4) Sleep Disturbances and CFS as sleep disorder continued

overview, see https://bra.in/4p6d3Q

 

​

 

5) Overview
CFS and Neurology  An overview of recent research https://www.prohealth.com/library/cfs-and-neurology-an-overview-of-recent-research-19550

 

Many observations suggest that CFS could derive from residual damage to the reticular activating system (RAS) of the upper brain stem and/or to its cortical projections. It should be pointed out that although the larger right greater than left asymmetry in regional cerebral blood flow is found at the parietotempotal level in CFS patients as compared to healthy controls, no significant correlations are found between frontal tracer uptake and right-left parietotemporal asymmetry, on the one hand, and clinically relevant CFS dimensions on the other. Damage to the RAS could be produced by a previous viral infection, leaving functional defects unaccompanied by any gross histological changes.

 

In this respect, fluorine-deoxyglucose positron emission tomography showed specific metabolism abnormalities in CFS patients (hypometabolism in right mediofrontal cortex and brainstem) as compared with both healthy controls and depressed patients. The most relevant abnormality is brain stem hypometabolism, which has been also reported in single-photon emission computed tomography studies and seems to be a marker for the in vivo diagnosis of CFS

 

Fatigue diagrams part 2

 

6) CFS similarities analogy to Hibernation state
Decreases in Sphingolipid, glycosphingolipid, phospholipid, purine, microbiome aromatic amino acid and branch chain amino acid metabolites, as well as in flavine adenine nucleotide (FAD) and lathosterol

 

7) Apnea

Untreated sleep apnea causes daytime tiredness, even with a full night’s sleep

 

I have mild sleep apnea and find the CPAP machine difficult to sleep with. I will try again. In the meantime, perhaps snore surgery reduces apnea? I've been using a CPAP machine for a couple months now and still haven't gotten used to it (I find it disruptive to my sleep). Seeing as it is logical to use (and my snoring bothers my fiance') I will continue to use it until I get used to it or until I opt for surgery. I found that keeping the air pressure to a low setting helps you to acclimate to the device (otherwise subconsciously I yank it off in a half sleep state

 

7b) Apnea Surgery
Tonsillectomy for Sleep Apnea as First-Line Treatment in Adults https://sleep-doctor.com/blog/tonsillectomy-for-sleep-apnea-as-first-line-treatment-in-adults

 

For adults with obstructive sleep apnea, the standard treatment is positive airway pressure therapy (such as CPAP, BPAP, or APAP).  Surgery is reserved for patients who are unable to tolerate or benefit from positive airway pressure therapy.  For children, adenoidectomy and/or tonsillectomy for sleep apnea is the standard treatment.  Positive airway pressure therapy is not an ideal treatment for most children.  This is due to concerns over effects on facial growth and difficulty that children may have with tolerating it through the night.  It is reassuring that surgical outcomes in children–while by no means perfect–are relatively good, especially when the tonsils or adenoids are enlarged and when the child is not considered substantially overweight.

 

What about tonsillectomy for sleep apnea as first-line treatment in adults?

Just like in children, adults with enlarged tonsils also do better after sleep apnea surgery that includes tonsillectomy.  One reason seems to be that the physical removal of the enlarged tonsils immediately opens up space for breathing and improves the sleep apnea.  Many have wondered whether adults with sleep apnea and markedly enlarged tonsils should be treated with surgery that includes tonsillectomy.

 

The December 2016 issue of the medical journal The Laryngoscope included an interesting study examining this question.  Twenty-nine adults with markedly enlarged tonsils (size 3+ or 4+ on the Friedman scale), obstructive sleep apnea, and no substantial obesity (body mass index below 32 kg/meters squared) underwent tonsillectomy alone.  One patient was lost to follow up, but the rest of the patients had sleep studies before and then 6 months after surgery.  Impressively, the average apnea-hypopnea index decreased from 40 to 7 events per hour after undergoing tonsillectomy for sleep apnea, with only 2 patients having anything worse than mild sleep apnea.  There were also substantial improvement in the score on the Epworth Sleepiness Scale score that measures daytime sleepiness (mean score decreased from 11 to 6

 

Are there other studies of tonsillectomy for sleep apnea?

This study followed previous smaller studies showing substantial improvement or resolution in sleep apnea after tonsillectomy alone and that tonsil size and body mass index were associated with outcomes after tonsillectomy alone and that tonsillectomy could reduce the required CPAP pressure in those who did not have resolution of their sleep apnea.  This was supported by a larger study of 202 adults published in 2015.  This study showed a 95% chance of surgical success after tonsillectomy for sleep apnea, with a decrease in the average apnea-hypopnea index from 18 to 3 events per hour.

 

So why isn’t tonsillectomy for sleep apnea a first-line treatment in adults?

There are likely many reasons.  First, not all patients have tonsils that are markedly enlarged.  I would estimate that this about 5-10% of all adults with sleep apnea would be ideal candidates for tonsillectomy as a first-line treatment. This figure seems relatively small, but it still is quite a few patients who could have their tonsils removed because sleep apnea is so common.  Second, most of these studies are relatively small.  It would be important to repeat the studies in larger groups, just to confirm the findings.  Third, the studies are not what are called randomized trials.  Randomized trials could include patients with sleep apnea and markedly enlarged tonsils, either performing tonsillectomy or observing them without treatment for a period of time (6 months, for example).  Unfortunately, it turns out that making people wait for surgery just to be part of a research study is incredibly difficult.  Patients will prefer not to be involved in these studies if they are interested in having surgery (or any treatment).  Finally, there are perceptions about surgery for sleep apnea that we have to overcome.  I have written before that most surgeons, other physicians, and the public think that there is only one surgery for sleep apnea. That is just not the case.

 

What would I recommend?

We are in the midst of a major change in rethinking sleep apnea surgery–for all parties involved.  The goal is developing a tailored approach to sleep apnea treatment with an approach that is often called personalized medicine.  I see many young adults with markedly enlarged tonsils who are struggling with positive airway pressure therapy, including many with mild sleep apnea who are not overweight.  For these patients, I think it is very reasonable to think about surgery as a first-line option instead of being on positive airway pressure for the rest of their life.  These patients have a greater than 90% chance of clearing up their sleep apnea with tonsillectomy alone.  Not every one of them will want to have surgery, but this should be part of the discussion because the results will be so good, based on everything we know about sleep apnea surgery outcomes.

