.

Sample Cases

Dr. Peterson reported on several cases, all of whom were men – something Dr. Peterson has said he likes to do to break up the notion that only women get this disorder.

  • A 27 year old college graduate  unable to work because of  constant flu-like symptoms, weakness and marked cognitive decline (math!) presented with low NK functioning, low VO2 max and HHV6 and cytomegalovirus infection. He was able to return to work after 24 weeks of bi-weekly infusions. His VO2 max on the exercise test went up went up 23%,  his NK cells a remarkable 400% and he tested negative for both viruses at the end of treatment. He had had ME/CFS for three years.
  • A 54 year-old former high school teacher unable to work due to extreme fatigue, flu-like symptoms and cognitive problems severe enough to keep him from being able to grade his students papers presented with active HHV6 and cytomegalovirus infections and low NK cell functioning and VO2 max. He was able to return to work after 24 weeks of bi-weekly infusions. His VO2 max increased 47%, his NK function test went up 20% and he tested negative for both viruses. He had had ME/CFS for five years.
  • The third patient had classic, acute onset ME/CFS which progressed to seizures. Both serum and cerebral spinal fluid tested positive for HHV6. At the end of the Cifodovir trial the  viral load in his cerebral spinal fluid dropped from 3670 copies/ml to undetectable levels. Serum HHV6 was dramatically reduced (47,000 copies/ml to 3,000 copies/ml). Still symptomatic and experiencing cognitive problems, he was nonetheless able to return to work.

Conclusions

The retrospective study indicated Vistide (cifodovir) can have dramatic effects on functional capacity in HHV6 and/or HCMV infected ME/CFS patients.

Increasing VO2 max appeared to be critical to increasing functionality as the partial responders did not increase their VO2 max while on Cifodovir. At the FDA Advisory Meeting for Ampligen Dr. Bateman noted that VO2 max test results probably were, given the exertional problems in ME/CFS, the most difficult to ‘move’ test result in this disorder.

VO2 max levels in Dr. Peterson’s patients prior to Vistide administration were exceedingly low; they appeared to in the ‘very low’ range even for people for 65 years of age and older. Vistide moved those test results about 20% on average; leaving them still, it appeared, below normal but sufficient enough for a significant increase in functionality.

A Vistide Example

Vistide_CFSThe VO2 max tests suggested most patients had not returned to full health and Dr. Peterson has said he knows of few complete recoveries. I interviewed a former patient of Dr. Peterson’s several years ago. Faced with the loss of his career and the ability to care financially for his family Vistide turned out to be a godsend.

Cut down by acute onset ME/CFS, his VO2 max score topped out at an unbelievably low 15 (which qualified him for heart disease) and he was a ‘2’ out of 10 on his own energy scale (had trouble sitting up to eat).  Within a month on Vistide he was at a ‘4’; the next month he was a ‘5’ and sleeping soundly for the first time since he’d gotten sick. The next month he was a ‘7’ and his VO2 max tests had doubled to 28; still far below the 44 expected at his age, but an amazing increase, never the less.  Three months later he was at ‘90%’, back at work and able to do everything except exercise.

CMX001 – The Future Vistide? 

Dr. Peterson didn’t report on CMX001 in Paris, but sitting in the background of all this is a analogue of Vistide called CMX001 which appears to be a safer and more effective,  if not yet available, version of it. A  2012 review named CMX001 as one the ‘ten hot topics’ in antiviral research.

Chimerix Pharmaceuticals modified Vistide so that it can easily be taken up into the  tissues. That means no need for infusions, no worries about kidney problem and according to Chimerix, dramatically increased effectiveness.

CMX001 has been in development for  some time but just this March the FDA awarded the drug ‘fast track’ status for the prevention of cytomegalovirus infection.  Phase II trials are finished  and Phase III trials will get underway this year.

Given Dr. Peterson’s success with Vistide, FDA approval of CMX001 could be very good news for ME/CFS patients with HHV6, HCMV and/or possibly EBV infections.

Wrap Up

In a retrospective study Vistide proved to be  effective  in treating severely ill ME/CFS patients with HHV6 and HCMV infections. Dr. Peterson called for double-blinded, placebo-controlled studies to further study Vistide’s efficacy and mechanism of effect.  The CFI’s pathogen discovery studies due out this year should shed light on what percentage of ME/CFS patients could benefit from Vistide.

A Vistide analogue under development called CMX001 which does not require infusions and does not effect the kidneys could be boon for ME/CFS patients with herpesvirus infections if it is approved by the FDA. CMX001 was given fast-track status by the FDA earlier this year.

