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'paper' on CFS/ME- the brain?

Hi, this is the paper I wrote last Spring 2016 during a month when I was too sick to work but well enough to sit at the dining table with a laptop and textbooks. It was written partly to educate the biochemist team at work about CFS/ME, partly as a platform for me to explore ideas and partly to keep my brain alive. It is flawed, speculative and incomplete but there is some interest (I think..). thanks to my wife for digging it out of the attic and typing it up.

Please note, my wife couldn't find the references page and gave up after one hour of cursing my untidiness. All numbered reference are valid however, sorry you will have to google if you wish to explore more deeply. I apologize for that but it is worth the time and effort for information topics you find of interest.


Pathogen tropism for the hypothalamus and associated limbic structures can result in Chronic fatigue syndrome (CFS) and myalgic encephalomyelitis (M.E.)


Premise: pathogen-immune system intervention mediates cell damage resulting in disruption to key areas of the brain's internal regulatory system. This dysfunction manifests in a broad spectrum of symptoms typical in CFS/ME patients.


CFS/ME remains the source of much controversy in the medico-scientific community. Pathogenesis of this highly debilitating disease state has yet to be firmly elucidated despite ongoing research programmes in Europe and the USA. It has been estimated that 1 million Americans suffer CFS/ME. The figure for the UK is considered to be approximately 200,000 people(2). The disease therefore is of major importance, yet there remains no cure. Prognosis is poor, especially for adults(3).


To review symptoms of CFS/ME I will largely draw on the Canadian Consensus Document(4). "CFS/ME is an acquired organic, pathophysiological, multi-systemic illness that occurs in both sporadic and epidemic forms. Myalgic encephalomyelitis (FCD-10-G 933) which includes CFS, is classified as a neurological disease in the World Health Organization's international classification of Diseases(ICD)"(5)


The hypothesis explored here examines links between symptoms and postulated immune-pathogen mediated damage to the hypothalamus. Prior to looking at these links however, it is necessary to briefly review the potentially damaging role of pathogens in the brain.

Evidence shows that >90% of adults are latently infected with one of the following (herpes family)virus. HSV1 HSV2, VZV, EBV, CMV, HHSV6, HHSV7(6). The blood brain barrier is subject to entry by microorganism by a variety of methods(7) Microbial presence in the brain is not limited to virus. Treponema pallidum infection in tertiary neurosyphilis is well documented(8). Borrellia burgdorferi - causative agent of Lyme disease has also been identified in neuroborreliosis(9).


Microorganism are able to evade the immune system response and persist.(10). Microorganisms that were considered to be purely extracellular have now been shown to be able proliferate or remain in dormancy intracellulary(11). Latent virus can reactivate, the immune system may or may not successfully challenge(12).


The model that considered the brain to be a site of "immune privilege" has had to be modified in the light of HIV associated dementia(13). It had been believed that inflammatory responses (and the activation of T-cells) were regulated in the brain in order to prevent damage to neurons and microglial cells(14). This does not necessarily seem the case.


Both serological and molecular testing for pathogen presence in "discreet" sites such as the brain have been shown to be flawed, unreliable or simply unworkable(15). Contemporary methods for detection of extra/intracellular pathogens in the brain are simply non-existent. The laboratory is unable to provide unequivocal evidence of infection.(16)


Viral tropism for the brain is proven(17). That tropism for specific areas of the brain occurs has been documented.(18) The hippocampus is targeted by both HIV and HSV1(19). Of note is that neurordegeneration in Alzheimer's disease has been found to originate in this part of the brain. The Hippocampus mediates between the cingulate gyrus of the limbic system and the hypothalamus.


Given such evidence, I consider it feasible that virus such as CMV or EBV is able to target specific loci responsible for internal regulation and integration, homeostasis, autonomic control (hypothalamus) and the variety of cognitive processing overseen by the hippocampus (20).


The extent and duration of neurologically damaging events by pathogen - immune interaction has been broadly examined in HIV infection of the brain.(21) There is inflammatory cytokine deregulation of normal brain immune inhibitory systems which causes neuronal death and damage. Astrocyte death, reactivation of microglial cells and astrocytes, dendritic simplification, dymelination and virus re-seeding can also occur(22).


Normal functioning of the brain is subjected to great stress during infection, functioning parameters become unstable or compromised. This hypothesis explored in this paper explores the possibility that herpes virus or Borrelia bacteria infection of specific areas of the CNS would lead to gross hypothalamic dysfunction resulting in symptoms concomitant with the multi-system deregulation found in CFS/ME.


