Recently scientists from the Whittemore Peterson Institute (WPI) led by Dr Mikovits, claim to have discovered a retroviral link to ME/CFS (1). This pioneering research has identified a retrovirus called XMRV, shown to be active in two-thirds of patients (published), and antibodies for the virus were present in 95% of patient (unpublished research).
Mikovits' team said further research must now determine whether XMRV directly causes CFS, is just a passenger virus in the suppressed immune systems of sufferers, or a pathogen that acts in concert with other viruses that have been implicated in the disorder by previous research.
A recent study carried out by Imperial College London attempted to mimic the results of the WPI study (2). They found no evidence of XMRV infection in the blood samples of 186 patients fitting the CDC criteria. They conclude that “Although we found no evidence that XMRV is associated with CFS in the UK, this may be a result of population differences between North America and Europe regarding the general prevalence of XMRV infection, and might also explain the fact that two US groups found XMRV in prostate cancer tissue, while two European studies did not”.
The purpose of this paper is to hypothesise how these findings may fit with the Amygdala Hyperarousal Model for ME/CFS (3).
Three Potential Hypotheses
Overall there are three broad hypotheses that we can infer from the findings so far, as per Mikovits’ statement:
- The XMRV virus directly causes the symptoms of ME/CFS
- The XMRV virus indirectly causes ME/CFS by suppressing the immune system in concert with other pathogens, allowing opportunistic viral and bacterial infections to flourish causing the symptoms of ME/CFS
- The XMRV virus is simply a passive opportunistic infection which establishes itself due to general suppression and dysfunction of the immune system from another source. (This general immune dysfunction may be caused by autonomic dysfunction as a result of amygdala hyperarousal).
There are two broad aspects to the immune system, TH1 and TH2. TH1 involves Natural Killer (NK) cells whose job it is to identify and destroy viruses. The TH2 side of the immune system involves, amongst other things, antibodies which respond to threats. There is evidence in the literature that patients with ME/CFS are “TH2” biased, i.e. the TH2 aspect of the immune system is over-activated, causing suppression of the TH1 side and high levels of inflammatory cytokines; patients have lower Natural Killer (NK) cell immunity. This bias may mean that opportunistic viruses and bacterial infections can no longer be kept at bay effectively by the TH1 side of the system.
RNase L conducts a function of holding the virus at bay until NK cells are available to eradicate the pathogen, however even the RNase L’s ability to perform this function can be compromised over time if TH2 dominates for too long. RNase L dysfunction was also reported in the prostate cancer cases of XMRV, although later research has not found a genetic link. In ME/CFS, any suspected Rnase L deficiency many simply be due to chronic TH2 dominance. If TH2 dominates for too long, it can be hypothesised that viruses such as HHV-6, Epstein Barr Virus (EBV), CMV and Parvovirus B19 can flourish, as well as bacterial infections such as mycoplasma and chlamydia pneumonia.
It has been established that the majority of neurodegenerative disease, fatiguing illnesses and neurobehavioral disease patients have chronic bacterial and viral infections. (4). In fact the WPI research claimed to have found higher levels of XMRA in “atypical” MS and Autism.
The XMRV virus may simply represent one of many viral and bacterial infections present in the blood of ME/CFS patients, and that many of these previous infections (including EBV) had been previously prematurely suspected as the root cause of ME/CFS. There have been many previous studies which have shown similar results to those found for XMRV. As an example, a 2002 study found that out of 261 patients with ME/CFS, 68.6% of patients had active mycoplasma bacterial infection present compared to 5.6% of controls, a similar result to that found for XMRV (5). A 2003 study found that 30.5% of CFS patients had active HHV-6 virus present, but only 9% of controls (6). For Chlamydia pneumoniae it was 7.8% of CFS patients compared to 1% of controls (6). For Parvovirus B19, it was detected in 40% of CFS patients but only 15% of controls (7).
What was interesting in the 2003 (6) study was that having one particular infection did not predict the likelihood of having another infection. This may indicate that the infections themselves are not cumulatively affecting the strength of the immune system to fight off opportunistic infections, but that a general immune deficiency is allowing particular types of infections to establish themselves in a pattern unique to each patient.
