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Revised: 5/3/04
The CFS Page
Part 1 Outline hypothesis Part 2 Detailed Case Study/test results of the author, (in preparation).
I’ve suffered with this condition for about 15 years now. I’m not that badly affected as I can walk and I'm still able to do short periods of sedentary work but I’m not able to exercise and reading is quite difficult.
I don't have any one fixed theory but rather as
research is published I often find myself adapting my ideas and
jettisoning ideas that don't stand up. The only thing I care
about is getting to the truth of the matter.
On this page I want to set out my ideas and to summarise some of
the best research going on and to include the results of some of
the tests I’ve had done over the years. Not all the
references and sections are directly on CFS but I believe them to
be relevant and they reflect my interests.
This page has not been peer reviewed.
Introduction
I'm proposing that the primary cause of CFS is toxic exposure
from a variety of sources that became increasingly common in the
late 20th century. A number of toxins such as organophosphates,
organochlorines, Volatile organic compounds (VOCs) and heavy
metals can produce CFS in susceptible individuals, giving rise to
variants of the condition.
At the root of the problem these compounds are either causing genetic abnormalities in the host or are causing CFS in people who have a genetic predisposition that makes them poor detoxifiers.
There also many other affects that bear on most
body systems causing a kind of inertia in which the body runs
down with low output of many hormones. The symptoms are numerous
and may be produced by abnormal cytokine production that follows
from the induced immune sensitivity to a variety of chemicals and
by the resulting highly compromised oxygen transport system which
effectively switches the body to 'anaerobic mode' with reduced
high energy phosphate metabolism.
Very small doses of small chemical molecules such as OPs/VOCs
complex with larger molecules (haptens) and induce the symptoms.
Organophosphates (OPs) are interfering with
normal phosphorylation in cells and initiating Ca channel cell
signalling and other affects beyond cholinergic
disturbance. Flowing from these are numerous secondary affects
involving neuro endocrine and immune dysfunctions. Dose, route of
exposure, type of toxin and host genetics are all factors that
contribute to the development of CFS.
Background
Fatigue Syndromes of varying degrees of
severity have been around in sporadic and epidemic forms for
centuries.
I’m not convinced by the argument that most of the CFS we
now see is just neurasthenia by another name. I think
the heated debate over the last 20 years to find a name for the
disease strongly suggests that we are dealing with a new
condition, or at least a clear, more common and intense variant
of something that has gone before. The sheer volume of patients
coming forward in the 80s surprised the medical profession. Why,
if CFS had always been around.
The emergence of the first dedicated journal of CFS in 1995, as
well as many ME groups, was presumably as a response to a need in
patients and physicians that had previously not been there.
A 1997 study (8.2)
found the 'top' cause of long term absence from UK schools was
ME/CFS. I know of no evidence that shows prior to CFS
neurasthenia was the top cause or even in the top ten.
It's unlikely to be a disease with a single causal agent but is almost certainly multifactorial (8.1) with variants and subsets of patients. There are some useful attempts to define the condition in terms of symptoms (8.5/6) and to find markers for CFS, of which there are now a number of promising, if not totally convincing candidates. (5.1, 6.4/6)
The condition affects more females than males.
An explanation for this may lie in hormonal differences (10.7) or
in differences in toxic bioconcentration ie manganese is greatly
increased with higher oestrogen levels. One would also need to
consider exposure to 'female' medications (birth control pill)
that may be relevant in gut flora disturbance and finally
occupational bias.
Some pesticides exhibit sexually di morphic affectation (9.33).
There's been a long and tedious debate about whether the
condition exists at all and what it should be called. I'll use
these two broad groups:
1) Post viral fatigue syndrome (PVFS) which develops after glandular fever or a other viral illness.ie Parvovirus.
2) Chronic fatigue syndromes (CFS) which I
believe are induced as a result of exposure to a single or
variety of chemicals, often over many months, often with a recent
precipitative exposure that causes mutations or other genetic
abnormalities. Many of these cases are so well documented by the
sufferers and by scientists that it astonishes me that so many
medics dismiss this explanation without reflection.
The exposure may not always be obvious to the sufferer.
Many toxins are now clearly implicated in CFS and similar
illnesses– Ciguatera Toxin (9.26), silicone (9.63-68), fluoride (9.25), mercury (9.12/13), the Butyltins (9.87/88). I would also consider some medications and a variety
of (hidden) occupational or domestic/hobby exposures (9.94/95/96) to be relevant and in
need of more research.
A genetic susceptibility is also likely because exposure to a
wide variety of toxins throughout life is now universal and CFS
is rare. Often overlapping with this category of CFS are Multiple
chemical sensitivity (MCS), (4.3/4; 6.8, 9.1/6/77;) Fibromyalgia and 'Sheep
dip flu'.(9.44)
PVFS.
My view is that underlying this condition there is chemical
exposure that has weakened and dis-regulated the immune system
perhaps through several mutations. The final trigger for the
condition is a severe viral attack, usually Glandular fever.
There is evidence that viruses can cause the type of long term
damage found in CFS in some people who are genetically
predisposed. ie Parvovirus B19.(12.30)
One of the most exciting lines of research in this field has been into cytokine profiles and the anti viral pathway, the important 2-5A synthetase/RNase L/protein kinase R which is chronically activated in CFS (5) which I deal with more fully in the paragraph on immune dysfunction.
In PVFS the up regulation continues.The immune messengers, Cytokines can produce their own destructive symptoms (12.28,29) and immune cleaving chemicals drive part of the syndrome disturbing protein synthesis and ATP production.
Most physicians pronounce the emerging PVFS
patient 'well' when the virus has been destroyed.
The standard tests don't pick up the abnormalities now
experienced by the sufferer.
CFS and MCS
I fall into this group and much of what follows below is based on
studying my CFS. There is an overlap with PVFS but there is no
obvious viral trigger. There are many variations within the group
but I would point to chemical insult as the prime cause. Host
genetics would be relevant as this determines the expression of
detoxification enzymes (9.42-48) that protect against toxic damage.
Most sufferers develop a degree of hypersensitivity to some
chemicals and in more severe cases this is often classified as
Multiple chemical sensitivity (MCS)
The toxin, through repeated exposure sensitises the susceptible
individual. This may involve an antigen type response with the up
regulation of cytokines which can cause headache, daytime
sleepiness, myalgia and possibly fatigue common in MCS.(12.28)
Part of the MCS scenario may be the generation of free radical
cascades that can move systemically at great speed through the
body when not intercepted by anti oxidant systems or the capacity
of toxins to alter quickly ion channel function.
Lab tests to show chemical sensitivity on certain white cells
(lymphocytes) are available and can be shown to reveal precisely
individual sensitivities. My hunch here is that 'over sensitive'
cells carry mutations or chromatid exchanges affecting the cells
structural proteins.
In one MCS study in rats (9.76/77) the researchers suggest that there is an increase in
the numbers of cholinergic receptors underlying this condition
resulting in cholinergic supersensitivity- to a number of
chemically unrelated compounds. MCS genotypes may therefore
naturally express greater numbers of these receptors.
A normal defense mechanism of the body to OP
exposure is to downregulate cholinergic receptors to mitigate the
excess of acetylcholine. Stone et al found that even a very low
level DFP exposure in rats produced a protracted decrease in
cholinergic receptors, probably hippocampal nicotinic, with
consequent reduction in memory related tasks and spatial
awareness. (9.109)
Cholinergic damage is a common finding in CFS.(14.37,38)
I have no doubt that MCS is a genuine, non psychogenic medical condition and part of the CFS spectrum: I have it myself to a moderate extent. Sufferers make the associations between their symptoms and the culprit product retrospectively and sometimes it takes months or years to work this out. Usually they have no prior knowledge of MCS. This rules out the favoured psychosomatic explanation that such people expect 'after-shave', or whatever it happens to be, to give them a headache and so it does. I'm also not sure what the exact mechanism here would be. How would a thought, an expectation consistently produce the same symptom in the same location.
In my own case early on I had identified, by some observational tests over a few months, chlorine, even at very low doses such as in tap water, as a chemical that always produced several dose related symptoms - headache, palpitations, tingling. The picture was filled out when several years later I found I had high levels of chlorinated pesticides in my fat cells- lindane, DDT, PCPs, PCBs etc. I am convinced that this is biologically significant in my case and not coincidence. The question remains as to how such low levels can produce such incapacitating symptoms and I'll consider the mechanism later.
I may well have damage/disruption to the
sodium-potassium-chlorine co-transport mechanisms which 2 key CFS
neurochemicals, acetylcholine and glutamate influence. Chlorine
also has a role in establishing the negative intracellular charge
(13.19) and cellular
electronics are important in CFS.