The various biological roles of the hypothalamus are complex, subtle and fundamental to normal human function. This small endocrine organ is subject to a range of inputs from the senses, the reticular formation, limbic system, visceral organs, hormones, glucose and sodium(Na)(23). Hypothalamus output includes mid brain motor, limbic system (parasympathetic and sympathetic functions), spinal chord (sympathetic) and pituitary hormones(24).


The hypothalamus operates as a "glucostat", plays a role in sleep, heat regulation, blood pressure, basal metabolic rate (BMR) and secretes vital modulating hormones within and outside these roles such as TRH, CRH, GnRH and GRH.(25). Since these functions appear to be the very areas of dysfunction in CFS/ME, I propose that deregulation of the hypothalamus is the source of symptoms in the disease state.


Below I will link Canadian document headings of symptoms with an exploration of this theory.

1. Fatigue: The patient must have a significant degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity level. (Also include post exertional malaise )


The defining symptom of CFS/ME is disabling physical and mental exhaustion(26). In many respects this gross fatigue shares characteristics with hypoglycaemia(27) for example, profound exhaustion could be caused by hypothalamic "glucostat" dysfunction in the following way; blood sugar is regulated in the brain via sympathetic neurons. In the adrenal medulla a long pre-ganglionic fibre (via a splanchnic nerve)(28) stimulates the chromaffin cells to release catecholamines (adrenaline) if blood sugar is low. Also, excitatory fibres from the hypothalamus descend the spinal chord stimulating the pre-ganglionic sympathetic neurons. Fibres of these neurons innervate the visceral organs and skin. Noradrenaline is released following stimulation.

Below as a summary of catecholamine function with regard to energy/energy production/manifestation.

Noradrenaline Adrenaline.

Glycogenolysis Glycogenolysis

Lipolysis Lipolysis

Blood pressure up Blood pressure up

Increased heart activity Increased heart activity

Brain arousal Brain arousal

Increased BMR

Bronchiole dilation (30)

Notably, in CFS/ME, low brain arousal and low blood pressure feature strongly in symptomatic patients.

Catecholamine activation increases energy availability in the liver and promotion of lipolysis in adipose tissue (31). Glycerol is converted to glucose in the liver following the lipolysis of fat. The liver glucose pool is boosted directly by glycogenolysis (32). I speculate that if the hypothalamic "glucostat" is dysfunctional, then it cannot respond appropriately to energy demands.

A potentially linked factor in disruption of energy production from fatty acids and glycerol is deranged liberation of GRH from the hypothalamus resulting is possible lack of stimulation in the pituitary gland to produce GH. GH targets fat cells (33).


Furthermore, in this state of low/no energy the hypothalamic involvement is of note with regards to activation of the CRH -ACTH axis which leads to release of cortisol from the adrenal cortex(34). Cortisol can function in the proper activity of GH on fat cells (35). Cortisol also mobilises amino acids from muscle and connective tissue. It also stimulates their utilization for gluconeogenesis in the liver (36).

Under conditions of hypoglycaemia there are manifestations of disturbed nervous, cognitive and conscious activity, movement may become uncoordinated and speech slurs. There is also fatigue, dizzyness, weakness, confusion and pallor (37).

Patients suffering from CFS/ME are very familiar with these symptoms yet the key question remains how could this mechanism be accurate and yet we find within normal range glucose blood test results in CFS/ME patients?

The issue of measurement is also pertinent in the area of thyroid activity. Hypothalmic dysfunction(38) can lead to symptoms of low base metabolic rate (BMR). Secretion of Thyroid Releasing hormone (TRH) from the hypothalamus stimulates release of Thyroid stimulating hormone (TRH) from the anterior pituitary which results in release of T3 and T4 from the Thyroid(39). TH increases metabolic rate by boosting the oxygen consumption rate and heat production. Heart rate, contractility and vascular responsiveness to catecholamines are also affected resulting in an increase in blood pressure (BP). Low BP is a feature of CFS/ME.


Sleep dysfunction - There is unrefreshed sleep or sleep quality or rhythm disturbances such as reversed or chaotic diurnal sleep rhythms.


A hallmark symptom of CFS/ME is gross unrefreshed sleep(41). It has been speculated that this part of the syndrome is the catalyst for all the other symptoms(42).