According to the WPI research, 4% of healthy controls had active XMRV virus in their blood (versus 67% of ME/CFS patients), which is similar to the levels of active mycoplasma infection in healthy controls. Therefore presence of active XMRV does not necessarily predict ME/CFS, and would not support the first hypothesis. If 4% of the US population were found to have active XMRV pathogen in their blood, this would amount to over 10 million people. Yet there is no evidence that XMRV causes cancer where it is active, or that it has any effect on health. It is merely a suspected link in 23% of prostate cancer cases where it is found in 1% of surrounding tissue, with no causal link established at this stage; one hypothesis is that its presence is simply linked to immune deficiency. Once again, the XMRV virus was found in 6% of benign biopsies showing that its presence may be widespread in the general USA population. Further research however is critical.
It may be that XMRV may be a localised virus to the USA, especially since a recent report from Germany (8) found that out of 589 biopsies carried out on prostate cancer cases, not a single patient showed any evidence of XMRV. They conclude that “One possible reason for this could be a geographically restricted incidence of XMRV infections.” (8) This seems to fit in with the findings of Imperial College London, in that no evidence of XMRV was found in the blood sample of 186 ME/CFS patients in the UK (2).
If 95% of ME/CFS patients show antibodies to XMRV (yet unpublished data from Mikovits’ team), yet only 67% show active virus, this could indicate that a third of ME/CFS patients no longer had the active XMRV virus, yet still were suffering from ME/CFS. If this is confirmed to be true, then the first hypothesis would seem redundant, and XMRV could only be the root cause of ME/CFS if the second hypothesis were correct, i.e. that XMRV had adversely affected the long term performance of the immune system. Alternatively the presence of antibodies could imply that the virus is still active in more that 67% of patients, but had not been picked up through previous methods. It would also be interesting to know the percentage of healthy controls that tested positive for XMRV antibodies which has not been revealed.
One way the link within the second hypothesis could be established, is to test whether the presence of active XMRV predicted higher levels of other opportunistic viruses and bacterial infections. According to the second hypothesis, presence of active XMRV should predict suppression of the immune system and further opportunistic pathogens. However, as previously mentioned, there is little evidence that having one opportunistic pathogen in ME/CFS predicts the likelihood of having another, therefore cumulative immune deficiency caused by XMRV attack is unlikely, otherwise previous studies would have highlighted this finding in the blood of ME/CFS patients. This once again seems to tentatively support the third hypothesis, in that XMRV may simply be a passive opportunistic virus similar to other herpes viruses such as HHV-6 and EBV. Even if presence of XMRV did predict the likelihood of secondary infection, it would still be difficult to infer causality.
The Amygdala Hyperarousal Model and XMRV
The Amygdala Hyperarousal model states that ME/CFS and Fibromyalgia may be caused by a conditioned trauma in the amygdala following an acute viral, bacterial or physical insult, combined with psycho-social distress. Once the classical and operant conditioning has occurred, the amygdala in association with the insula, become hyper-sensitive to signals from both the body and external stimuli, and magnify both the extent and frequency of the incoming stimuli in the sensory thalamus and cortex. This then produces the ME/CFS vicious circle, where an unconscious sensitivity reaction to symptoms causes chronic stimulation of the HPA axis, immune reactivation/dysfunction, chronic sympathetic stimulation leading to autonomic dysfunction, mental and physical exhaustion, allergies, compromised detoxification, mitochondria dysfunction, oxidative stress and a host of other distressing symptoms and secondary complications. And these are exactly the symptoms that the amygdala, the insula, and associated limbic structures are trained to monitor and respond to, perpetuating a vicious circle.
The Amygdala model predicts that there is likely to be TH2 dominance over TH1 due to overstimulation of the sympathetic nervous system. This has already been extensively documented in many studies of sympathetic overactivity due to acute stress and anxiety (9, 10, 11). Although an ME/CFS patient may not necessarily mentally experience acute stress or anxiety, the model predicts that the physiological aspects of the stress response are chronically engaged, thereby causing disruption in various systems of the body including the immune system. TH2 will dominate over TH1, causing a likely increase in opportunistic viral and bacterial pathogens such as XMRV, as well as an increase in allergic responses due to TH2 over-sensitivity, as well as increased propensity to produce antibodies. There is extensive evidence of increased chemical and physical sensitivities in patients. The parasympathetic system is suppressed, compromising digestive and detoxifying processes in the body.
Once the sympathetic autonomic system is conditioned to be chronically activated, it is very difficult for autonomic and Th1/Th2 balance to be restored. Opportunistic viruses and bacterial infections flourish, in themselves causing further symptoms in addition to the ones caused directly by amygdala hyperarousal.