Another well known variant of CFS is 'Sheep dip' flu, caused in
my view by exposure to the OP Diazinon (9.41), principally as an airborne vapour. Of course you do
not need to be a sheep farmer to be exposed to OPs and to carry
residues of OPs (9.99)
The reason why only some farmers who used diazinon became ill is
due almost certainly to a genetic weakness ( a polymorphism on
the PON 1 gene) that leads to a major OP detoxification enzyme
(paraoxonase) having only partial functionality(9.42-48) and leaving the farmers at
greater risk. Diazinon is now being phased out due to high risk
of several adverse affects. (9.99-105)
Aircrew are increasingly reporting developing a severe
'aerotoxic' fatigue syndrome and they and some researchers have
highlighted the way OPs are used on flight decks to control
insects and how OPs can leak from engine lubrication oils into
the air conditioning systems on aircraft.(9.113-115) Where these systems are of the re-circulation type the
danger is far greater. I think they are correct in attributing
their illness to the OP exposure.
One of the best hypotheses on toxin induced CFS is by J.E.Phelps. (9.91) His thesis is that several toxic metals, such as Beryllium, and other chemicals (Fluorides) form insoluble mineral deposits in the body and activate macrophages which transport the deposits to the lymph nodes. This toxic debris and cell debris from the TH1 battlefield generates chronic immune responses with characteristic cytokine profiles (TNFalpha/RNaseL ) that begin with cell orientated TH1 type and move towards a TH2 type response when TH1 starts to fail. This leaves the path relatively clear for pathogens to thrive which adds further to the CFS burden.
Symptoms
The symptoms in CFS are not vague symptoms that
come and go. Most of them are precise and are with you for 24
hours a day for 365 days a year and it is this unremitting
pain/discomfort and the large number of symptoms that can wear a
sufferer down. At its worst CFS causes sufferers to be wheelchair
bound or bedridden for months or years.
There is a base level of intensity which is the best you will
get. Certain factors quickly exacerbate many of the symptoms
– ie exposure to a variety of chemicals, walking or standing
in my case.
The range of symptoms is very wide, and any theory must attempt
to explain them all.
The most severe symptom is permanent muscle fatigue which ranges
from about 5% - 20% of the level of a healthy person.
To give an example. Last time I swam in the sea about 7 years ago
I managed 5 breast strokes then I had to rest my arms
for a minute, then 4 strokes, rest, then 3 strokes etc. That was
at a good time of day and with the benefit of cold induced
adrenalin. At a bad time there wouldn't have been anything in my
muscles to swim at all.
When I received various test results this degree of tiredness
became entirely understandable. It is utter nonsense for
physicians to pronounce that this degree of weakness is feeling a
'bit under the weather' or middle aged unfitness. It is a simple
matter for a sufferer to make comparisons with the way they were
before the illness and also to make comparisons with age/sex
matched controls. I experienced a very dramatic change
over a short period of time.
I list my own fairly typical symptoms below.
Permanent Symptoms
Occasional symptoms
Main findings of Current Research
Over the last 15 years research into CFS has
uncovered many abnormalities amongst sufferers. Much of this is
non specific : you might find it in toxic as well as
viral/bacterial caused disease. I will argue that this picture of
abnormality is totally consistent with toxic damage and indeed
likely to be toxic in origin.
The most important and consistent findings being damage to the
Hypothalamic-pituitary-adrenal axis (HPA)- Low, time shifted
cortisol production; cholinergic/serotonergic supersensitivity;
orthostatic hypotension; reduced activity of natural killer
cells, up regulation of several immune cytokines and of the
2-5OAS /Rnase L/ apoptosis pathway, increased Reactive Oxygen
Species.
CFS and the mind
The explanation that CFS is a stress related/psychogenic disease,
malingering, hysteria, 'post 25 year old' disease or a type of
depression (10.1-3)
has no convincing scientific basis and cannot account for many of
the biochemical abnormalities that are found in this condition or
the pattern of its onset.
The stress argument makes no epidemiological sense in view of
patterns of stress in the 20th century : World war, shorter life
expectancy, bereavement, lack of comfort and medical support,
severe unemployment etc prevalent in the first half of the
century should have resulted in the burgeoning of CFS if this
were true.
There is interesting work that looks at stress and its affects on
the cholinergic system. I would accept stress may have a role
here and possibly in its impact on the HPA, but I think this is
minor. The damage to the cholinergic system found in CFS is, I
believe, by OPs that target this system.
On a purely anecdotal note I would say that CFS patients are very
often highly sensitive people and it is an intriguing question as
to whether this emotional sensitivity is beget by hard wired
expression of cholinergic or other receptors which in turn makes
these people more susceptible to environmental insult.
Studies on taxi drivers' brains indicated that their intense
study of London streets to get 'the knowledge' resulted in
greatly increased neuronal density in the hippocampus.
Looked at another way perhaps up and down
regulation of our physical body components and messengers is a
response to our 'nurture' or that it is our unique 'persona' that
fashions and subtly influences our bodies changing structure.
The stress argument is usually a quick medical 'cop out.' In my
own case I function slightly better under stress
(adrenalin presumably).
In 2001/2 I was involved in one of the most stressful events of
my life - a court case in which I faced bankruptcy. It made no
difference to any of the symptoms described above even on the
blackest of days.
Similarly hysteria and culture or class do not illuminate or
explain CFS and whilst these trendy theories may have a place as
conversational fodder at the dinner parties of the chattering
classes they are of no scientific merit and stultify progress.
CFS is not the same as clinical depression
because it produces many different test results.(10.1-8, 14.2)
Depression or stress is the usual diagnosis of the GP confronted
with CFS symptoms and graded exercise or cognitive behaviour
therapy (CBT) are the current treatments offered. The former
would be impossible for most sufferers that I know and in my view
would damage sufferers. The fatigue or inability to exercise is a
wise body's defense mechanism against the damage from excess
'unharnessed' oxygen.
Similarly the research evidence that CBT will help address the
biochemical abnormalities of CFS is poor.
One trial (11.41) found CBT could raise cortisol levels in a
group of healthy individuals however this is not a good predictor
for CFS where adrenals are atrophied.
Anecdotally all indications are that CBT makes no real difference
to symptoms and my personal view is that it's a waste of time and
money researching it further.The MRC have set aside 2 million to
research CBT in CFS!
The CFS environment
The aetiology of many CFS cases is often
illuminated by a detailed study of the sufferer's work, home and
recreational environment often dating back over years. A greater
awareness of how many seemingly safe compounds can interact with
the body is definately needed. Having said that it is virtually
impossible to prove cause and effect in most cases.
An interesting couple of studies (8.8/9) looked at CFS sufferers and pets - the incidence of
CFS patients keeping them v controls, the nature of the contact
and a health profile of the pets. Sufferers frequently had pets
that had various chronic health problems and there was usually
significant physical closeness in this relationship. One might be
tempted to say that this supports the view of an environmental
cause for CFS where both pet and person are chronically exposed
to a common toxin in the home /garden that affects them both.
Another scenario might be that the person through intimate
contact with the pet has picked up a low level bacterial
infection (via fleas?) that escapes current testing protocols or
again been chronically exposed to a pesticide treatment given to
the pet. The Parvovirus can be caught from animals and can
produce long term CFS. However the diseases of the pets were too
loosely defined to offer strong support for this thesis.
Secondary Microorganisms
A number of microorganisms have also been
implicated in CFS (15.1-7) such as Mycoplasma/Brucellosis, Candida Albicans
(mycellial form) but I'm not convinced that these are primary.
The main reason for fungal overgrowth in CFS is the anaerobic
environment of the CFS host in which these organisms flourish.
Microorganisms are often present as opportunistic infections that
can also thrive due to a compromised immune system with high
lymphocyte apoptosis (programmed cell death), low levels of
natural killer cells and reduced cytolytic activity (12.3-6)
Fungi are normally controlled by the neutrophils' myeloperoxidase
lyse but I'm not aware of any research into this process in CFS.
MERGE are looking at neutrophil apoptosis.
These organisms are very common in other immuno deficient
diseases such as AIDS.
Nevertheless eradicating candida etc forms the basis of some of
the most worthwhile treatments for CFS.
I think it is plausible that mycoplasmae are ahead of our current
orthodox detection protocols (Polymerase chain reaction (PCR)
identification) and they have adapted in reponse to antibiotics.
Currently only 6 strains are recognized but there are some
complementary practitioners who would say there are 4 times this
number affecting us. The subject of microorganisms species
jumping, as suggested in the aetiology of AIDS, and gaining
potency is an interesting one.
It would be very neat if all CFS was caused by a new micro organism that was not being detected by current testing. But when one looks at the timescale of the disease in many cases following on from obvious toxic exposures, such as sheep dippers, and how all the symptoms and abnormalities are consistent with the known toxin then the microorganism theory doesn't stack up.
Natural and synthetic Toxins
Naturally occurring toxic substances have
always been around and some of these may have been involved in
early Fatigue Syndromes and other illnesses. It's interesting
that Organophosphates were 'plagiarised' from some snake venoms.
Mankind has of course always created a degree of pollution ever
since he lit his first fire.(polycyclic aromatic hydrocarbons
(PAHs) and dioxins) and mined and worked the first metal.
Our body exploits toxic gases such as oxygen, hydrogen peroxide
and nitric oxide for its survival.