Normal sleep patterns consist of 3 non REM phases. Each phase is characterized by specific changes in Electroencephalography (EEG) (43). There follows a period of Rapid Eye Movement (REM) sleep. The four phases in total makes up one cycle of normal sleep of approximately 90 minutes duration.(44).


The phase of sleep that is most relevant to normal functioning is N3 deep sleep(45). This phase is characterized by slow, large delta waves (previously denoted as stage 4 sleep). It is concomitant with "refreshing sleep"(46). The N3 stage is considered to be of greatest physiological importance(47) because deprivation of N3 leads to physical, mental and emotional fatigue and diminished ability to perform higher level cognitive functions.(48). Lack of refreshed sleep has been shown to course neuronal degradation from the activity of free radicals (and an increase in glucocorticoids)(49).

During sleep, most body systems are in a heightened anabolic state - accentuating the growth and rejuvenation of immune, nervous and muscular skeletal systems(50). Further, secretion of Growth Hormone, which is pulsatile with episodic bursts, occurs in N3 stage sleep. This is precisely the phase of sleep which is deregulated in CFS/ME(51). There is evidence that Alzheimer's disease may be the result of chronic sleep debt(52).

Patients suffering from CFS/ME report refreshed sleep deprivation being the norm, suffered continuously not occasionally. Profound fatigue results(53).

Warwick University studies (54) indicate lack of sleep can double the risk of death from cardiovascular disease. Direct results of sleep deprivation include memory lapse, impaired judgement, impaired immune system, risk of Type 2 diabetes developing, increased reaction time in muscle and tremor(55).


Studies of sleep deprivation in CFS/ME clearly show disruption of N3 stage sleep.(56). Hence, the metabolic benefits of refreshed sleep are lost, for example increased glymphatic clearance of metabolic waste products produced by neural activity in the brain (57). Sleep combats the accumulation of free radicals in the brain, in which glial cells are restored with glucose (via activity of GH)(58). N3 stage sleep is necessary for survival. (59)


Does dysregulation of N3 stage sleep implicate disruption of hypothalamic function? Sleep is highly dependent on the activity of the hypothalamus and reticular formation (RF) (60). The RF cholinergic system is linked to the hypothalamus and and has active involvement in the generation, timing and execution of sleep and the regulation of transition between the different sleep stages.(61).

Projection neurons in the RF modulate EEG waves(62). The hypothalamic suprachiasmatic nucleus (brain's biological clock) controls diurnal cycles thus regulating the timing of sleep and wakefulness(63). Prostaglandins are released to generate sleep(64). Also of note is that the adrenergic system (medulla) generates wakefulness (65). If the hypothalamus is indeed damaged in its normal functioning capacity this "wakefulness" system could be compromised.


Hypothetically, then, dysfunctional hypothalamic activity can affect sleep regulation. Sleep deprivation is N3 stage could be the direct cause of neurological/cognitive manifestation, such as "brain fog" in CFS/ME. "Confusion, impairment of concentration and short term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perception and sensory disturbances -eg spatial instability and disorientation and inability to focus vision. There many be overload phenomenon (hypersensitivities to stimuli that have changed from pre-illness status).

Cognitive, sensory eg photophobia and hypersensitivity to noise and /or emotional overload. HM may lead to "crash" periods (temporary period of immobilising physical/cognitive fatigue)and /or anxiety." From Canadian document.


The hippocampus is located under the cerebral cortex in the brain in an area which intersects lymbic system and hypothalamus(66) The hippocampus is thought to function in a variety of ways including short term memory, information processing, categorizing, word retrieval and spatial navigation.(67). Of note is that damage to this area is found in the early stages of Altimeter's disease. Could damage to this area of the brain via pathogen/immune interaction result in such a manifestation as a type of CFS ataxia?


Neuroendocrine manifestations such as loss of thermostatic stability- Subnormal body temperature and marked diurnal fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities,intolerance of extremes of heat and cold, marked weight change, anorexia or abnormal appetite, loss of adaptability and worsening of symptom with stress.


The hypothalamus acts as the body's temperature regulator(74), stimulation of the anterior section of the gland activates the heat loss mechanism, i.e. it acts as a cooling centre. Stimulation of the posterior section of the gland activates heat conservation ( it acts as a heating centre(75) .Deranged hypothalamic function could be the reason for loss of thermostatic activity in CFS/ME.


Conclusion.

The brain is susceptible to infection by pathogen. Immune system activation and ensuing interaction with foreign protein can damage brain tissues and persist as chronic disease.