In the field of Psychoneuroimmunology, many studies have shown that excessive sympathetic activity can have an immuno-suppressive effect on the body via Neuropeptide Y release, thereby pointing to another pathway by which excessive sympathetic stimulation may compromise immune function. A study by Fletcher et al (12) seems to model this effect in ME/CFS patients. ME/CFS patients tend to show low natural killer cell cytotoxicity, (NKCC), and it is known that Neuropeptide Y (NPY) suppresses NKCC. NPY is concentrated in the sympathetic nerve endings, and following stress, is released together with adrenaline and noradrenalin. Fletcher et al’s study tested the hypothesis that elevation of NPY occurs in ME/CFS and that the elevation of NPY is associated with severity of clinical symptoms. They found that NPY was significantly associated with severity of clinical symptoms, and that NPY could be a potential bio-marker for ME/CFS. This shows a direct link between levels of symptoms, and sympathetic overactivity where the most likely culprit is amygdala hyperarousal.
The WPI team are working on the hypothesis that many of the symptoms of ME/CFS may be caused by XMRV attacking the cells of the immune system, thereby compromising immunity. However, there is potentially another culprit for reduced immunity as discussed: chronic sympathetic activity. This has already been shown to suppress general immunity and especially TH1 function, whilst at the same time causing TH2 dominance, inappropriately stimulating allergic responses in the immune system. (9,10,11)
There is a possibility that XMRV somehow directly affects TH1 function, and simultaneously directly affects the autonomic nervous system, however there is no evidence of this and further research is required.
What is most interesting about the XMRV announcement is that the team also found higher levels of XMRV in people with Autism and atypical Multiple Sclerosis (as yet unpublished). A study by Nicholson et al (13) looked at the presence of co-infections in ME/CFS patients versus patients with Autism Spectrum Disorders. The study found that both groups had higher incidence of multiple, systemic bacterial and viral infections compared to controls, but interestingly, both ME/CFS and Autism patients had very similar levels of active infections when compared to one another. Autism is a disorder where sustained amygdala hyperarousal is accepted as a model for partly explaining the disorder (14), so once again there is tentative support for the amygdala’s role in ME/CFS.
This is a very important finding because of the differences and commonalities between ME/CFS and Autism. We would not necessarily expect any commonalities with respect to infections as the conditions seem to have a very different neurobiological basis. However, the common factor may be sustained amygdala hyperarousal, but due to very different causes. The sustained amygdala hyperarousal in Autism may develop in early childhood due to socio-biological reasons, whereas sustained amygdala hyperarousal in ME/CFS may develop as a result of several co-curring acute factors triggering a conditioned trauma in the amygdala later in life. Both conditions then result in a unique pattern of chronic sympathetic stimulation, but for very different reasons, causing similar levels and types of opportunistic viral and bacterial infections. It is likely that the level of hyperarousal in ME/CFS is much more severe and dwarfs that of Autism, but both conditions exhibit enough of a chronic long term sympathetic response to result in opportunistic infections.
Several recent studies have reported abnormalities in amygdala volume in Autism. (15,16). Furthermore, most studies in Autism show abnormal processing by the brain and the amygdala in response to emotional stimuli, and continual background amygdala hyperarousal is once again suspected (14). Further research is required to test any abnormalities in the function of the amygdala in patients with ME/CFS, which may not show up on standard brain scans. It would be interesting to understand the levels of active XMRV virus and antibodies in Autism.
Finally there are a host of physical changes in the brains and bodies of ME/CFS patients which have been well documented and which are consistent with the concept of chronic autonomic dysfunction. These findings cannot be ignored as a result of the XMRV announcement, but need to fit within an integrated hypothesis.
There are many patients who do recover from ME/CFS and Fibromyalgia over time, and yet may not have taken any kind of anti-viral medication. This may indicate that changes that a patient themselves initiate, may be enough to strengthen the immune system, bring the body back to homeostasis, and eradicate opportunistic infections such as the suspected XMRV.
How Amygdala Retraining Might Reduce XMRV and other Opportunistic Pathogen Levels
Amygdala retraining aims to reduce the stimulation of the sympathetic nervous system by creating a projecting neurone from the prefrontal cortex to the amygdala to control its over-zealous reactions. This in turn would reduce the sympathetic overload, allowing TH1/Th2 ratios to gradually return to normal, allowing the body’s own immune system to fight off opportunistic infections such as the suspected XMRV. Symptoms from amygdala hyperarousal (including changes in the brain), and symptoms from opportunistic infections would then subside, as well as any allergic effects of TH2 dominance.