The study of volcanic impacts on disease through potentially
toxic products (ie manganese, fluorides) and acidity remains
woefully under researched but is fascinating.
Icelandic disease.
ME has been known as 'Icelandic disease' because of a major
outbreak that occurred in Akureyri, a large town in a volcanic
region of North Iceland in 1948 when 500 people suddenly became
ill. Ironically I visited this town, which was one of the most
intense Rida (scrapie) hot spots on the Island, when I was
researching with my brother in 1998 without knowing this.
My hunch is that this outbreak is related to volcanic and
sub-terrainean change and its toxic products - ie. metals and
fluorides (rather than hysteria). I have read that salads
were/are grown in greenhouses in the volcanic areas of Iceland
and that they are heated by steam from natural vents below
ground. It's feasible that these vents went through an isolated
pollution phase affecting the food products which produced the
ME. A reasonable degree of recovery was seen in these patients
over several years.
Another CFS cluster outbreak at Lake Tahoe on
the California border in the mid 1980s has been linked by Paul
Cheney to volcanic contaminants of local well water discussed by
Phelps(9.91)
The first major introduction of new chemicals and pollutants came
with the 19th century European industrial revolution. Some
studies are showing that PAHs from combustion of fossil fuels (8.4) were widespread and profound as
far back as the early 19th century.
The second major wave was the introduction of synthetic pesticides and related toxic chemicals which became widespread after the second world war. Organo- Chlorine (OC) pesticides were the first to be introduced into common use in the late 40s and some are still used to this day. These were followed by other pesticides ie. the Carbamates, Pyrethroids, PCPs and PCBs. The OCs started to fall out of favour in the 60s due to their bio-concentration in the food chain and persistence in the environment (9.29)and they were gradually largely replaced as the pesticide of choice by OPs, which date back to the 19th century.
The use of pesticides increased over the 60s,
70s and 80s and they became common in every sphere of life. We
can encounter them in the home as timber treatments, fire
retardants, flea collars, head lice shampoo, pest control (9.103,105), spray drift from near by
farmland, food residues, in tap water and gardening products.
During this period Industry was also changing : cleaning up its
act in some respects but also introducing new, under researched
insidious pollutants.ie the change to unleaded petrol
manufacture.
There are many occupations where pesticide exposure could occur:
agriculture - sheep dipping, warble fly pour-ons, worm and lice
treatments, spraying crops/ grain stores/ feed crates, use in
garden centres/nurseries, Chemical manufacture and timber
preservation.
Armed service personnel encountered them in the Gulf War (4),
Aside from pesticides one needs to consider less obvious toxins such as the ubiquitous volatile organic compounds (VOCs) and heavy metals found in many seemingly safe occupations and hobbies -ie Art (9.94-96) and a host of less safe ones - carpentry, car mechanics, welding and printing.
Pesticides
Pesticides: acute and chronic exposure.
I think its worth doing a general summary to give some perspective here.
Most of the research work has been carried out
on the acute affects of pesticides. In the case of OPs they are
well known to bind to the Cholinesterase family of enzymes but
their sphere of damage is far wider than this. (9.110,116) Interestingly there is
variation in the affected locations of cholinesterase. Diazinon
'sheep dip' doesn't inhibit peripheral cholinesterase following
sheep dip exposure (9.104).
Currently Medicine recognises OPs causing an Acute phase
toxicity, a short Intermediate Syndrome, Organophosphate Induced
delayed (poly)neuropathy (OPIDN) and Chronic Organophosphate Induced
Neuropsychiatric Disorder (COPIND) (118), a low dose poorly
defined neurotoxic disorder.
Acetyl, Butyrl and pseudo cholinesterase
enzymes regulate the levels of a neurotransmitter, Acetylcholine
by breaking it down after release at nerve synapses. When these
enzymes are inhibited by an OP Acetylcholine builds up causing
overstimulation of the cholinergic nerves producing tremors and
racing heart and in extremis killing the exposed
individual.
The chronic affects of pesticides are less well covered in
research although this is now improving.
Some of the affects are summarised in the table below.
| Receptor | Agonists | Antagonist | Location of target tissue | Mechanism |
| Nicotinic | ACh, Nicotine, Carbachol | Curare, Hexamethonium | skeletal m, motor end plate, postganglioic neurons, SNS and PNS, adrenal medulla | opening Na+ and K+ channels depolarization |
| Muscarinic | ACh, Muscarine, Carbachol | Atropine | All effector organs of PNS: (heart, GI tract, bronchioles, bladder, male sex organs), some effector organs of SNS: (sweat glands, vascular smooth muscle) | activation of phospholipase C à formation of IP3 à release stored Ca+2, intracellular [Ca+2] |
The CNS effects are confusion and seizures.
The Muscarinic Effects are increased contractions of smooth
muscle, bradycardia, bronchoconstriction, GI tract, increased
secretions of gland cells: lacrimal, sweat, salivary, gastric,
intestinal, pancreatic.
Some Pesticides can cause mutations and sister chromatid exchanges in chromosomes, although there is some dispute about their potency in this respect and which pesticides are a risk. My strong hunch is that there are non life threatening somatic mutations that have not been detected in previous routine testing.
Interestingly a recent pilot study conducted by
Dr Jonathan Kerr of the National Heart and Lung Institute at
Imperial College, London found all 25 CFS patients studied had
over or under activity in between 30-60 genes v controls. These
patients had had Parvovirus infection, which in some cases
produces a long term CFS. This research didn't look at possible
causes of or the nature of these abnormalities. Dr Kerr has also
found evidence for predisposing polymorphisms in cytokine genes
in people who develop CFS after Parvo infection.(12.29,30)
Another study found an association between a serotonin
transporter gene polymorphism and CFS.(14.39)
Pesticides can contaminate fats, organ tissues, bone, nerves and can interact, inhibit (9.121) and cause damage to proteins.(9.27) Most can cause damage through the common biochemical mechanism of oxidative stress by the generation of free radicals (9.16/17/19/20/28/56). This may be the mechanism of genetic damage.
Is it all in the Dose?
Much of the debate is about whether pesticides pose a risk at the usual very low doses encountered in life (9.38/39/109) and to what extent recovery from exposures can be expected. Supporters say pesticides are safe if used in the recommended manner and when the dose is very low - an ideal scenario that is clearly infringed from time to time.
Perhaps the most important factor in the dose
argument has been missed : hosts with rare polymorphisms in detox
enzymes will be far more vulnerable to harmful affects. If one
looks at the toxicity studies this has never been checked. It
would be easy to set up a trial with genetically modified
paraxonase /cytochrome polymorphisms.
Low dose is safe is an oversimplistic maxim that one often
hears.
The long term subtle effects in the animal as a whole are rarely studied, likewise the synergistic affects of many pesticides (9.107) and host biochemical weaknesses are rarely considered by manufacturers.
The tendency is for scientists and governments
to talk pesticide risk down because pesticides are useful, as
well as big business, and the tide of public opinion has not yet
turned against these substances. Smoking of course was once
totally acceptable but is now invoked as a cause or contributory
factor to almost anything.
The trend in pesticide research over half a century clearly
reveals a knowledge base that still grows vastly year by year, in
spite of these substances being in common use for over 50 years
and supposedly adequately tested when introduced.
Quite a high percentage of non organic food and
tap water contains low residues of the more aggressive
pesticides. Occasionally these levels are found to be above the
recommended maximum but supporters argue that sufficient safety
margins are built in.
Organic food is not always totally pesticide/toxin free and may
be produced with low levels of safer long established pesticides.
Organic farms cannot always exclude spray drift from neighbours
and high level toxic precipitations.
The research into the wider scope and mechanisms of affect of
chronic low level pesticide exposure is only slowly being carried
out (9. 38,39,109) and CFS may be one of the
conditions that has been missed so far because it develops later
and is more subtle in its effects.
Much of the extant research is not fully independent and
concentrates on the acute affects of individual pesticides such
as mutagenicity, teratogenicity, toxicity (Lethal dose 50 - the
lowest dose that killed 50% of the experimental animal group),
and in the case of OPs, their anti Cholinesterase affects.
For example I have the OP Mevinphos in my fat cells. Its
extremely toxic, LD50 around 3-10 mg/kg in animals and featured
as one of the 'dirty dozen' pesticides. It was the subject of
heated licensing debate between the EPA and the manufacturer,
which eventually led to its ban in the USA in 1996. In spite of
this high toxicity the EPA can’t yet tell me whether this OP
is 'neuropathic' (ie can cause irreversible inhibition to
Neurotarget esterase, NTE)(9.58/59) or non 'neuropathic', because the delayed
neurotoxicity research to NTE in hens has not been carried out
yet. Mevinphos was licensed in 1957!
Reports in the media have lead
to the withdrawal of long established household insecticides
containing Dichlorvos as we are now told that this OP is highly
likely to be a carcinogen.