 

As a sleep surgeon, I see many patients who want surgery because they simply do not like positive airway pressure therapy, even though they are doing well with it.  In fact, I actually discourage many of these patients from surgery.  My approach is always the same: if you are doing well with positive airway pressure therapy, keep using it.  The one caveat are those patients who have a very high chance of resolution of their sleep apnea with a straightforward procedure like tonsillectomy

 

Treatment considerations for excessive daytime sleepiness (EDS) in OSA https://edsandosa.com

• While continuous positive airway pressure (CPAP) is considered the gold standard of treatment for obstructive sleep apnea (OSA). EDS may persist despite optimal CPAP use
• Sleep apnea treatments like CPAP have been proven to decrease symptoms such as apneas, hypopneas, and snoring, and improve sleep structure in patients with OSA.
• However, CPAP and CPAP alternatives may not address the brain alterations and subsequent neurologic dysfunction that OSA can leave behind

 

Pharmacotherapy should be considered for patients who have unresolved EDS despite optimal CPAP compliance'°

 

7c) CPAP and surgery alternatives
CPAP alternatives include bilevel positive airway pressure (BPAP). automatic (or autotitrating) positive airway pressure (APAP), oral appliances, and upper airway stimulation devices.'

 

7e) Neurological Effects of Apnea

Emerging science can help explain the link between excessive daytime sleepiness (EDS) and OSA

• EDS is one of the most common symptoms of obstructive sleep apnea (OSA)
• Animal and human studies suggest that the recurring cycle of intermittent hypoxia and sleep fragmentation associated with OSA may result in changes to the brain
• The subsequent disruption in neurologic function + may manifest as excessive sleepiness during the day
• While brain alterations have been linked to sleepiness, persistent EDS may be due to other factors such as chronic sleep loss and coc disorders1"

 

In an animal model of severe sleep apnea, chronic intermittent hypoxia led to significant neuronal injury'

Long-term hypoxia significantly increased oxidative injury to wake-promoting dopaminergic and noradrenergic neurons compared with the control group (Pc-0.01)2*

 

The loss of medial dendrites represents irreversible and functionally significant injury to wake-promoting regions of the brain'

 

At 6 months, a 40% JOSS of select wake-promoting dopaminergic and noradrenergic neurons was associated with irreversible wake impairments'

 

In a separate animal model of OSA, chronic sleep fragmentation led to a significant loss of wake-promoting neurone

Exposure to sleep disruptions over 14 weeks caused a significant reduction of wake-promoting noradrenergic neurons compared with the control group (P<0.001), even after 4 weeks of recovery'

 

Excessive daytime sleepiness (EDS) in OSA is associated with significant changes to the brain

Obstructive sleep apnea (OSA) is associated with reduced gray matter concentration"

 

Imaging studies in patients with severe OSA showed reduced gray matter concentration in certain brain regions compared with healthy volunteers, including the frontal cortex, anterior cingulate cortex, and thalamus.''

 

Some of these regions are involved in wakefulness and neurocognitive performance in' • Problem-solving • Planning • Decision-making • Attention/concentration

 

EDS in OSA is associated with significant white matter structural alterations despite the optimal use of CPAP'

Widespread white matter changes were observed in patients with OSA-associated EDS despite optimal CPAP adherence hours for 1 month) vs nonsleepy patients'

 

These changes ideate potential myelin damage and compromised neuronal connectivity'

 

This may help explain why EDS can persist in patients with OSA, even with optimal CPAP use?

 

Excessive daytime sleepiness (EDS) in OSA is more common than you may think

• Animal and human studies indicate a link between obstructive sleep apnea (OSA) and changes to the brain—and these changes have been associated with a disruption in neurologic function'
• While CPAP is needed to address the airway issue in patients with OSA, it may not address all aspects of compromised neuronal activity, and EDS may persist"

 

In a study of patients with OSA,

1 IN 3 WHO USED THEIR CPAP 3 HOURS A NIGHT STILL REPORTED FEELING SLEEPY DURING THE DAY"

`A study of 174 patients with moderate to severe OSA using continuous positive airway pressure (CPAP). Daytime sleepiness was assessed before and after 3 months of CPAP therapy using the Epworth Sleepiness Scale.' 'Includes average CPAP use of 2 or fewer hours per night, up to 7 or more hours per night.'

 

8) Hypothalamus

 