Amygdala retraining aims to bring homeostasis back to the body after a period of imbalance, where the balance between the sympathetic and parasympathetic systems returns to normal, as does the TH1/TH2 balance.
The WPI findings are indeed a step forward in ME/CFS research, and are significant findings. However, further research is required to validate the idea that XMRV is a contributing factor in the pathogenesis of ME/CFS, versus being simply another passive co-curring infection such as mycoplasma, HHV-6 and EBV.
The Imperial College London study (2) attempted to detect XMRV in patients in the UK, and found no evidence. This would lead us to tentatively conclude that XMRV may represent an opportunistic pathogen localised to North America, although much more research is required to validate that conclusion.
Amygdala retraining aims to reduce the levels of opportunistic infections such as the suspected XMRV virus by strengthening the immune system through balancing the TH1/TH2 ratio and bringing the body back to homeostasis.
Further research is required to answer the following questions:
- What was the percentage of healthy controls that tested positive for XMRV antibodies? (The 3.7% figure seems to be referring to the percentage of healthy controls which tested positive for XRMV virus DNA rather than antibodies in unpublished research)
- What percentage of people with Autism display evidence of active virus or antibodies?
- What percentage of patients with other neurodegenerative disease, fatiguing illnesses and neurobehavioral disease show evidence of XMRV?
- Can the studies be replicated effectively across the ME/CFS population?
- Can the studies be replicated in different parts of the world?
- Why are controls which have active XMRV not displaying obvious pathology?
- Mikovits JA et al. Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science. 2009 Oct 8
- Erlwein O, Kaye S, McClure MO, Weber J, Wills G, et al. (2010) Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome. PLoS ONE 5(1): e8519. doi:10.1371/journal.pone.0008519
- Gupta, A. Unconscious Amygdalar Fear Conditioning in a Subset of Chronic Fatigue Syndrome Patients. Medical Hypotheses Volume 59, Issue 6, 12 November 2002, Pages 727-735
- Nicolson, G.L. Chronic Infections in Neurodegenerative and Neurobehavioral Diseases. Lab Medicine 2008; 39 (5): 291-299
- Nijs J et al. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunol Med Microbiol. 2002 Nov 15;34(3):209-14
- Nicolson GL et al. Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS. 2003 May;111(5):557-66.
- Frémont M et al. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In Vivo. 2009 Mar-Apr;23(2):209-13
- Hohn 0 et al. Lack of evidence for xenotropic murine leukemia virus-related virus (XMRV) in German prostate cancer patients. Retrovirology. 2009 Oct 16;6(1):92. [Epub ahead of print]
- Hashizume H et al. Anxiety accelerates T-helper 2-tilted immune responses in patients with atopic dermatitis. Br J Dermatol. 2005 Jun;152(6):1161-4
- Ermolao A et al. Relationship between stress hormones and immune response during high altitude exposure in women. J Endocrinol Invest. 2009 May 21. [Epub ahead of print]
- Höglund CO et al. Changes in immune regulation in response to examination stress in atopic and healthy individuals. Clin Exp Allergy. 2006 Aug;36(8):969-71.
- Fletcher AM et al. Neuropeptide Y (NPY): Correlates with Symptom Severity in Chronic Fatigue Syndrome. Abstract of presentation to IACFS/ME Conference, Mar 2009, Reno, Nevada
- Nicolson G. et al. (2009) Similarities of CFS and Autism Spectrum Disorders: Comparison of Blood Co-Infections. (Source: Abstract of presentation to IACFS/ME Conference, Mar 2009, Reno, Nevada. By Nicolson GL, Nicolson NL, Haier J. The Institute for Molecular Medicine, Huntington Beach, California, USA; Department of Surgery, University Hospital, Munster, Germany.
- Kleinhans NM et al. Reduced neural habituation in the amygdala and social impairments in autism spectrum disorders. Am J Psychiatry. 2009 Apr;166(4):467-75
- Schumann CM et al. Amygdala Enlargement in Toddlers with Autism Related to Severity of Social and Communication Impairments. Biol Psychiatry. 2009 Sep 1 [Epub ahead of print]
- Mosconi MW et al. Longitudinal study of amygdala volume and joint attention in 2- to 4-year-old children with autism. Arch Gen Psychiatry. 2009 May;66(5):509-16.