Another OP, Diazinon, widely used in sheep
dip and for general pest control for years, is at last gradually
being phased, for similar reasons.(9.99-106)
Another example of the adhoc way in which knowledge of pesticides is acquired is the many changes that the OP Phosmet has now been found to produce in the prion protein. Not surprisingly none of these effects were picked up or dreamt of when it was first licensed.(9.27)
Research by the Medical Research Council is now
starting to find major new protein targets for OPs (9.110)- In particular a 30 and 85kDa
polypeptide. The 85kDa polypeptide is a sub unit of acyl-amino
acid ecopeptidase (ACPH). MRC toxicology unit
These examples demonstrate that we are guinea pigs in pesticide
research and it is totally feasible that pesticides could be
causing or contributing to an array of, not yet fully understood,
non fatal symptoms that are too diffuse and non specific to give
a precise disease name.
A brief internet search into pesticides on Medline reveals a far more complex picture of further affects/target molecules of OPs and OCs which again makes it feasible that they are producing both established diseases (like Parkinson's and Guillain Barre syndrome) and 'new' ones like CFS.
Organophosphate Induced delayed
(poly)neuropathy (OPIDN)
A sub group of OP compounds, which became known as
'neuropathic' OPs, was discovered to produce a delayed neuropathy
with a degree of paralysis, which became known as OPIDN. It
occurs as a 2 stage insult :
1). Irreversible inhibition - phosphorylation of the nerve
membrane protein, Neuro target esterase (NTE).
2). Cleavage of one residual
group from the OP- de-alkylation or aging.
This occurs when approx 70-80% of NTE is inhibited. There is a
delay after exposure before stage 2 is complete (about 3 weeks in
the hen/human)
The first recorded example of OPIDN dates back to the 1930s American prohibition era and became known as the 'Ginger Jake' incident. 20,000 people were severely paralysed or died following exposure to tri-o-cresyl phosphate (TOCP or TOTP) used to shine ginger that made an illegal 'alcoholic' ginger beer.
A type of OPIDN is a convincing explanation for the core condition of GWS (4.2) albeit in variant form precipitated by the unique spread of toxic exposures first encountered in the Gulf War by British and American servicemen.
Most people with CFS notice many similarities
with GWS and OPIDN. I consider that many cases of CFS may in fact
be a milder form of OPIDN in which less than 70% of NTE is
inhibited. At low dose, neuropathic OPs such as DFP will cause
problems whilst not producing OPIDN.(9.109)
More likely to be critical are the inhibitory affects on brain
Na, K and Ca ATPase enzymes and pump mechanisms (9.112) which are linked to the
altered nerve membrane function. In this study the reduced Ca
ATPase level continued right up until full OPIDN developed.
In the CFS scenario the paralysis of OPIDN does not ensue but
calcium channel/pump affects which drive destructive pathways do
occur with limited phosphorylation without dealkylation.
OPs directly affect a second messenger protein
known as calmodulin protein kinase II, (CAM) an enzymatic
catalyst that phosphorylates, and consequently destroys a number
of cytoskeletal proteins in the nerves. (9.60,61,70,71)
Substantial research now shows how the increased phosphorylations
by the neuropathic OP DFP of nerve cells causes neurotubules and
neurofilaments to break down and bind together into nerve tangles
of the type typical of degenerative diseases. It is possible that
the damage to neurofilament may be an artefact and not part of
the precise mechanism of neurotoxicity (9.108)
It has been shown that pesticides can also produce similar conditions to OPIDN such as Guillain Barre syndrome in which there is also peripheral nerve damage usually with auto antibodies to nerve membrane proteins: pyrethroids (9.118), OPs (9.119-123).
Pesticides should, in theory, be quickly metabolised by a variety
of enzymes, but this doesn’t always happen and the
lipophilic varieties may eventually lodge in fat cells and lipid
membranes avoiding metabolism if not broken down. Chlorinated
pesticides are now probably present in the fat of most people and
animals. Fat bound OP residues are found in blood and fat (9.1,99) but are rarer.
The pesticides are not inert but are released slowly into the
blood - the amount would increase with exercise, heat, stress,
dieting etc. The blood levels are low - healthy people might
expect to have 2 or 3 parts per billion (ppb) of an OC
circulating. CFS people might expect 2 or 3 times this. The
question is are these levels high enough to cause symptoms either
directly or via initiation of the cytokine immune response.
In 2 studies R.H.Dunstan et al (9.4/5) found total organochlorines in the blood to be
significantly higher in CFS patients v healthy controls: 15.9 v
6.3 ; and 14.2 v 2.5 ppb. This is an interesting result and it
would be worth seeing if CFS is more prevalent in populations
such as the Inuit, known to have the highest OC concentrations in
their bodies due to their high consumption of contaminated sea
mammal fat (9.29).
It would also be worth including OPs in further studies of this
type as they may be the chief culprit because of their capacity
to phosphorylate and cause mutation.
Rachel Carson foresaw CFS.
In her classic book Silent Spring,
first published in 1962, Rachel Carson carried out a brilliant
survey of the effects of pesticides on the eco-system. Her
chapters on pesticides and human health (11,12,13,14) warn of
many of the adverse effects that were becoming apparent at that
time, and to a large extent have never really been owned up to by
science.
In many ways when I read these chapters I feel she is often
describing CFS type syndromes.
She obviously concentrated on chlorinated pesticides and noted
how OCs have the capacity to uncouple the energy molecule ATP
(chapter 13) leading to fatigue; how DDT derivatives such as DDD
have a strong affinity for the steroid receptors of the adrenal
cortex - she refs studies on this and Ive included some of these
One of the major consistent findings in CFS is
insufficiency/atrophy of the adrenal cortex leading to low, time
shifted cortisol production. In view of Dunstan's studies (9.4/5) above it seems that this may
be because OCs or metabolites have bound into the steroid
receptors here and no doubt elsewhere.
Primary cause and the possible mechanisms of CFS
Type V hypersensitivity?
1. In classical allergy medicine 4 types of
Hypersensitivity are recognized. I'm proposing that this should
be extended to include a Type V Hypersensitivity that defines
MCS/CFS.
The mechanism would explain how minute amounts of toxins can
quickly cause multiple symptoms.
The official view at present seems to be that MCS is
scientifically impossible and the symptoms must therefore lie in
the mind of the patient. I disagree with this.
I think these toxic molecules are acting as haptens following
several exposures sufficient to 'sensitise' the immune system.
The molecules are too small to act as antigens themselves but in
MCS/CFS patient they combine with larger antigenic proteins and
the resultant complex evokes an immune response.
A hapten is a small molecule, not antigenic by itself, that can
react with antibodies of appropriate specificity and elicit the
formation of such antibodies when conjugated to a larger
antigenic molecule, usually a protein, called in this context the
carrier. Antibody production involves activation of B lymphocytes
by the hapten and helper T lymphocytes by the carrier.
This mechanism is scientifically accepted; the link to CFS is
generally not or has probably never been considered.
2. The exposures cause agony mainly in the serotonergic and
cholinergic system which in turn causes damage to some nerve
receptors ie 5HT1A
with a knock on affect for the many systems mediated by
serotonin, acetylcholine and dopamine.
Many pesticides (OCs,OPs) are known to agonise serotonin due to
their inhibition of monoamine oxidases, the enzymes responsible
for serotonin catabolism by deamination (2, p344)-. Similarly they cause the agonisation of
acetylcholine (by inhibiting its degradation enzyme,
Cholinesterase) and dopamine and also the loss of brainstem
muscarinic cholinergic receptors.
see below for more detail.
3. The OP affects the muscarinic cholinergic receptors on the red blood cell (9.23) which overdrives the phospho inositide 2nd messenger signal transduction cycle.
4. Increased Reactive Oxygen Species generated by the pesticide.
Primary damage may occur in receptors in exposed regions of the hypothalamus/pineal body not protected by the blood brain barrier (bbb) /blood nerve barrier, with more serious forms of CFS occuring when the pesticides are able to cross or by-pass these protective barriers as a result of stress and the higher levels of blood pesticides seen in CFS sufferers.
Pesticides are released slowly into the blood
stream from fat storage, adding to daily exogenous exposures from
food, home etc. The effect of this is to tie up degradation
enzymes to a point where they cannot keep ahead in the
detoxification process.
In addition there is a probability that some sufferers have rare
genetic polymorphisms, such as PON 1/paraoxonase, rendering key
OP degradation enzymes less affective in detoxification.(9.42-48). This sets up a chronic
status quo where the toxic parent compound and the often more
toxic first metabolite oxone are free to access
‘pathogenic’ receptors and to deleteriously affect a
wide range of molecules in the body.
I think that in CFS the increased survival time of the parent compounds leads to a widespread pattern of adverse physiological pathways that are related in their mechanism to neurodegenerative diseases but differ in location and are usually less severe.
The primary damage to hypothalamic/pineal body leads to dysregulation of a number of body functions, dependant on the lesioned area, associated with CFS : sleep patterns(7), temperature control/vasoconstriction and dilation, sweating, osmotic regulation, ionic balance, mood, heart rate, gut motility and oxygen transport.