                    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus (click to open)http://jpet.aspetjournals.org/content/jpet/early/2018/08/03/jpet.118.250845.full.pdf Chronic fatigue syndrome and disturbed homeostasis AbbreviationsADP=adenosine diphosphateAMPK=5’ adenosine monophosphateactivated protein kinaseApoE= Apolipoprotein EAT=anaerobic thresholdATP=adenosine5’\triphosphateANS= autonomic nervous system BMI=bodymass index βFGF=βfibroblast growth factor CGRP= calcitoningene related proteinCNS=central nervous systemCRH= corticotropinreleasing hormoneCSF= cerebrospinal fluidCVD= cardiovascular diseaseFAD=flavine adenine nucleotideFMS= fibromyalgia syndromeGWI= Gulf War IllnessHDL=highdensity lipid (cholesterol)HPA=hypothalamicpituitaryadrenal axisIBS=irritable bowel syndromeIFNγ= interferonγIL1β= interleukin 1betaIL33= interleukin 33IL37= interleukin 37LDL=lowdensity lipid (cholesterol)MCAS=mast cell activation syndromeMCP=monocyte chemoattractant proteinME/CFS=myalgic encephalomyelitis/chronic fatigue syndromeMetS=metabolic encephalomyelitisMI= myocardial infarctionMIF=macrophage inflammatory factorMiRNA= microRNAMIP=macrophage inflammatory protein mtDNA= mitochondrial DNA NGF=nerve growth factorNE=norepinephrinePTH= parathyroid hormonePDH=pyruvate dehydrogenasePDGF=plateletderived growth factorPPS/IC=Pelvic pain syndrome/Interstitial cystitisPoly (I:C)=polyinosinic:polycytidylic acidPOTS= Postural orthostatic tachycardia syndromePPAR=peroxisome proliferatoractivated receptorRANKL= Receptor activator of nuclear factor kappaΒ ligand ROS=reactive oxygen speciesSCF=stem cell factorSEID=systemic exertion intolerance diseaseSP= substance PTCA=tricarboxylic acidT2DM=Type 2 Diabetes MellitusTGFβ=transforming growth factor βTNF= tumor necrosis factorUCP2= uncoupling protein 2VEGF=vascular endothelial growth factor Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by debilitating fatigue, lasting for at least 6 months, with associated malaise, headaches, sleep disturbance and cognitive impairment, which severely impacts on quality of life. A significant percentage of ME/CFS patients remains undiagnosed, mainly due to the complexity of the disease and the lack of reliable objective biomarkers. ME/CFS patients display decreased metabolism and the severity of symptoms appears to be directly correlated to the degree of metabolic reduction that may be unique to each individual patient. However, the precise pathogenesis is still unknown preventing the development of effective treatments. The ME/CFS phenotype has been associated with abnormalities in energy metabolism, apparently due to mitochondrial dysfunction, in the absence of mitochondrial diseases, resulting in reduced oxidative metabolism, mitochondria may be further contributing to the ME/CSF symptomatology by extracellular secretion of mitochondrial DNA, which could act as an “innate” pathogen and create an autoinflammatory state in the hypothalamus. We propose that stimulation of hypothalamic mast cells by environmental neuroimmune pathogenic and stress triggers activates microglia leading to focal inflammation in the brain and disturbed homeostasis. This process could be targeted for the development of novel effective treatments.Myalgic Encephalomyelitits/Chronic Fatigue Syndrome (ME/CFS) is defined by the original diagnostic criteria (Fukuda, et al., 1994), and by the Canadian Consensus Criteria (Carruthers, et al., 2003), (Carruthers, 2007) followed by an international consensus (Carruthers, et al., 2011) and newer clinical diagnostic criteria developed by an NIH pathways to prevention workshop (Haney, et al., 2015) and the Institute of Medicine (Germain, et al., 2017). ME/CFS has also been known by other names (Unger, et al., 2016), most recently as Systemic Exertion Intolerance Disease (SEID),(Monro and Puri, 2018) ME/CFS is a complex disease that involves the muscular, nervous, hormonal and immune systems (Natelson, 2001),(Georgiades, et al., 2003), (Brurberg, et al., 2014), (Brigden, et al., 2017), (Scheibenbogen, et al., 2017). As the name implies, ME/CFS is characterized by debilitating fatigue lasting for at least 6 months, with severe impairment of daily functioning and associated symptoms, such as sleep disturbances, muscle aches, flulike malaise, gastrointestinal symptoms, orthostatic intolerance, chronic or intermittent pain, as well as cognitive impairment reflected as memory and concentration difficulties (Natelson, et al., 2007), {25039),(Yancey and Thomas, 2012), (Ganiats, 2015), (Komaroff, 2015), (Scheibenbogen, et al., 2017). The intensity of symptoms appears to be significantly affected by exertion (Rowe, et al., 2016). Anxiety and increased vulnerability to stress are also common in ME/CFS patients, including children affected by the disease (Smith, et al., 2003), (Crawley, et al., 2009). Abnormal hypothalamicpituitaryadrenal (HPA) axis activity has been observed in many patients (Cleare, et al., 2001), thus suggesting an association between ME/CFS and disturbed neuroendocrine mechanisms. Interestingly, ME/CFS patients are more likely to have migraine headaches than normal controls (Ravindran, et al., 2011). ME/CFS is often comorbid with disorders (Table 1) that are characterized by central nervous system (CNS) dysfunction, (MartinezMartinez, et al., 2014) and which are also negatively affected by stress (Theoharides and Cochrane, 2004), (Theoharides, 2013): Gulf War Illness (GWI) (Gwini, et al., 2016), Pelvic Pain Syndrome/Interstitial Cystitis (PPS/IC) (Whitmore and Theoharides, 2011), Fibromyalgia Syndrome (FMS) (Theoharides, et al., 2015c), and Mastocytosis (Theoharides, et al., 2015d) or Mast Cell activation syndrome (MCAS) (Petra, et al., 2015), (Akin, 2014). However, there are distinct differences between these other diseases such as between ME/CFS and FMS (Abbi and Natelson, 2013), (Pejovic, et al., 2015). ME/CFS is estimated to affect as many as 2.5 million people in the US, which corresponds to about 1% of the total US population. (Vincent, et al., 2012), (Komaroff, 2015), (Ganiats, 2015) Other studies (Jason, et al., 2009), including Minnesota (Vincent, et al., 2012), as well as from the UK (Nacul, et al., 2011), (Collin, et al., 2017), Norway (Bakken, et al., 2014) and Italy (Capelli, et al., 2015) report a lower incidence. Women are apparently more susceptible than men, with an estimated ratio of 4:1 (Germain, et al., 2017). The disease predominantly affects adults, even though symptoms may appear in childhood andadolescence (Crawley, 2014), (Nijhof, et al., 2011) ,(Jason, et al., 2006). Unfortunately, a significant number of suspected ME/CFS patients remain undiagnosed (Jason, et al., 2006) mainly due to the complexity of the disease and the lack of reliable diagnostic biomarkers (Klimas, et al., 2012). Multisystem diseases such as ME/CFS are often very timely and expensive to diagnose, and most patients go through years of searching and agony, as well as significant financial expenditures and impairment of their quality of life (Germain, et al., 2017). The economic health burden for ME/CFS in the USA was estimated to be $24 billion in 2018. (Jason, et al., 2008) . This makes imperative the need for the development of objective diagnostic biomarkers that will not only assist in the critical identification of patients with ME/CFS, but will also provide essential information on the pathophysiological mechanisms involved. A number of mechanisms and molecules