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Simmaron Research Mobilizes Unique Assets to Push ME/CFS Field Forward: A Look Back at the First Year

April 4, 2013

We envision a world where ME/CFS is treatable and well-understood. To get there, we are scientifically redefining ME/CFS.

Simmaron focuses on chronic fatigue syndrome research

Simmaron has moved quickly in the past year and half and is involved in a variety of potentially groundbreaking studies.

The latest addition to the ME/CFS Research Foundation scene, the Simmaron Research Foundation started off small. There were no huge endowments, no connections to major academic centers; in fact, Simmaron was located in little Incline Village off of Lake Tahoe, a locale rich in chronic fatigue syndrome (ME/CFS) history but definitely not known for its medical resources.

What Simmaron did have was Dr. Daniel Peterson, a practitioner whose deep experience and extensive biobank is unparalleled in ME/CFS. Since the early days of the Incline outbreak in the early 1980’s Dr. Peterson has been immersed in chronic fatigue syndrome.  Now with the Simmaron Foundation’s support he had the opportunity to put his experience and samples to the test. It turned out that the ME/CFS research community was very interested in what he had to offer.

After just a year and a half, the Simmaron Foundation is making its mark.With studies underway that will help to redefine ME/CFS and how it gets researched and treated, Simmaron has quickly become perched on the front lines of ME/CFS research.

A Vital Resource – Finally Hitting Stride

Dr. Peterson quickly knew something had gone very wrong with the sick patients crowding his  door in Incline Village in the 1980’s, and early on  he began collecting samples for the studies he felt had to come.  It took decades but that time has come, and given the technology and the quality of the researchers  he and Simmaron Foundation are working with now, it was probably worth the wait.

Chronic Fatigue Initiative Pathogen Study

Simmaron Research provided 40  patient and 40 control samples to the biggest, most  rigorous and comprehensive ME/CFS pathogen study ever –  the Chronic Fatigue Initiative’s Pathogen Discovery project. Lead by Dr. Mady Hornig and Dr. Ian Lipkin, this project will set the stage for pathogen research in this disorder for years to come.

Simmaron’s eighty samples will join samples from four other ME/CFS clinics in a search that will:

  1. screen for 18 viruses, bacteria or protozoa  already associated with ME/CFS. If that hunt proves unsuccessful they will
  2. sequence everything in the blood to look for known and unknown viruses
  3. then develop tests for any new pathogens they find as well as
  4. look for unique protein signatures and
  5. analyze 50 markers of immune activation/inflammation/oxidative stress

The well-characterized, rigorously documented samples Simmaron is providing will play a key role in this study.  Of all the clinics in this project, Dr. Peterson’s stands out in its focus on immunologically challenged patients.  If the Lipkin/Hornig team finds pathogens, they will likely show up in the Simmaron samples.

The results from these studies are coming in and  by the end of this year we’ll finally have some answers to one of the biggest questions facing ME/CFS researchers and patients for over twenty years – what role pathogens play in this disorder.

ME/CFS Cerebral Spinal Fluid Samples – Meet Top Pathogen Experts in the World

The large pathogen discovery study funded by the Chronic Fatigue Initiative will dramatically increase our knowledge of the role pathogens play in ME/CFS but, for all the tissues it was studying (tears, saliva, blood and fecal samples), it was missing an important one – perhaps the major one – until Simmaron stepped in.

Cerebral spinal fluid circulates around the brain stem and the outside margin of the brain. When it’s collected, down near the tailbone, it bears traces of its path through the brain. If pathogens, unusual proteins or inflammatory markers are present in the brains, as so many believe,  the CSF is the best way, short of an autopsy or biopsy, to find them. CSF fluid analysis is used to assist with diagnosis in a number of neurological disorders.

Watch Cerebral Spinal Fluid Circulate Around the Brain

The Director of the HHV6 Foundation, Kristin Loomis, considers the Simmaron spinal fluid samples critical to the CFI project’s success because many of the viruses suspected in chronic fatigue syndrome simply don’t show up in the blood, the saliva, etc.  She noted that several theories suggest the pathogens present (HHV6, EBV, enteroviruses) have assumed unusual forms that make them difficult to trace in the blood.

It wasn’t just the size of Simmaron’s spinal fluid contribution – 60 of these difficult to collect spinal fluid samples – something Dr. Mady Hornig called ‘unparalleled’ – but who they’re from that makes them so special. Dr.  Peterson doesn’t routinely do spinal fluid tests; these samples are from patients -often the illest of the ill – he suspected had neuro-inflammatory problems and his superb diagnostic skills means the CFI can have confidence in what kind of patients they’re looking and that’s unusual in ME/CFS research.