I have attempted to correlate established symptoms of CFS/ME with posited hypothalamic dysfunction. There is, I believe supportive evidence to suggest that the variety of symptoms in this disease are related to the disruption .of this gland's normal functioning.



copyright 2016 62milestogojoe
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Comments

How do you theorise steam and massages to alleviate said hypothalamic dysfunction, which has 'cured' your case of CFS/ME
 
Hi Jon, thanks for posting. Steam in this treatment is used over a period of 5 days or more as part of the detox process which includes fasting/restricted diet, administration of increasing dosages of detox fluid, massage and liquid and tablet form ayurvedic medicine. i don't think you can remove one part of the treatment from the equation. The detox process occurs at the front end of the process before actual treatment takes place. look at the album photos if you wish to see other treatments and there are discussions on the forum relating in particular to nasyam (snorting medicine). However, sauna has a very long history of use therapeutically. As the preamble to the 'paper' says, I am speculating on possible mechanisms. It is not written in stone. I am PgCert qualified not a post doc or a Prof. Good luck with your CFS/ME Jon
 
Joe, what are your thoughts on cases that start out viral, like mono from EBV, but after a few years shift into autoimmunity? I read your paper above and it seems like the treatment you did would be more helpful in cases of current viral activity in brain vs autoantibodies from B-Cells at the cause. Am I understanding it correctly? Am very interested in all possible causes and treatments. Thanks and am so happy you found something that worked for you!
 
Hi Gingergrrl. Thanks for your comment, CFS/ME has been the worst time of my life, not understanding why I couldn't walk anymore, slurring my words like a drunk, isolated and worst of all perhaps having no real answers from the established medical community and no treatment. Anyway, your question...I have worked for 17 years as a lab rat, 5 years of which was spent in Virology undertaking molecular work (6 or 7 PCRs a day). The bulk of experience is in biochem. In our building each floor has a different discipline. Autoantibody studies take place in Immunology so I am loathe to speculate. I do not know what the catalyst was for my illness, onset was very sudden and decline into the 'acute' stage was rapid. i always suspected pathogen involvement but this was not proved by lab tests. I think my hypothesis is sadly based on some science I am familiar with but the result is octagonal pegs in round holes maybe. If i get the time Gingerggrl I will try to explore your question. Thanks
 
Gingergrrl. i am in the lab tomorrow and will pop up to immunology and sound out some consultant/scientist on this question. Autoimmune disease like CFS/ME in some respects is still not very well understood. Do you want me to ask if autoantibody is present in the brain? Have a think and we'll try asking some much brighter people than me.
 
Sorry for my delay and anything that you are able to ask your immunology colleagues would be very interesting to me. There is great confusion re: whether I have an ME/CFS diagnosis but I have 11 auto-antibodies (maybe more) and am pursuing many of the same interventions used in ME/CFS. I had viewed auto-antibodies as in the body vs. brain but now realize that maybe I am totally wrong on that. Thanks again!
 
Sorry I missed you. I am in work again on Friday and will essentially ask is there evidence of auto antibody activity in the brain. Do you think that's OK?
 
No worries and that would be great! My treatments are focused on destroying and eliminating these autoantibodies and they are working (but I wish I understood how they were working)! I do not have cognitive issues but have severe autonomic problems (which I know come from the brain so there is some connection). I know my case is very different than yours but I found your treatment very interesting and wondered if any connection to IVIG (what I wrote in your thread).
 
Hi Gingergrrl. had an interesting chat with one of the autoimmune disease scientist who pointed out there are up to 20 types currently known with more coming on line all the time.. She gave me the insert booklet for the assay they are running which I got some photos of naming the autoantibodies plus related info. I can write the list or if you want the 'leaflet' give me some time and I'll blog it for you. identified include Anti-LG1, GABA receptors etc.
 
Thank you so much and many thanks to your wife as well. I hope she is taking magnesium...
 
Thanks Chocolove. Progress still positive with the deepest N3 sleep yet (on my scale of 3.3), swimming, cycling and gym and 2 full days a week as bank staff in the lab. My wife isn't taking Mg so I will recommend but she is beginning yoga this week in preparation for Kerala. Good luck
 
There has been some amazing research in the last few years showing a lymphatic system in the brain/CNS. http://neurosciencenews.com/lymphatic-system-brain-neurobiology-2080/
Little has been done (nothing) to link these new developments to CFS or autoimmuinity but it seems to me that this is a crucial pathway. Has there been other discussion of this 'science' on PR?
 

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