have been implicated in the pathogenesis of ME/CFS(Gerwyn and Maes, 2017). Autoimmune (Sotzny, et al., 2018) and metabolic (Tomas and Newton,2018) pathways appear to play key roles in the pathophysiology of ME/CFS (Theoharides, et al.,2004b), (Maes, et al., 2011), (Booth, et al., 2012). Neuroimmune and neuroendocrine processes might also be involved, but are still largely unknown (Dietert and Dietert, 2008), (Bower, 2012). Clinical and subclinical viral infections have been suspected, but never confirmed, as a possible risk factor for the development of ME/CFS (Katz, et al., 2009), (Fremont, et al., 2009). The involvement of neuroinflammation of the brain has recently been suggested without any specific pathogenetic mechanism. (Glassford, 2017), (Tomas and Newton, 2018), (Morris, et al., 2018) Here we give an overview of the current understanding of the associations between ME/CFS and metabolic disease, and propose that focal inflammation in the hypothalamus due to local activation of mast cell and microglia, may alter homeostasis and provide a target for novel treatment approaches. Metabolic IrregularitiesME/CFS has been found to involve irregularities in the metabolism, energy, amino acid, nucleotide, nitrogen, hormone, and oxidative stress metabolism (Armstrong, et al., 2014), (Germain, et al., 2017). In particular, it has been proposed that the severe and prolonged fatigue experienced by ME/CFS patients may be a consequence of abnormalities in bioenergetic function (Tomas, et al., 2017). Much evidence suggests that the pathophysiology of ME/CFS is highly associated with alterations in normal energy metabolic processes (Fluge, et al., 2016) and abnormalities in cellular bioenergetics (Fluge, et al., 2016;Hornig, et al., 2015), (Fluge, et al., 2016), (Tomas, et al., 2017). There is also evidence to suggest that patients with ME/CFS might be at an increased risk for developing metabolic syndromeassociated diseases, such as diabetes, cardiovascular disease and thyroid disease (Maloney, et al., 2009). Apparently, systemic exertion intolerance in repeated cardiopulmonary exercise tests was demonstrated in ME/CFS patients present as compared to healthy controls suggesting insufficient metabolic adaptation to incremental exercise (Vermeulen and Vermeulen, I, 2014), (Keller, et al., 2014). It should be noted, that the Vermeulen and Vermeulen study including controls, which were not matched to ME/CFS in terms of fitness, while the Keller et al study had no controls. McCully et al published a number of papers showing that when matched for aerobic fitness, cardiorespiratory responses to exercise in patients with ME/CFS only and ME/CFS plus FM were not different from those in sedentary healthy controls (Cook, et al., 2006). Such intolerance, if real, may involve a switch to anaerobic glycolysis, i.e. a reduction in oxidative metabolism, and an increase in lactate production (Murrough, et al., 2010), (Shungu, et al., 2012b), which constitute the most common metabolic alterations observed in patients with ME/CFS. These characteristics have mainly been attributed to deconditioning, a state characterized by loss of muscle tone and power from prolonged lack of use (Bains, 2008). However, even though increased lactate production was originally noted, possibly related to the reduction of postexercise oxygen delivery (McCully, et al., 2004), the same effect could not be substantiated suggesting a possible decrease in oxygen delivery perhaps due to reduced blood flow (McCully and Natelson, 1999). In particular, there was elevated ventricular lactate, but no significant difference in high energy phosphatase metabolites in patients with ME/CFS as compared to patients with major depressive disorder or healthy volunteers (Shungu, et al., 2012a). In some cases, alterations in glucose utilization and lactate production were evident only after physical exercise of ME/CFS patients (Fluge, et al., 2016). ME/CFS plasma and serum metabolomics point in the direction of a hypometabolic state (Naviaux, et al., 2016), (Fluge, et al., 2016), (Germain, et al., 2017), (NagySzakal, et al., 2018). ME/CFS association with metabolic diseaseMetabolic syndrome (MetS) is a disorder characterized by an imbalance between energy expenditure and storage, and is diagnosed by the simultaneous presence of three of the following five conditions: (a) central type (or abdominal), (b) obesity, (c) increased blood pressure, elevated fasting glucose levels, (d) high levels of serum triglycerides, and (e) decreased highdensity lipid (HDL) cholesterol levels (Mottillo, et al., 2010), (Kaur, 2014). MetS is also linked to insulin resistance, a condition in which, despite normal insulin secretion by pancreatic βcells and hyperinsulinemia, can lead to hyperglycaemia and the development of Type II diabetes mellitus (T2DM) (Petersen and Shulman, 2006). In addition, high blood pressure and high cholesterol levels are closely linked to increased oxidative stress and endothelial dysfunction, thus enhancing the proinflammatory nature of microvascular atherosclerotic disease (Li, et al., 2007). In other words, subjects with MetS are at an increased risk of developing cardiovascular disease (CVD) and T2DM (Isomaa, et al., 2001), (Dekker, et al., 2005), (Petersen and Shulman, 2006). Approximately half of patients with ME/CFS also appear to have a previously undiagnosed medical condition, most often diabetes, CVD and thyroid diseases (Maloney, et al., 2009). Few studies have investigated the possible associations between MetS and ME/CFS (Maloney, et al., 2009), (Naviaux, et al., 2016), (Germain, et al., 2017), (Bozzini, et al., 2018). It was first suggested that patients with ME/CFS were twice as likely to have MetS, as compared to controls, after adjusting for bodymass index (BMI), waist circumference, triglycerides and glucose levels (Maloney, et al., 2009). MetS components in the ME/CFS group were significantly correlated with worse fatigue, but not with worse physical or mental functioning, contrary to previous observations (Tsai, et al., 2008), (Maloney, et al., 2009). A correlation of MetS with fatigue has also been observed in patients with FMS, a condition clinically similar to ME/CFS in which muscle pain and fatigue are the main symptoms; specifically, MetS components [lowdensity lipoprotein (LDL) cholesterol, as well as urinary norepinephrine (NE)/epinephrine and NE/cortisol rations], were significantly higher in women with FMS, as compared to healthy controls (Loevinger, et al., 2007). Some studies have reported abnormal findings concerning the cardiovascular system, but one study was in patients with small hearts (Miwa and Fujita, 2009;Azevedo, et al., 2007) and the other was in adolescents (Wyller, et al., 2008),and autonomic nervous system (ANS) dysfunction (Meeus, et al., 2013). Low blood pressure was noted in certain ambulatory cases of patients with ME/CFS (Newton, et al., 2009), (Wyller, et al., 2011), (Frith, et al., 2012). However, when patients with ME/CFS were matched to healthy controls by V02 max there were no differences in cardiovascular parameters (Cook, et al., 2006). Dysautonomia including Postural orthostatic tachycardia syndrome (POTS) may be present in many patients with ME/CFS (Hollingsworth, et al., 2010) and could also explain other ME/CFS symptoms, such as fatigue, vertigo, decreased concentration, tremors and nausea (Bozzini, et al., 2018). Interestingly, the low systolic blood pressure