This study is not just about pathogens; the Center for Infection and Immunity will be looking cytokines and other biomarkers that could tell us more about the health of ME/CFS patients’ brains. Recent successes documenting  unusual proteins in ME/CFS patients cerebral spinal fluid suggest  the spinal fluid may indeed be the place to look.

Dr. Hornig, the leader of the CFI’s pathogen discovery effort, called the Simmaron spinal fluid samples ‘a really unique opportunity’. It’s no surprise Simmaron made funding this study a top priority.

ME/CFS Cerebral Spinal Fluid Samples –  Meet the Top Natural Killer Cell Experts

natural killer cells

The extensive immune analysis given to Simarron’s spinal fluid samples will provide insights into the immune status of the brain in ME/CFS

We journey halfway across the world down to the Southeast coast of Australia for Simmaron’s next spinal fluid study where the ME/CFS research group led by Sonya Marshall-Gradisnik, PhD, now centered at Griffith University, will be digging deep into the immune profile of the same samples CFI researchers are analyzing for pathogens.

Griffith is now ground zero for  natural killer cell research in ME/CFS.  Griffith researchers recently contributed a chapter on natural killer cell dysfunction in ME/CFS and at the Ottawa conference they  documented the NK cell dysfunction present in ME/CFS,  identified miRNA’s contributing to the NK cell  dysfunction, documented the same dysfunction in T-cells, and identified cytokine abnormalities in the blood. Now they’ll look for these abnormalities in Simmaron’s spinal fluid.

These two studies put the Simmaron Foundation’s spinal fluid samples at the heart of a  double-barreled research effort.  CFI researchers will  determine whether pathogens/markers they’ve found in the blood, saliva, etc. are also in the spinal fluid, while Griffith researchers will determine whether their immune abnormalities show up in the  spinal fluid.  At the end of this process not only will we know a lot more about the brain in ME/CFS, we’ll know much more about where to look for the biomarkers this disorder needs so badly to move forward.

A Multi-Site Clinical Assessment of ME/CFS

CDC multi-site CFS study

Dr. Peterson’s unique focus on immunologically challenged patients will pay dividends in the CDC multi-site definition study.

How to define properly  Chronic Fatigue Syndrome is another issue that’s plagued the field for decades. Perhaps no issue is more important to the field. Inadvertently involving different types of patients, for instance, in research studies could explain the inconsistent research and treatment trial results that have stifled interest in this disease for decades. Drug companies are reluctant to enter into treatment trials for an  illness they don’t feel has a real definition.  The list of negative effects from having a vague definition goes on and on.

With their participation in the Center For Disease Control’s Multi-Site Assessment study, however, the Simmaron Foundation and Dr. Peterson’s Sierra Internal Medicine, will be helping to provide answers to this perplexing and important question.

In this study led by the Open Medicine Institute, Simmaron joins seven other clinical sites to provide electronic data on diagnostic procedures, test results, treatments and outcomes on over 800 patients to the CDC for analysis. The project will, for the first time, produce statistically based analyses of the different subsets ME/CFS practitioners are likely seeing and will bring  the practices and insights of ME/CFS professionals to the fore in scientific publications for the first time.

Once again, Dr. Peterson’s unique focus on immunologically dysfunctional patients will play a vital role in highlighting this significant subset of patients. Promising first results have lead the CDC to refund and expand the project to include more physiological measures.

Charting Long term (gulp) ME/CFS Prognosis

Few studies have looked at a vital subject for most ME/CFS patients; what they can expect in the future.  Is ME/CFS progressive and, if it is, what does it progress to? Some researchers believe ME/CFS may progress to range of other disorders and a recent study found significant fatigue predated the development of multiple sclerosis in many patients. This study will catch up with patients seen at least 10 years ago in Dr. Peterson’s practice and see how they are doing.  The results could profoundly effect our understanding of ME/CFS and will provide physicians important clues how to best manage it.

Post-Infectious Cardiomyopathy Study

Simmaron’s identification of  four  patients in its surrounding community with mysterious  heart problems (cardiomyopathy) provides a new opportunity learn more about the possible role of infection in this heart condition.

Simmaron has recruited the Centers for Infection and Immunity at Columbia University to dig into these patients serum, plasma and other biological samples to see if they can figure why they developed this unusual form of heart disease.  Possible infections will be given a particularly close look.

This study should be published this year.

Conclusion

Dr. Peterson’s years of experience and his extensive data bank have brought new opportunities for Simmaron and for the ME/CFS research field. With collaborative efforts ranging from New York to Atlanta to Australia, the Simmaron Foundation, located in little Incline Village, has developed world-wide connections and is engaged in studies that could redefine ME/CFS, provide vital insights into its longterm prognosis and its neuroinflammatory nature.  Simmaron has been indeed been rising.