Watershed Paper Provides Conclusive Evidence of Underlying Pathology of ME/CFS and Fibromyalgia

The study "Adrenergic and Sensory Receptor Expression on Leukocytes Increases After Moderate Exercise in Chornic Fatigue and Fibromyalgia"  by Alan Light et. al clearly demonstrate the physiological processes behind Chronic Fatigue Syndrome.  Like many of the good papers that have come out, Dr. Light found himself having difficulty getting it published.

In simplified terms, you've got the muscles, a messenger in between, and then the recipient (nerve endings).    The situation that results in Fibromyalgia and ME/CFS is as follows:  Following muscle injury, white blood cells pick up certain chemical signals from the muscles, and pass them on to the nervous system, specifically the sympathetic nervous system.  Using currency as an example:  Excercise A produces 5 units of fatigue, and white blood cells in the muscles read 5 units of fatigue, and is supposed to pass on 5 units of fatigue to the central nervous system, but instead passes on 50 units of fatigue to the nervous system, or alternatively the white blood cells misread the signal, and pass on 50 units of fatigue to the nervous system. So in essence, the sympathetic nervous system is receiving a forged document.

How does the mechanism fit in?  In both CFS/ME and Fibromyalgia, acid-sensing ion channels, P2X4 and P2X5 purinergenic receptors, adrenergenic receptors, transient vanilloid type receptors and IL-10 were upregulated.  The only difference was that in Fibromyalgia, P2X4 (Pain signals) and TRPV1 (receptor responsible for binding capsaicin - causing burning pain) was dominant, while in CFS P2X5 (Fatigue signals) was dominant.  The effects were that changes occurred within 30 minutes of exercise in both disease cohorts, while in normal subjects, there was a considerable delayed onset, returning to baseline within 48 hrs.  The amounts measured in endurance athletes after running a marathon did not even come close to the levels attained in disease cohorts.  Incidentally, activation of P2X4 receptors has the effect of lowering blood volume, and increasing vascular resistance.

The effect is that the brain perceives the body to be under tremendous stress - it is well established that stress fundamentally disrupts the HPA axis (There is nothing better than pain for disrupting the HPA Axis!).  The brain then sends signals for bodily functions to slow down - which involves downregulating mitochondrial function.  It also means an increase in serum cortisol early on, followed by a period of adrenal fatigue.  Essentially, earlier studies on pain amplification in Fibromyalgia shed some light, but we now have a mechanism.  It was earlier thought to be as the result of too much substance P at the nervous system level.  It is mechanism that has been around since the mankind: when it hurts or when fatigued, the body sends a signal to the rest of the body to slow down.

How does this fit in with XMRV?  Much research needs to be done on this.  XMRV enters the cell via XPR1, which is a G-protein coupled receptor, which in turn invokes a reaction cascade in the cell.  Retroviruses rely on retroviral promoters to replicate once they are integrated in human DNA.  XMRV could act by enhancing the transcription of receptors involved in pain signals if the sequence of the XMRV promoter also binds to the same region that codes for pain receptors on the human genome - alternatively, XMRV triggers a signalling cascade through a G-Protein coupled receptor that upregulates pain receptors.  The effect can be further enhanced by cytokines triggered by XMRV.

These findings create optimism in finding small molecule therapeutics for both disorders, however it does not address the underlying viral pathology.    The ideal drug design target would be inhibitors of P2XR4 and P2XR5 - however the risk of side effects is always there with small molecule therapeutics.  One of the therapeutics Lyrica (Pregabalin), works by blocking pain transduction by Gabaergic mechanisms. However, it is a dirty drug, targeting other systems as well.

Testimony From a patient

A patient which I will only identify by the name of Ms. X, has provided me with her account of living with CFS, and how as a desperate measure she finally found a doctor that would prescribe her antiretrovirals.  Ms. X is 36 years old, and has been living with CFS since age 24.  She was once a very active person - having completed the Boston Marathon one year before coming down with CFS.  It all started with flu like symptoms she states, but she never fully recover until...  By age 25, she would endure malaise on a daily basis - seeing specialist after specialist - two rheumatologists, a sleep specialist, cardiologist.  By age 28, she would struggle to work part-time.  At age 31, she was admitted to a psychiatric hospital after becoming suicidal as a result of doctors giving her the runaround.  It was at this time that she was diagnosed with CFS - and she began graded exercise therapy, which left her even more fatigued.

At the time the Mikovits et. al study came out, she had been unemployed for 3 years.  At this time, she began to travel around the country looking for a doctor that would prescribe her antiretrovirals - most doctors were extremely relucatant, until she found one in San Francisco that treated HIV patients early in the epidemic.  She was given a two drug combination - Isentress (Raltegravir), and Viread (Tenofovir).  Initially, she felt worse (Fever, chills, cough), and almost stopped taking the drugs, but after 21 days began a rapid and sustained improvement.  After 3 months, she no longer experienced any musculoskeletal pain, nor any post-exertional malaise, she would return to work full time by 4 months - and currently is capable of exercising 1 hour per day.  For her, the monthly cost of the combo treatment comes to a staggering $1500 a month - something she could not afford on her own, nor would any HMO or drug plan want anything to do with it - luckily for help from her family.