observed in ME/CFS patients is usually accompanied by exaggerated diurnal variation, which is inversely correlated with increasing fatigue (Davis, et al., 2000), (Newton, et al., 2009). Overall, it appears that metabolic disease components show significant correlations with the fatigue in ME/CFS patients and not with the disease itself. For example, blood pressure, as well as insulin resistance, are probably secondary to fatigue, and most probably reflect the lack of physical activity and prolonged lack of muscle use in ME/CFS patients. This makes sense if one considers that low blood pressure could give rise to fatigue through brain/or muscle hypoperfusion (Newton, et al., 2009), and that insulin sensitivity is highly dependent on the oxidative capacity of the muscle (Canto and Auwerx, 2009). Metabolomics, smallmolecule metabolite profiling (Daviss B., 2005), has provided relevant information that could distinguish ME/CFS patients (Naviaux, et al., 2016). Several studies have performed metabolite analysis of various biological fluids, [urine, blood, serum and cerebrospinal fluid (CSF)] from ME/CFS patients (Georgiades, et al., 2003), (Jones, et al., 2005), (Niblett, et al., 2007), (Suarez, et al., 2010), (Armstrong, et al., 2012), (Armstrong CW, et al., 2015), (Hornig, et al., 2016). However, despite confirming disturbances in energy, amino acid, nucleotide, nitrogen, hormone and oxidative stress metabolomics, they have not been able to determine a distinct, reproducible metabolic profile for ME/CFS (Germain, et al., 2017). Nevertheless, one study identified nine biochemical disturbances that were common to both male and female patients with ME/CFS, but not healthy controls (Naviaux, et al., 2016). Overall, there were marked decreases in sphingolipid, glycosphingolipid, phospholipid, purine, microbiome aromatic amino acid and branch chain amino acid metabolites, as well as in flavine adenine nucleotide (FAD) and lathosterol, which identified hypometabolic profile for ME/CFS. These changes correlated with disease severity and had an apparent diagnostic accuracy that exceeded 90% (Naviaux, et al., 2016). Interestingly, the metabolic abnormalities found in ME/CFS patients, were opposite (i.e. decreased instead of being increased), to those observed in MetS suggesting that ME/CFS patients could be more resistant to hypertension, dyslipidaemia, obesity and insulin resistance even though previous studies discussed above had reported an increased association between ME/CFS and metabolic syndrome.Another study that used targeted plasma metabolomics reported a similar trend of hypometabolic state in ME/CFS patients (Germain, et al., 2017). Even though the metabolite compounds were not all identical to the ones studied by Naviaux at al., both agreed on the presence of disturbances in lipid and fatty acid metabolism (Germain, et al., 2017). These findings are also in agreement with reported deficiencies in the urea and the TCA cycles, (ornithine/citrulline and pyruvate/isocitrate ratios), which ultimately result in reduced levels of ATP production in patients with ME/CFS (Yamano, et al., 2016). Other studies revealed that ME/CFS have reduced substrates that enter oxidation downstream of pyruvate dehydrogenase (PDH), such as glutamine, glutamate and phenylalanine, thus suggesting impaired pyruvate catabolism, which ultimately results in increased utilization of acetylCoAproducing amino acids as alternative substrates for fuelling aerobic metabolism via the TCA cycle (Armstrong, et al., 2012), (Armstrong CW, et al., 2015), (Fluge, et al., 2016). Reduced concentrations of amino acids that maintain TCA cycle capacity were detected in patients with ME/CFS (Fluge, et al., 2016), suggesting impaired fuelling of the TCA cycle by pyruvate. This finding is in line with the results of other studies where TCA cycle intermediates were also found to be reduced in both urine (Niblett, et al., 2007) and plasma (Yamano, et al., 2016) samples from ME/CFS patients. Mitochondrial dysfunctionOverall, the ME/CFS phenotype has been associated with mitochondrial dysfunction, 5' adenosine monophosphateactivated protein kinase (AMPK) impairment, oxidative stress and skeletal muscle cell acidosis (Myhill, et al., 2009), (Kennedy, et al., 2005), (Brown, et al., 2015), (Tomas, et al., 2017). The main ME/CFS symptoms, such as fatigue, exercise intolerance and myalgia, are also shared by patients diagnosed with primary mitochondrial disorders (Filler, et al., 2014), (Gorman, et al., 2015). However, unlike the mitochondrial dysfunction observed in mitochondrial disorders is known to be caused by mutations in either nuclear or mitochondrial DNA (mtDNA) (Tomas, et al., 2017), these mutations in patients with ME/CFS are extremely rare (BillingRoss, et al., 2016), (Schoeman, et al., 2017). In addition, certain mitochondrial enzymes have been found to discriminate between mitochondrial disorders and ME/CFS. Notably respiratory chain complex (RCC) I, III and IV activity (Smits, et al., 2011) appears to be significantly higher in ME/CFS patients. Instead, ATP production rate was found to be within the normal range in ME/CFS patients, but significantly decreased in approximately three quarters of the patients with mitochondrial disease, and was therefore regarded as the most reliable discrimination test (Smits, et al., 2011). Muscle biopsies from ME/CFS patients have shown mitochondrial degeneration, atrophy of type II fibers and fusion of mitochondrial cristae, decreased mitochondrial membrane permeability, severe deletions in mtDNA genes that are involved in cellular energy processes, as well as oxidative damage from increased production of free radicals (Myhill, et al., 2009), (Morris and Maes, 2013). Mitochondrial dysfunction has also been observed in peripheral mononuclear blood cells (PMBC) of ME/CFS patients, even though it has not yet been elucidated if they constitute the cause of the disease (Myhill, et al., 2009), (Myhill, et al., 2013), (Tomas, et al., 2017). Notably, a significant correlation has been observed between the extent of mitochondrial dysfunction and the degree of ME/CFS severity, thus suggesting that mitochondrial dysfunction might be a contributing factor in ME/CFS pathology, at least in a subset of patients (Myhill, et al., 2009), (Booth, et al., 2012). However, it is difficult to assess mitochondrial dysfunction that is usually done by measuring the levels of lactate and pyruvate in the serum, best done by serial serum sampling from an arm after a brief period of exercise. When limited amounts of oxygen are available, as is usually the case with intense exercise, anaerobic glycolysis, or otherwise called the lactic acid system, provides an effective means of energy production. During this process, glucose is catabolized via the glycolytic pathway, resulting in pyruvate being converted to lactate by lactate dehydrogenase. This process lasts 1030 seconds during maximal effort and produces about 5% of the glucose energy potential in the form of adenosine5´triphosphate (ATP) molecules (2 molecules of ATP for every molecule of glucose). ATP synthesis can be estimated by measuring the anaerobic threshold (AT), i.e. the rate of oxygen consumption at work rate when blood lactic acid begins to accumulate, and the maximal work rate (Morris and Maes, 2014). The AT indicates a switch during which ATP synthesis stops being produced by mitochondria and occurs via the anaerobic route (Morris and Maes, 2012), whereas anaerobic threshold and recovery time following exercise depends on lactate production and clearance rates (Fluge, et al., 2016). When aerobic conditions are normal, pyruvate is transported into mitochondria and converted to acetylCoA by either PDH or via degradation of fatty acids and ketogenic amino acids. In either case, acetylCoA is further oxidized in the tricarboxylic acid (TCA) cycle, producing some ATP, and the electron transport chain (respiratory chain), which generates ATP from ADP by oxidative phosphorylation (oxphos). AcetylCoA thereby serves to fuel mitochondrial respiration and ATP production by oxidative phosphorylation (Fluge, et al., 2016) for essential tissue functions (Myhill, et al., 2009). Reduced ATP production is associated with increased levels of reactive oxygen species (ROS), which may ultimately lead to mitochondrial damage and the hypometabolic profile of ME/CFS (Naviaux, et al., 2016), (Armstrong CW, et al., 2015). Severely reduced or impaired mitochondrial oxidative phosphorylation in ME/CFS patients is highly correlated with significantly increased intracellular lactate levels, even in the recovery phase of a mild exercise where ATP synthesis is extremely low (Vermeulen, et al., 2010), (Morris and Maes, 2014). Among the factors that may contribute to mitochondrial dysfunction, the most prominent ones appear to be increased levels of proinflammatory cytokines, such as interleukin1beta (IL1β) and tumor necrosis factor (TNF), which directly inhibit mitochondrial respiration by increasing mitochondrial membrane permeability, which ultimately leads to membrane depolarization and an increased production of ROS (Morris and Maes, 2013). However, even though TNF is elevated in the serum of patients with FMS, (Theoharides, et al., 2010c) it was not consistently elevated in ME/CFS (Brenu, et al., 2011), but was apparently associated only with increased IL4 (Hanson, et al., 2001).There was also no significant difference in serum cytokine levels across the night (Nakamura, et al., 2010) or post exercise (Nakamura, et al., 2013). There is some evidence of stronger correlation of cytokines alterations early in the course of illness rather than severity (Hornig, et al., 2015). It has been proposed that “cytokine coexpression networks” may be more predictive of ME/CFS phenotype (Klimas, et al., 2012), (Hornig, et al., 2016), but looking for such biomarkers in the periphery would not reflect inflammation in the brain. One study reported that of 27 cytokines studied in CSF from ME/CFS patients, only IL10 was significantly reduced {26107}. Another paper using network analysis of CSF cytokine levels reported an inverse relationship with interleukin 1 receptor antagonist only in classical, but not in atypical ME/CFS (Hornig, et al., 2017). Certain microRNAs (miRNAs) may turn out to be distinct or differentially expressed in ME/CFS. Recently, miRNAs have been implicated in the hypothalamic control of energy homeostasis (Najam, et al., 2018). However, the available studies in patients with ME/CFS did not report any consistent pattern whether pre\ or postexercise, plasma,(Brenu, et al., 2014) NK cells (Petty, et al., 2016) or CD8+ cells (Brenu, et al., 2012). One recent important study showed exercise induced changes in CSF fluid from patients with ME/CFS, Gulf War Illness and sedentary controls found twelve diminished miRNAs after exercise (Baraniuk and Shivapurkar, 2017), (Baraniuk and Shivapurkar, 2018). Focal Inflammation in the Diencephalon and Dysfunctional HPA axisNeuroinflammation (Nakatomi, et al., 2014), (Glassford, 2017), (Tomas and Newton, 2018), (Morris, et al., 2018) and immune dysfunction (Morris, et al., 2014), (Nijs, et al., 2014), (Trivedi, et al., 2018) have been suggested as being involved in the pathogenesis of ME/CFS, but serum levels of proinflammatory cytokines have not been confirmed as discussed later. Considerable evidence indicates that ME/CFS is characterized by dysfunction of the HPA axis, (Theoharides, et al., 2010b), (Morris, et al., 2016) and symptoms are known to worsen by stress (Smith, et al., 2003)), (Theoharides and Cochrane, 2004), ((Crawley, et al., 2009;Theoharides and Cochrane, 2004;Theoharides, 2013). Stress can also worsen or precipitate obesity and cardiovascular events (Theoharides, et al., 2008), (Theoharides, et al., 2011), (Alevizos, et al., 2013), (Sismanopoulos, et al., 2013), through local inflammation (Matusik, et al., 2012;Libby, et al., 2002). Corticotropinreleasing hormone (CRH) is secreted from the hypothalamus under stress and stimulates the HPA axis via activation of two main types of G proteincoupled receptors, CRHR1 and CRHR2 (Chrousos, 1995). CRH secreted under acute stress, has been implicated in the pathophysiology of neuroinflammatory disorders and myocardial infarction (MI) (Jiang, et al., 1996;Krantz, et al., 2000;O'Kane, et al., 2006;Slominski, 2009). We propose that stimulation of hypothalamic mast cells by environment, neural, immune pathogenic (Lyme, mycotoxins) or stress triggers (CRH, somatostatin) activates microglia leading to focal inflammation and disturbed homeostasis (Figure 1). Mast cell and/or microglia triggers may derive from the nasal cavity, or may reach the brain area through a disrupted BBB or through the lymphatics. Stimulated mast cells could secrete molecules that can alter homeostasis directly (via secretion of CRH, urocortin) or activate microglia (via secretion of histamine, tryptase and mtDNA). Microglia then release more inflammatory molecules (IL1β, IL6, and CCL2) that further disrupt homeostasis, causes mitochondrial dysfunction and contribute to fatigue both centrally and peripherally. In fact, activated microglia have been reported to contribute to the pathophysiology of sleep disorders (Nadjar, et al., 2017). The involvement of more than one trigger can lead to a significantly heightened response and lower the triggering threshold of both mast cells and microglia leading to chronic symptoms. Mast cells are unique tissue immune cells involved in allergic reactions (Theoharides, et al., 2015d), but also act as sensors of environmental and psychological stress (Theoharides, 2017). Even though we invoke stimulation of mast cells in the hypothalamus, it does not necessarily mean that mast cells should necessarily be stimulated outside the CNS. Nevertheless, there have been reports of an association between ME/CFS and acute rhinitis including significantly higher TNF and CXCL8 levels in nasal lavage fluid (RepkaRamirez, et al., 2002). In addition, chronic rhinosinusitis symptoms were significantly higher in patients with ME/CFS (Chester, 2003), apparently due to nonallergic rhinitis (Baraniuk and Ho, 2007). It is well known that both allergic and perennial rhinitis involve activation of mast cells (Bachert, et al., 2018). More recently, it was reported that the incidence of ME/CFS was higher in patients with a history of atopy (Yang, et al., 2015). Moreover, circulating blood mast cell precursors were found to be higher in ME/CFS patients (Nguyen, et al., 2017).Mast cells are located perivascularly in the hypothalamus, thalamus and third ventricle of the diencephalon (Edvinsson, et al., 1977), (Pang, et al., 1996). CRH could stimulate MC in the hypothalamus since CRHR1 gene is expressed on human cultured mast cells, activation of which induces production of vascular endothelial growth factor (VEGF), (Cao, et al., 