I would predict that pesticides are also
capable of initiating the kind of destructive cellular cycles
which are starting to be recognized as characteristic of CFS such
as the 2-5OAS/ RNaseL. Some toxins are known to do this.(9.91) It
is likely that this would occur via upregulation of cytokines
such as TNF alpha. The secondary abnormalities are many and
usually involve the immune system and the nervous system. (12.10/11, 14.11)
All pesticides and many toxins are known to exert Reactive Oxygen
species (ROS)(1) as well as having specific affects, and this is
a common mechanism of damage. ROS such as nitric oxide (NO)
produce widespread secondary and tertiary affects that also
contribute to the many symptoms of CFS. These lead to severe
compromise to oxygen transport and tissue damage.
The Serotonergic, Cholinergic and Dopaminergic receptors :Primary damage in CFS?
Serotonin or 5Hydroxytryptamine (5HT) is a
monoamine neurotransmitter concerned with cholinergic and
adrenergic regulation and its receptors are concentrated at
specific sites in the body, many associated with CFS- The
chromaffin cells of intestinal mucosa, smooth muscle particularly
in the gut which it constricts(2) and it's also found in blood
platelets and mast cells.
Studies have found abnormalities in serotonin's mediatorial role
in CFS particularly in relation to the HPA axis(11.12/21); serotonin transporter gene
(14.39)
Low/ disturbed 5HT metabolism (11.2)(also Acetylcholine ) is linked to mood
swings/depression and anxiety which are common in CFS.
5HT is biosynthesised from the amino acid L-tryptophan. There is
evidence that OPs such as Diazinon interfere with tryptophan
metabolism by inhibiting a liver enzyme, Kynurenine
formamidase.(9.53/54).
5HT also has an absolute requirement for a healthy molecular
oxygen level in tissues. (2 p345)
I am proposing that a central feature of CFS is O2 depletion due
to erythrocytic sacrifice and oxidation of haemoglobin to
methaemoglobin (6.1/2/3) or poor release of O2 from haemoglobin's ferric ions :
this would further limit 5HT production.
There may also be abnormality through mutations in one of the
enzymes involved in the RBC's hexose monophosphate shunt -
glutathione peroxidase, diaphorase 1 and 2.
O2 is also used in production of some ROS such as NO which are
likely to be up regulated in CFS via cytokines.
This oxygen depletion would also drive glutamate and the
excessive NMDA receptor firing.
Finally it would necessitate anaerobic respiration. I had a
myothermogram test which indicated that in one simple muscle
movement of the arm the muscle was in anaerobic mode.
Most of these scenarios have been found in CFS.
The affects on serotonin by OP pesticides and the consequent
disturbance of serotonin's mediatorial roles has been noted as
important in TSEs and ME/CFS (9.15) in relation to adrenocorticotrophic hormone (ACTH),
prolactin, melatonin, T lymphocytes and interleukins.
Some studies have been carried out to compare 5HT receptor
mediation in CFS and clinical depression (14.2, Bakheit et al) and OP induced
neurobehavioural syndrome and CFS and controls (9.92/93, Behan). The former looked
at the release of a hormone prolactin (mediated via 5HT1A receptors) in response to an
agonist, Buspirone, and found that the CFS group differed from
depressed/control group. The latter found an identical pattern of
release between CFS and OP exposed (using buspirone,
dexamethosone and pyridostigmine ) v controls, suggesting that
these receptors are similarly affected in the 2 conditions as
distinct from controls and in clinical depression.
Other studies have supported these findings.
Behan noted that there was an inexplicable delay, sometimes of
months/years between OP exposures and onset of symptoms. An
explanation of this might be that the permanent receptor damage
is not directly attributable to OPs but is caused by a long term
mild serotonin/acetylcholine agony.
The affect of chronic overdrive in serotonergic nerves is to
reduce binding efficacy of and to lose serotonin receptors as a
defense against the neurotoxic status quo. This can deplete
serotonin turn over and would result in altered levels in
hormones and cellular affects mediated by serotonin such as the
brain's pineal gland and melatonin, the
Hypothalmic/Pituatory/Adrenal axis, gut wall, and would be likely
to cause some of the extensive systemic abnormalities of CFS. Add
to this the reduced oxygen availability and possible interference
of 5HT biosynthesis via the Kynurenine pathway at the very least
one would expect disruption to 5HT levels.
The Hypothalamus in CFS
Many studies have now found damage to this part of the brain in
CFS, known to be important as the emotional/autonomic control
centre in the brain. As would be expected there are abnormalities
in its mediatory axes such as the pituitary/adrenal axis in CFS
(11.2/12/21)
The hypothalamus regulates the anterior pituitary gland by
secreting several hormones such as- growth hormone releasing
factor (GHRF), Somatostatin, corticotrophin releasing hormone
(CRH), prolactin inhibitory factor (PIF). These hormones act on
specific anterior pituitary secretions- growth hormone (GH),
thyrotropic hormone (TSH), adrenocorticotrophic hormone (ACTH),
prolactin (PRL).
In one study (9.80)
the OP DFP was found to disrupt severely anterior pituitary
hormones depressing PRL, TSH, GH, luteinising hormone and raising
ACTH and cortisol implicating cholinergic modulation.
The hypothalamus also links to the posterior pituitary gland
which secretes vasopressin (anti diuretic hormone ) and oxytocin
both of which are often disrupted in CFS.
The levels of pituitary hormones are influenced by negative
feedback on the hypothalamus based on hormonal blood levels and
by direct factors such as toxins, drugs, circadian rhythms and
stress.
Parts of the Hypothalamus are especially vulnerable to toxins
such as :
Hypothalamus and yawning (16.1-6)
Interestingly I yawn excessively and the
hypothalamus is thought to be involved in this action. Research
has shown that some neurotransmitters such as dopamine,
excitatory amino acids, such as NMDA, nitric oxide and
neuropeptides increase yawning if injected in the hypothalamus of
animals.
Also linked with yawning response is both stretching and penile
erection, although the I wouldn't describe myself as an excessive
penile erector and have never noticed a link with yawning.
The Hypothalamic/pituitary/adrenal
axis.(11.12/21) CRH > Adrenocorticotrophic
hormone ACTH > Cortisol.
Growth hormone (11.2)
Many studies have found abnormalities
in the HPA with low Cortisol - an adrenal
glucocorticoid stress hormone linked to circadian input via the
hypothalamus.(10.9, 11.1/2/39/40) The cortisol output curve is often shifted in the 24
hour cycle suggesting secondary or tertiary adrenal insufficiency
(11.42/43)
My cortisol is very low in the early morning and
it rises gradually just hitting the
bottom of the reference curve mid afternoon. (12 hour out of
sync) This is the opposite of normal but is typical of CFS.
This suggests several lesions -suprachiasmatic nucleus, control
loop CRH/ACTH.
I chose a typical working day for the test -average stress, but
the very low cortisol result indicates adrenal
insufficiency/atrophy.
Rachel Carson noted in her book Silent
Spring how some OCs like DDD, a breakdown product of DDT,
were especially toxic to the adrenal cortex and a number of
studies have borne this out and found wider damage to the HPA
axis.(11.27-35) As
noted above 2 small studies found that CFS patients have much
higher levels of OCs than controls.
Hontela et al have also found in several studies in fish and
amphibians that pesticides and heavy metals affect HPA axis,
particularly via upline ACTH or cAMP impairment,lowering cortisol
by different mechanisms - Cadmium (11. 26) glutathione protection
(11.27), endosulfan (OC) (11.30,34) and atrazine(11. 28), the OC o,p'-
dichlorodiphenyldichloroethane o,p'- DDD (11.29,
31), various pesticides (11.32, 35) poor cortisol stress response
in presence of PAHs, PCBs mercury (11.36)
As adrenocorticoids have been found to exacerbate the
neurotoxicity of OP in hens (11.25) it may be that the body is lowering cortisol as a
defense mechanism to reduce ongoing OP damage.
The adrenal corticosteroid stress hormones, cortisol
and DHEA and other hormones are produced in large
amounts after traumas and interact together with the cytokines.
Cortisol is vital for maintaining blood pressure, blood sugar
level, body fluids and electrolytes and damping down the immune
system's excessive inflammatory response.
Stress is an explanation often offered, along
with clinical depression, for CFS by
physicians and is clearly wrong in this scenario. Both stress and
depression have been associated with adrenal swelling whereas CFS
has been found to produce adrenal atrophy and produce different
profiles. (10.1/5,
11.9).
However both cortisol and DHEA have been found to be low in CFS
patients and this would no doubt result in a compromised stress
response for such patients. My hunch is that the atrophy of the
adrenal has been caused by the toxin. Many pollutants would be
expected to build up in the kidney.
Pineal gland.