2005) which could increase permeability of the bloodbrain barrier (BBB) (Theoharides and Konstantinidou, 2007), (Theoharides, 1990), (Esposito, et al., 2002) leading to inflammation of the brain (Theoharides, et al., 2004a). Moreover, CRH is synthesized by mast cells (Kempuraj, et al., 2004) implying it could have autocrine effects. Interestingly, even somatostatin stimulates mast cells (Theoharides, et al., 1990). Mast cells are also found in the pineal, the pituitary and the thyroid glands (Theoharides, 2017) further extending their contribution to the symptoms of ME/CFS such as sleep disturbances dysfunctional HPA axis and fatigue due to thyroid dysfunction. Mast cells are wellknown for their role in allergic reactions, (Beaven, 2009) but mast cells are now considered important in innate and acquired immunity, (Galli, et al., 2008) antigen presentation, (Gong, et al., 2010) and inflammation (Theoharides, et al., 2010a). Mast cells can be stimulated by neurons, hormones, environmental, neuroimmune, pathogenic and stress triggers. (Table 3), (Theoharides, et al., 2015d), (Theoharides, 2017). Reactive oxygen species (ROS) can also stimulate mast cells (Swindle and Metcalfe, 2007). (Robuffo, et al., 2017), (Toniato, et al., 2017) Mast cells also secrete leptin that could contribute to cachexia and fatigue (Taildeman, et al., 2009). Mast cells secrete as many as 100 different mediators (Table 4) (Mukai, et al., 2018), (Theoharides and Kalogeromitros, 2006) (Wernersson and Pejler, 2014) often selectively without degranulation (Theoharides, et al., 2007), utilizing different secretory pathways (Xu, et al., 2018). Mast cells can also secrete danger signals, (Theoharides, 2016), including many chemokines and cytokines (Conti, et al., 2017),(Mukai, et al., 2018) especially mitochondrial DNA (mtDNA), (Zhang, et al., 2012) which could act as an “innate pathogen” (Zhang, et al., 2011) leading to a localized brain autoinflammatory response (Collins, et al., 2004;Marques, et al., 2012;Sun, et al., 2013;Theoharides, et al., 2013). Extracellular mtDNA could either be secreted directly in the diencephalon or could reach the brain through lymphatics (Louveau, et al., 2015). We had reported that mtDNA is increased in the serum of children with autism spectrum disorder (ASD) (Zhang B, et al., 2010). Mast cellderived mediators can then stimulate microglia (Zhang, et al., 2016), (Patel, et al., 2016) to secrete additional proinflammatory and homeostasisdisrupting molecules (Table 5) contributing to fatigue and neuropsychiatric symptoms (Theoharides TC., et al., 2016). It is interesting that peptide Y was found to be elevated in plasma of patients with ME/CFS and correlated significantly with stress (Fletcher, et al., 2010), as this peptide is known to stimulate mast cells (Mousli and Landry, 1994). An important part is that combination of triggers is likely to play a more important pathogenetic role than individual ones. For instance, we reported that combination of CRH and NT have synergistic action in stimulating VEGF secretion without tryptase from human mast cells (Donelan, et al., 2006), as well as induce the expression of each other’s receptors on human mast cells (Alysandratos, et al., 2012). More recently, we showed that the combination of SP and IL33 has synergistic action in stimulating TNF secretion without tryptase from human cultured mast cells (Taracanova, et al., 2017c). CRH is often released together with another peptide, neurotensin (NT), which is vasoactive (Leeman and Carraway, 1982) and has also been implicated in inflammation (Mustain, et al., 2011) and neurological diseases (Caceda, et al., 2006). NT is increased in the skin following acute stress (Theoharides, et al., 1998) and increases vascular permeability, an effect synergistic with CRH (Crompton, et al., 2003), (Donelan, et al., 2006). Mast cells are also stimulated by the peptide Substance P (SP), (Church, et al., 1991;Theoharides, et al., 2010d;Taracanova, et al., 2017a) initially characterized by Leeman and colleagues, (Chang and Leeman, 1970;Carraway and Leeman, 1973) and shown to participate in inflammatory processes (Mashaghi, et al., 2016;O'Connor, et al., 2004;Hokfelt, et al., 2001;Douglas and Leeman, 2011). IL33 is a member of the IL1 family of cytokines and has emerged as an early warning sign (dubbed “alarmin”) (Moulin, et al., 2007) in autoimmune or inflammatory process (Saluja, et al., 2015;Theoharides, et al., 2015a;Theoharides, 2016). IL33 is secreted by fibroblasts and endothelial cells, (Liew, et al., 2010) but also from mast cells. (Tung, et al., 2014) IL33 augments the effect of IgE on secretion of histamine from mast cells and basophils (Moulin, et al., 2007), (Silver, et al., 2010), but the effect of IL33 when used by itself or in combination with SP on secretion of IL1β from human mast cells has not been reported. Substance P stimulated secretion of VEGF, an action augmented by IL33 (Theoharides, et al., 2010e). We recently showed that stimulation of human mast cells by SP given together with IL33 markedly increases secretion and gene expression of the proinflammatory cytokine, TNF (Taracanova, et al., 2017b). Interestingly, chronic rhinosinusitis, which is quite common in patients with ME/CFS as discussed earlier, has been associated with high levels of nasal IL33 (Ozturan, et al., 2017), which could reach the hypothalamus through the cribriform plexus. Does any treatment modality work?There are currently no FDA approved drugs for the treatment of ME/CFS and the available psychological, physical and pharmacological interventions do not appear to be effective (Bains, 2008;Pae, et al., 2009;Morris and Maes, 2014;Loades, et al., 2016;Collatz, et al., 2016;CastroMarrero, et al., 2017;Brigden, et al., 2017). Mitochondria appear as one appealing drug target for the treatment of ME/CFS, but other papers reported no apparent alteration in ATP production (Shungu, et al., 2012b). Chemokines and cytokines have been proposed as targets for neuroinflammatory disorders (Pranzatelli, 2018), but such have not been tried in ME/CFS.The peroxisome proliferatoractivated receptor (PPAR) agonist bezafibrate improves mitochondrial function by stimulating mitochondrial biogenesis and increasing the oxidative phosphorylation efficiency in a number of studies (Valero, 2014;Wang, et al., 2010;Johri, et al., 2012). It has also been suggested that, since fatigue is associated with hypotension in ME/CFS patients, increasing blood pressure might present an effective therapeutic approach to this symptom. Even though previous studies using the mineralcorticoid fludrocortisone failed to show any improvement (Peterson, et al., 1998), (Rowe, et al., 2016), use of the agonist midodrine to increase blood pressure has produced some improvement of the fatigue (Naschitz, et al., 2004). Interestingly, angiotensin II inhibitors have been shown to increase mitochondrial membrane potential, to improve mitochondrial function and to stimulate mitochondrial biogenesis (Morris and Maes, 2014), (de Cavanagh, et al., 2011). Indeed, blockade of angiotensin II has been shown to prevent the onset of T2DM in mice by increasing fat oxidation, decreasing muscle triglycerides and improving glucose tolerance (Mitsuishi, et al., 2009). The angiotensin receptor blocker telmisartan improves mitochondrial dysfunction by enhancing mitochondrial biogenesis and protecting vascular and endothelial cell damage (Takeuchi, et al., 2013), (Kurokawa, et