(2 p344)
The pineal is one of the most highly serotoninergically
ennervated zones in the body and contains all the enzymes for its
role to secrete melatonin, a hormone and anti oxidant that
modulates sleep, from serotonin. In CFS increased sleepiness and
disturbance in sleep pattern is very common.(7.1,2,5)
Darkness stimulates melatonin via up regulation of cyclic AMP
through the adrenergic sympathetic innervation, light has the
opposite affect. OPs also up regulate cAMP and serotonin and this
gland would therefore be a prime candidate for receptor lesions
in chronic pesticide exposure, being situated on the risk side of
the bbb where it would be particularly vulnerable to toxins in
the blood.
Intolerance of and even violent reactions to bright lights is
another common symptom reported in CFS, also an affect seen in
some OP poisoning.
A further possible explanation for the increased sleepiness ('feeling as if I have been drugged' is a common comment) in CFS (7.1,2) could come via the ability of some OPs to inhibit fatty acid amide hydolases shown in a study in mice (9.106) This would lead to increased oleamides and anandamides which would enhance sleep and analgesia respectively.
Oxidative stress and free radicals -
There is growing evidence that free radicals
are involved in a number of diseases such as Alzheimers,
Parkinson’s, Heart disease, TSEs and CFS.
In CFS patients Richards et al (6.1/5) found
increased methaemoglobin (associated with general symptom
expression) and malondialdehyde, 2,3-diphosphoglycerate that were
associated with brain symptoms such as sleep disturbance. The
same group found that the red cell itself could protect against
superoxide if the cells' glutathione system was intact and the
radical could permeate the cell membrane (6.2) which led to their hypothesis of a superoxide channel
in red cells enabling the cell to function as an antioxidant.(6.3).
A similar pattern of stress and inhibition
would exist in lymphocytes when glutathione reserves are over
stretched (13.12) by
ROS and competition from skeletal muscle.
Pesticides, herbicides and many other environmental toxins
(naturally occurring and synthetic) are known to be potent
generators of free radicals. Besides red blood cell work (6.1/2/3) other interesting work is
starting to focus on Nitric oxide-peroxynitrite and hydroxyl
radicals (6.8) This
scenario would fit well with pesticides as a primary insult.
The toxic gas Nitric oxide (NO) is essential to
life in short, controlled bursts. It is produced by the 3 Nitric
Oxide synthase (NOS) enzymes in many cell and tissue types with
oxygen, arginine and NADPH as co-factors.
Inducible NOS (iNOS) /NO can be induced by cytokines (6.12/14) that are elevated in CFS -
IFN-gamma, TNF-alpha and IL-Ibeta. The OP DFP and carbofuran,
were found to increase NO in several regions of the brain with a
corresponding decrease found in high energy phosphates ATP and
phosphocreatine.(9.97)
This reduction in high energy phosphates is central to muscle
weakness and would crrelate with the lack of energy of CFS.
Nitric oxide is also thought to affect ion channels and up
regulation might lead to decrease in depolarisation value of
muscle fibre nerves.(13.11)
OPs do much of their damage by disrupting intracellular signalling and I consider this to be a major feature of CFS. The starting point for this is the calcium channel in cells and the raising of intracellular Ca levels- which enhance levels of PKA and Calmodulin kinase II for example. Some of my first investigations in my own case were into intracellular ions and I found considerable abnormality in red and white cells. Lymphocyte Ca was way above reference; RBC Ca and Na were right at the top of the reference with deficient K and Mg levels.
Neuronal and endothelial NOS produce NO in response to increases in intracellular Ca which leads to increase in calmodulin which binds to NOS. iNOS is independant of Ca but does depend on calmodulin binding and it does result in higher concentrations of NO. OPs upregulate both Ca and Calmodulin in the cell and I consider that this is producing greater quantities of NO which are producing some of the affects seen in CFS. Low blood pressure would be expected via eNOS. The requirement for oxygen raises the point about how this pathway is driven and is this just another way in which O2 is being used up or is the already depleted O2 a limiting factor. Hypoxia on its own does not increase iNOS but it does seem to indirectly affect the enzyme via cytokine modulation of NOS.(6.12)
There have been some reports of defects in the
mitochondrial membrane enzymes, transport proteins, and structure
in CFS. The mitochondria are the power centres of the cell
involved in ATP production and respiration. They're located close
to the inner cell membrane adjacent to sites of maximum ROS. They
also have their own DNA (37 maternally inherited genes) which is
vulnerable to damage from ROS and they lack effective repair
mechanisms making them candidates for somatic (non inherited )
mutations.
Energy production is by electron transfer between a series of
proteins – complex 1-4 with enzymes such as co-enzyme Q 10
and involves oxidative phosphorylation. When the output of ATP
drops this is reflected by a reduction in the transmembrane
potential (TMP) both in the mitochondrion and the cell. This
further affects the N-Methyl d-aspartate (NMDA) receptor that is
stimulated by a neurotransmitter called glutamate. O2 depletion
seems to be involved here : Glutamate production is known to be
stimulated by oxygen deprivation, such as in stroke or this may
also be the case to a lesser degree in CFS where I think the
sufferer crosses an aerobic/anaerobic threshold very quickly.
L-glutamate is also thought to regulate the resting potential of
nerves controlling skeletal muscle.(13.11) Excess glutamate and NMDA reducing depolarization by
approx 2/3. This is thought to be via NMDA activated Ca2+ influx
NOS and finally NO which may affect the ion channel proteins.
A vicious cycle thus becomes perpetuated as reduced circulating
oxygen due to haemoglobin oxidation and poor RBC movement through
capillaries promotes glutamate production and overstimulation.
Reduced oxygen metabolism has been found in CFS.(13.5) I had a myothermogram carried out at the Bio Lab which detects abnormal muscle oxidative metabolism. As expected my muscle was abnormal in this respect and started anaerobic metabolism very early.
In CFS there may be overstimulation of the NMDA
receptor. The normal balancing inhibitory effects of the GABA
receptor firing are exceded. GABA neurones are sensitive to
cytokines such as
IL1beta and hormones, GHRH (11.26). The result is that much
weaker stimuli start causing neuronal firing which leads to
hypersensitivity. In the extreme this would produce continual
firing or stroke.
This may explain many of the hypersensitivity symptoms of CFS -
pain sensitivity, irritable bowel, light and sound sensitivity.
This is supported by the efficacy in some sufferers of drugs that
downregulate/block the NMDA channel - Magnesium sulphate,
benzodiazipines, melatonin and calcium channel blockers. There's
a Zinc (Zn2+) inhibitory divalent cation site on the receptor(2)
and Zn could have potential as a therapy.
Glutamine/ L-glutamate stimulate the receptor and the author's
experience of taking this supplement once were marked up-
regulation of pain- so beware.
The glycine binding site on the receptor is also attracting
interest and kynurenate, a metabolite of tryptophan, an
endogenous brain chemical, is proving a good inhibitor of
NMDA.(2)
Magnesium
(magnesium site )
Magnesium has been studied in relation to CFS and has been
reported by some to be at low level in CFS sufferers and to be a beneficial therapy as
an intramuscular injection. (13.29) A follow up study by a different group (13.30) found normal Mg RBC levels in
CFS patients and concluded that MgSo4 was not an appropriate
treatment as there was no Mg deficiency.
I'm not convinced that there is often total body Mg deficiency,
(mine is normal) but this does not mean that Mg is not a useful
therapy.
The point here is that transport of Mg, and other ions, in and
out of cells is likely to be erratic therefore intra cellular
tests for overall status would not be reliable. A test for the Mg
level in the RBC of a CFS patient would not necessarily tell you
the overall body level of Mg. It tells you more about the ion
channel function for the cell at the time the sample was taken.
If the channels are working and mechanisms for mineral
reabsorption from the kidney and from bone are also working then
the body would be expected to nab Mg and other ions when
necessary to service vital cells.
If I'm correct then in CFS you would expect Ca to be high with
fluctuating Mg and K, Na within white and red cells through
leakage, expulsion - in short you would expect ion channel damage
generated by continuous toxic presence or past mutation that
produces changes in channel proteins.
A better protocol would be to test all ions in plasma, RBC and
hair. If Mg was low in all three then you're looking at Mg
deficiency. Normal Mg in plasma, but low in RBC tells you the
channel or associated mechanisms are abnormal.
In the end testing levels may not be so
important as MgSO4 has a range of very useful pharmacological
affects when Mg is normal. Research (13.31) shows how effective Mg So4 is as an anti arrhythmic
when plasma Mg is normal; 13.29 and anecdotal reports suggest it is effective in some
CFS cases.
In my view it is the sulphate that is mopping up toxins and
reducing their downline affects and that it is the extra free
ionised Mg, (13.31) as against the protein bound fraction, that is
blocking the overstimulated NMDA receptor - it is not to do with
correcting a deficiency.
Mg SO4 has many other positve properties that may be contributing
- mild vasodilatory properties, aids K absorption and has been
found to be a beneficial treatment in many conditions such as
sensorineural hearing loss (13.23), migraine (13.24), tetanus (13.27), asthma (13.28), some heart arrythmias (13.31,32)
My own cell studies done at the Bio Lab revealed RBC Ca and Na right at the top of, but just within the reference range with Mg and K just below ref range. Lymphocyte Ca was way above the top of the ref. range, but other ions were within normal range. These tests were performed at different times. Also de-polarisation studies on my cells done at the same lab showed that my Ca transport was severely disrupted and that adding extra cellular Mg made things worse! I'd previously had a course of 9 injections of Mg SO4 (1g.injections for about 3 months) that had no affect on any symptoms.
Red Cell Morphology (3)
Following on from ionic disruption you might expect Red cells to be abnormally shaped, or rather the proportion of the various shapes to vary v controls. In fact in CFS they resemble shapes found in marathon runners (3.1) temporally close to exercise suggesting oxidative/anaerobic stress.
Many chemicals such as hormones, neurotransmitters, xenobiotics are reported to affect the osmotic fragility, deformability and gross membrane structure of the red blood cell. These changes indicate compromise to many cell functions and are also characteristic of apoptotic cells (in which all function has ceased) These effects can be mediated very quickly and give rise to profiles indicative of CFS. Morphology is constantly changing and would be dependant on changes in OS.(3.1-3)
Cholinergic muscarinic agonists such as carbachol and OPs increase the cellular cation permeability of Na (9.23) for example which in turn can trigger the release of intracellular free calcium and cyclic GMP. The influx of calcium into the cell is one of the most important steps leading to increase in membrane rigidity, shape change, metabolic rates, electrolytic contents enzymatic activity.
Some cytokines also seem to cause calcium influx to some cell types. (12.31,14.24)
Such stressed red blood cells would have reduced oxygen levels binding to haemoglobin and this could explain symptoms of dizziness/excessive yawning there being insufficient healthy cells to deliver enough O2 to the brain. The cells also show increased viscosity in cell membranes and stiffen so that they are unable to penetrate the smallest bore of blood capillaries at the extremities- hands, feet and brain. The RBC are wider than the bore of the capillaries and there is consequent difficulty for rigid cells to reach the extremities. This could explain cold hands/feet, dizziness and possibly also tingling sensations in these areas.
I had my RBC morphology checked out and found considerable abnormality in the numbers of different cell shapes, the most significant being a very high number of flat cells. I haven't yet worked out the dynamics of this although I think it would be possible to work back from the shape to the exact location of the stress abnormality.
Is CFS exacerbated by mitochondrial damage
caused by pesticide/toxin induced ROS?
There's some evidence for mitochondrial damage in CFS.
Mitochondrial mutations can be directly inherited or they can
develop gradually building up in certain tissues over a lifetime
- somatic mutations.
These non inherited mutations are rarely life threatening, and
its feasible in CFS that pesticides,VOCs heavy metals are causing
such a mutation to the gene encoding for one of the respiratory
chain proteins. Many ubiquitous OPs and OCs have a high
probability of mild mutagenicity in humans. Its also feasible
that OPs' phosphorylations may be interfering with oxidative
phosphorylation itself.
The nature of these site specific mutations is to reduce ATP
production in the cells long term. Because the by products of the
respiratory chains are reactive oxygen free radicals and these
increase when a pathogenic cycle is set up with the radicals
continuing to damage mitochondrial DNA and perpetuate the
problem.
In CFS it seems likely that higher levels of
circulating pesticides and immune chemicals ( interlukines and
interferons) and other toxins are producing high levels of ROS
near the mitochondrial sites of DNA. This could be inducing
irrepairable strand breaks and mutations and a release of
cytochrome c and triggers the elevated apoptosis often seen in
CFS.
Serum L-Carnitine is at low levels in CFS. (13.13/14) This amino acid has
important protective properties for mitochondria as it suppresses
mitochondrial membrane permeability and cytochrome c release,
inhibiting apoptosis.(13.33) The low level would seem to indicate that excessive
demands are being made on carnitine to combat mitochondrial ROS
effects.
The body's first defense to ROS is to invoke anti oxidant supplies and degradation enzymes. There's a consequent further defense mechanism where the body reduces the stress from normal aerobic respiration by switching to the inefficient 'anaerobic mode'. This is a damage limitation exercise resulting in the lesser damage of lactic acidosis with its accompanying discomforts muscle pain/stiffness central to CFS and life compromises ie you are unable to exercise.
Stamina and weakness in CFS
The principal symptom of CFS is pronounced continuous (6 months and over) muscle weakness that is not alleviated by rest. There are several possible explanations for this. The first is compromised ATP production proposed above as a result of up regulated RNaseL pathway described below - immune dysfunction (9.97)
In CFS (and hepatitis C) low levels of serum
acyl carnitine are found (13.13/14) that relate to symptom
severity .This amino acid is important in intramitochondrial
coenzyme energy production of skeletal muscles and could be one
factor.
Another relevant factor is the failure in CFS to regulate the
cellular ingress and egress of ions – Potassium (K+),
Calcium (Ca 2+), Sodium (Na2+), Magnesium (Mg 2+) and Chloride
(Cl -). The cell must achieve the correct balance of ions
necessary to maintain a reasonable potential difference across
the cell membrane. It is from this resting position of
equilibrium, known as the Nernst potential (around -50 – 70
milli volts), that it is able to generate its signalling by
action potentials to muscles, glands and organs.
Ion channel abnormality has been proposed as a cause of CFS (14.3/7)
The role of calcium ions has been widely
studied in relation to several conditions. In CFS you would
expect to find high intracellular calcium (may still be within
reference range) Similar compromise knock on effects may well be
in the endocrine system. This mechanism may explain why so many
hormones are found to be low or deficient in CFS. Ie.Thyroxine,
Cortisol, DHEA, CRH, ADH.
Basal ganglia dysfunction in neurological diseases is often
associated with fatigue. One study found a highly significant
increase in choline containing compounds in CFS basal
ganglia.(14.41) Yet again focus brings to bear on the cholinergic
system in CFS.
Immune dysfunction
(12)
A consistent finding in CFS research is the activation of
part of the immune system but with a reduction in natural killer
cell (NKC) number/activity.
NKCs lytic activity is mediated by cytosolic serine protease
enzymes. As would be expected OPs bind strongly with these
proteins (9.79/80/81)
and it seems feasible that where OPs are present in the blood
that this would result in some binding and inhibition of NKCs.
NKCs are however found to be compromised in a number of other
scenarios - ie. in response to silicone (9.66)
OPs are also involved in other types of immune suppression (9.74)
Cytokines are soluble immune proteins that the body produces to fight invaders. They are secreted mainly by activated white immune cells - lymphocytes, monocytes and macrophages and form part of defense against pathogens, cancer, auto-immunity (12.28). They act on many target cells and are frequently found to be over or underexpressed in CFS. Unfortunately cytokines produce side effects that could account for many of the symptoms of CFS.
Many cytokines are activated in CFS. ie TNF alpha, (12.8) IFN alpha. In theory when the antigen is removed the cytokines are switched off. In PVFS when the virus is destroyed the cytokine and other immune pathways don't switch off.
Cytokines can either be Pro-inflammatory having
a stimulating effect on the inflammatory response.ie. tumor
necrosis factor (TNF), interleukin-1(IL-1) and IL-6.
The anti-inflammatory cytokines IL-10, IL-1ra (IL-1-receptor
antagonist) and TNFsr (TNF-soluble receptors) are also produced
by lymphocytes, monocytes and macrophages.
They act by lowering or blocking the inflammatory response,
either by inhibiting the production of the pro-inflammatory
cytokines, indirectly by neutralizing circulating
pro-inflammatory cytokines or by stimulating the production of
receptor blocking cytokines IL-1ra and TNFsr.
They are involved in many CFS symptoms ie sleep disturbance (7.7,8) and are also well known to
induce some of the potent free radicals such as nitric oxide. As
mentioned above some cytokines also seem to cause calcium influx
to some cell types. (12.31, 14.24)
Cytokines can also be released in response to exercise stress
from the muscle cells.(12.32)
My theory here is that a toxin albeit at low
level and that had been present prior to the viral illness, now
presents as antigen and drives the response.
The other alternative would seem to be that the antigen
recognition switching mechanism is somehow 'locked'. The
overactivity of the immune pathways may well explain many of the
core symptoms of CFS. The question is why does this cycle
continue after the virus is apparently destroyed and this is
where I think low levels of pesticides /toxins come in.(9.7/8/9/10/11/14/15/21/32/)
RNaseL pathway
One of the most interesting fields of research is looking at abnormalities in a normal IFN alpha - induced anti viral/anti cancer pathway - the 2-5a synthetase (2-5OAS), RNaseL, protein kinase R( PKR) pathway (5).
Several researchers (5.2/3) have found the presence of a low molecular weight 37KDalton (Kda) protein at high levels in patients in the absence of viral infection and cancer. It's not strictly a marker for CFS but in controls it is rare and present at low levels. There also seems to be a correlation between severity of symptoms and the amount of the 37kda protein present. It seems likely that the structurally similar lmw protein is cleaved from the 80kDa protein, as the latter reduces proportionally as the former increases.
The defensive enzyme RNase L is activated by the binding of 2-5OAS. Once activated, RNase L normally attacks and degrades viral mRNA, inhibiting viral replication as well as initiating apoptosis and killing the virus by killing off cells in which they reside. The enzyme is non specific and therefore can degrade mRNA of host cellular proteins as well, leading to reduced protein synthesis. This 'blunder-bus' approach is acceptable during the usually short term viral purge but if it persists, damage to protein synthesis and to ATP production will ensue.
Another protein, RNase L Inhibitor (RLI) is thought to oppose the proliferation of 2-5OAS/RNase L. A study by Vojdani (5.5) found a decrease in mRNA for RLI in CFS patients and this was in inverse relationship to RNase L/ 2-5OAS activity. The lack of RLI may therefore be responsible for the excess of the other enzymes. The final phase of the RNase L anti viral pathway is apoptosis or cell suicide.
This pathway would be normally up-regulated to combat a virus but should subside when the virus is eliminated. In PVFS the up regulation continues for some reason. The result is a longevity and over production of inappropriate immune cleaving chemicals, that themselves can produce symptoms of the syndrome by killing off too many cells, disturbing protein synthesis and critically, ATP production.
There is an element of non specificity because some toxins can also activate this anti viral pathway (5.4, 9.11) My strong hunch is that OPs and possibly organochlorines (OCs) if at a high enough level will also do this. Whilst a virus initiates the normal up regulation of the pathway the presence of higher than average endogenous toxins in these patients, such as pesticides, keeps these pathways active. Most physicians pronounce the emerging CFS patient 'well' when the virus has been destroyed : the standard tests don't pick up the abnormalities now experienced by the sufferer.
Kinases
Kinases are a very important protein group in cell signalling and
they activate various targets by phosphorylation. Some are
capable of auto phophorylation.
Pesticides and transition metal salts have been shown to activate
key signalling proteins such as protein kinase C involved in cell
proliferation and lipid hydrolysis.
UV activates a stress induced kinase (PERK) which phophorylates
an initiation factor for protein synthesis, eIF-2. This is a key
switch thought to govern much cell proliferation, apoptosis and
protein synthesis.
If OPs are present at 'pathological' levels then it could be that
they are capable of phosphorylating the kinase targets such as
eIF2 or even kinases themselves and initiating the destructive
pathways. Normal Kinase phosphorylations would be under careful
control of homeostatic balance and immune modulation.
Apoptosis
Apoptosis is a normal, non specific process
where the body kills off selected cells. It provides a mechanism
for controlling the number and types of active blood cells, as
well as for the elimination of virally infected cells. Genetically it's promoted by
certain genes ie p53, p73 and opposed by others bcl-2, bcl-x.
Environmentally a number of factors and agents can trigger
apoptosis as a defense mechanism ie viruses/ bacteria, all
pesticides, radiation, heavy metals and chemotherapy. Cellular
respiration itself induces mild OS and can drive apoptosis.
Apoptosis is characterised by cell shrinkage, changes in cell membrane viscosity (to stiffer, distorted shapes), dysregulation, reduction of ATP, reduction in oxygen transport. Apoptosis also represents a defense mechanism against cancer by up regulating apogens and encouraging cells to die.
Vojdani et al. found high levels of lymphocytic apoptosis - up to 50% in many CFS sufferers.(9.8) 50% of my lymphocytes were found to be apoptotic.
In healthy individuals <10% of the lymphocyte population are undergoing apoptosis and a further 1or 2% represent necrotic cells leaving about 90% to carry out lymphocyte functions. When the apoptotic proportion increases the same functional loads, such as immunity fall on a small number of healthy cells.The logical outcome of this is reduced efficacy in these areas which equates with many of the reported symptoms of CFS. White cells may be up-regulated to compensate.
I thought it was highly likely that apoptosis
was relevant in my CFS - the logical end-point of the high cell
calcium that I have.
I approached an immunologist, Dr Ruben Valeta Calvino (Kings
College Hospital, Rayne Institute, London) whom I knew from BSE
work. His colleagues were able to carry out a standard flow
cytometric test on a sample of my blood using Annexin V and
propidium iodide stains to identify apoptotic populations of
Lymphocyte cells.
Only one control was used (but normal values are well known). Result: 49.57% of my lymphocytes were found to be apoptotic with 1.78% being necrotic. ie.expressed annexin V.
The control person had 6.28% apoptotic cells with 0.72% being necrotic.
In my case the figure is very high and I think one could extrapolate in reverse to raised 2-5a synthetase and RNase L levels and I suspect up regulation in the phospho -inisotide signal transduction pathways and toxin derived ROS as being ultimately responsible. Ultimately I suspect mutations underly this result due to the consistency of the symptoms.
Therapy.
There's no obvious course of treatment for CFS. Few GPs take much notice of CFS and no-one knows how to treat it. There are some Doctors and alternative practitioners who can be contacted privately and will offer various treatments.
The standard NHS treatment is graded exercise,
Cognitive Behaviourial Therapy or anti-depressants ie SSRIs. My
personal opinion is that the former 2 are a waste of time and not
supported by any good scienctific or anecdotal evidence. There is
some evidence that low dose SSRIs such as Prozac can help.
I was unable to tolerate Prozac (stomach burn) and even at very
low dose I was becoming jumpy and aggressive and the drug made no
difference to any symptom so I stopped.
One interesting therapy for someone with
pesticide exposure is that of heat depuration (Sauna/massage)
which mobilises fat bound pesticides into the blood stream for
metabolism and excretion.(8.3) Most people won't be able to participate in the full
regime in this paper but some CFS sufferers attest to benefit
from a course of saunas. There's evidence that it does help lower
pesticide levels in the body and some sufferers do improve. I
tried this for 3.5 months and it didn't help. If irrepairable
mutations have been caused by the pesticide then this wouldn't
help much.
Therapy aimed at 2ry infections such as Candida fungus or Mycoplasma bacteria seems worth a try because it is relatively easy for a month or two. Polymerase chain reaction testing for mycoplasma activity is available in the UK and US. Its not too expensive but may produce a false negative. Testing for candida overgrowth is usually via a gut fermentation test and case history.
Some non prescription and prescription anti
fungals are available in addition to some dietary manipulation.
Doxycycline is the anti biotic of choice for mycoplasma, but a
course for a month or two is recommended. There's quite good
evidence (mainly anecdotal) that when appropriate these
treatments have beneficial effect on some symptoms.
I found some benefit, for 2 to 3 weeks, from very low amytriptilene. 5-10 mg per day is all I could tolerate. This had quite a strong effect on my muscle power. I could climb a stair without thinking about it - first time in a decade! It also makes you a bit high all the time, which is a mixed blessing because you are not really in control. Unfortunately the affect on my muscles wore off completely and I discontinued the treatment. I think this worked because of its anti cholinergic affect.
One approach I looked at was the reduction of cytokines. I get a lot of headaches and often took various painkillers. Something I noticed was how my excessive urination returned to normal for about 12 hours after taking the tabs, as well as some small benefit to fatigue and other symptoms. About that time I was looking at cytokines in CFS and found that one of the most effective blocking agents of cytokines is ibuprofen. This is probably the mechanism of benefit. I now take ibuprofen from time to time when I am very low or when I need a bit of a kick start for going out - one 200mg tab seems to do it.
This one is unusual: Some red wine has had a similar powerful affect to amytriptilene. I discovered this by accident twice. Both times the drinking was over several hours and not excessive. The second wine was a Cotes du Luberon and I'm investigating the chemistry of this. My best guess is high pro antho cyanidin anti oxidants are perhaps very well absorbed from this wine when delivered over a period of hours. The affects lasted for a couple of days.
If I am correct in pointing to genetic abnormalities as driving CFS then strategies involving gene therapy may prove to be the only real solution.
It is essential to conduct some studies into genes and CFS. Micro array scans might be a good place to start because you can scan the activity of thousands of genes easily. Likely candidate genes, of which their are many, could be specified. I'm still looking for a lab to do this for me for.
Conclusion
All the pathways that are activated in CFS and the kind of systemic damage and the nature of the symptoms are consistent with a toxic cause. In some cases there is no question that a 'CFS' is produced by the toxin. I would argue that toxicology, already a highly specialised field, is sometimes just so complex by virtue of the timescales, the cross reactions, the dose affects, the potential breadth of systemic effects, the lack of research, that it is virtually impossible to pin down a cause. It doesn't follow that CFS doesn't exist just because it is not as simple, like mumps or measles.
It's unfortunate that if you have CFS the NHS does not welcome you. You're effectively dumped. I've found Scientific curiosity to be totally absent here and I've heard some of the most crass, ignorant and insulting statements emanating from the medical establishment on CFS. Hence I get on with things myself.
Clearly if someone has permanent 50% apoptosis
levels, intracellular Ca way up and cortisol way down and out of
sync etc etc then they are ill. Aren't they?
These kinds of result are non specific, but so what, such a
person is obviously ill and needs recognition, support and
treatment.