al., 2015). Similarly, the angiotensin receptor blocker losartan has been shown to improve mitochondrial respiratory chain function and coenzyme Q10 (CoQ10) content in hypertensive animals (Sumbalova, et al., 2010). However, given the blood pressure lowering effects of these agents it is unlikely they will be useful in ME/CFS, except maybe in select patients. Several natural compounds may have a beneficial effect on mitochondrial function. Magnesium ions play critical roles in energy metabolism and in maintaining normal muscle function, by being positively active regulator of glycolysis and of all enzymatic reactions involving phosphate group transfer from ATP (Dominguez, et al., 2006), (Morris and Maes, 2014). Several studies have demonstrated that magnesium ion supplements significantly increase muscle strength and maintain optimal physical activity performance in humans (Brilla and Haley, 1992), (Newhouse and Finstad, 2000), (Kass and Poeira, 2015), (Zhang, et al., 2017). In experimental animals, this improvement in exercise performance seems to occur via enhancing glucose availability in the brain and muscle, and via reducing/delaying lactate accumulation (Zhang, et al., 2017). Magnesium sulphate may also improve mitochondrial respiratory function and prevent nitrous oxide production in the brain (Xu, et al., 2002), (Yang X, et al., 2007). Coenzyme Q10 deficiency has been reported in patients with ME/CFS (Maes, et al., 2009), (Maes, et al., 2012), (Filler, et al., 2014). However, administration of CoQ10 to patients with ME/CFS have failed to show any benefit (Campagnolo, et al., 2017). Naturally occurring flavonoids have potent antioxidant, antiinflammatory and neuroprotective actions (Guo, et al., 2009;Middleton, et al., 2000;Xiao, et al., 2011) and are generally considered safe (Harwood, et al., 2007;Kawanishi, et al., 2005;Theoharides, et al., 2014;Theoharides, et al., 2014). The flavonoid genistein, attenuates muscle fatigue in humans by downregulating oxidative stress and enhancing antioxidant enzyme activity (Ding and Liu, 2011). The flavonoids epigallocatechin, naringin and curcumin can ameliorate ME/CFS symptoms in experimental models (Sachdeva, et al., 2009), (Vij, et al., 2009), (Gupta, et al., 2009), (Sachdeva, et al., 2011). Other reports have documented similar chronic fatigue attenuating effects for the Astragalus flavonoids (Kuo, et al., 2009) and of olive extract (Gupta, et al., 2010). The isoflavones genistein and daidzein, have been shown to reverse the effects of polyinosinic:polycytidylic acid (poly(I:C) on mouse locomotor activity and brain inflammatory mediator expression in a mouse model of fatigue (Vasiadi, et al., 2014). Quercetin appears to increase exercise tolerance by attenuating oxidative stress in mouse brain, while at the same time conferring antioxidant and antiinflammatory action (Kempuraj, et al., 2005), (Davis, et al., 2009), (Ishisaka, et al., 2011). Luteolin suppresses adipocyte activation of macrophages and inflammation (Deqiu, et al., 2011;Ando, et al., 2009), while it increases insulin sensitivity of the endothelium (Deqiu, et al., 2011). Luteolin also inhibits mast cells (Asadi, et al., 2010;Weng, et al., 2015;Patel and Theoharides, 2017) and microglia (Jang, et al., 2008),(Patel, et al., 2016). In this context, it is interesting that luteolin improved symptoms of both ASD (Taliou, et al., 2013), (Tsilioni, et al., 2015), postLyme syndrome (Theoharides and Stewart, 2016) and brain fog (Theoharides, et al., 2015b) in openlabel trials. We recently showed that tetramethoxyluteolin is more potent than luteolin in its ability to inhibit human cultured microglia (Patel, et al., 2016) and mast cells (Patel and Theoharides, 2017). Intranasal administration of select flavonoids may reduce inflammation in the hypothalamus and correct the central pathogenesis of ME/CFS. Novel treatment approaches are required to address the central pathogenic processes. For instance, intranasal administration of microvesicleentrapped curcumin was shown to inhibit inflammation of the brain in a mouse model (Sun, et al., 2010). ConclusionsOverall, the ME/CFS phenotype has been associated with apparent abnormalities in the metabolic profile, possibly due to local inflammation in the hypothalamus. Compounds that could inhibit inflammation in the brain, such as tetramethoxyluteolin or the antiinflammatory cytokine IL37 (Dinarello, et al., 2016), (Mastrangelo, et al., 2018), may be potential treatment options.  DISCLOSURESTCT is the inventor of US patents No. 7,906,153; No. 8,268,365 and PCT application No. 13/722, 397 for the treatment of neuroinflammatory conditions. Diagrammatic representation of the proposed mast cellmicroglia interactions in the hypothalamus, contribute to the pathogenesis of ME/CFS, and could serve as targets for treatment.Hypothalamic mast cells are stimulated by stressassociated triggers such as CRH, HK1 and SP along with mtDNA and IL33, some derived from nasal cavity, while others may reach the area through a disrupted bloodbrain barrier or through lymphatics. Stimulated mast cells then secrete molecules such as CXCL8, NT, TNF, tryptase and mtDNA, (CXCL) which activate microglia to secrete more inflammatory molecules especially, IL1β, IL6, and CXCL8 that further disrupt homeostasis, causes mitochondrial dysfunction and contribute to symptoms of ME/CFS. Luteolin could inhibit these processes at different steps as shown. Table 1. Conditions Often Comorbid with ME/CFS\_______________________________________________________________________\_• Chronic inflammatory response syndrome (CIRS)• Fibromyalgia syndrome (FMS)• EhlersDanlos Syndrome (EDS)• Gulf War Illness (GWI)• Interstitial cystitis/bladder pain syndrome (IC/BPS)• Irritable bowel syndrome (IBS)• Mast cell activation syndrome (MCAS)• Multiple chemical sensitivity syndrome (MCSS)• PostLyme syndrome• Postural orthostatic tachycardia syndrome (POTS)• Posttraumatic stress disorder (PTSD)• Restless leg syndrome\______________________________________________________________________\_   Table 2. Dysregulated Molecules that May Contribute to the Pathogenesis of ME/CFS \______________________________________________________________________\_ • Cachexins• Calcineurin• Heavy metals• Herbicides• Inflammatory cytokines• Leptin• Melatonin• miRNAs• Mitochondrial enzymes• Neuroendocrine disruptors• Neuropeptides• Neurotransmitters• Reactive Oxygen Species• Toxins (mycotoxins, Borrelia toxins)• Uncoupling protein 2• Xenobiotics\______________________________________________________________________\_   Table 3. Mast Cell Triggers  Stimulating degranulation AcetylcholineAdenosineComplement fragments* C3α, C4α, C5αDrugs* Local anesthetics, lactam antibiotics, neuromuscular junction blockers, vancomycinEosinophil granule proteinsIgEIgG1IgG4LysophosphatidylserineHistamineSerotoninLysophosphatidic acidPeptides* Adrenomedullin, CGRP, Endorphin, Endothelin, Hemokinin1, Leptin, Mastoparan,Neurotensin, NGF, PTH, Somatostatin, SP, Thrombin, VIPTryptase Stimulating selective release of mediators without degranulation ATPBorrelia burgdorferi (Lyme Disease)CRHHeavy metals* Aluminum, cadmium, mercuryHerbicides* Atrazine, glyphosateIL33MycotoxinsLPSSCFViruses    _\__\__________________________________________________________________\_ Table 4. Mast Cell MediatorsMediators Pathophysiologic effect PrestoredBiogenic AminesDopamine NeurotransmissionHistamine Vasodilation, angiogenesis, mitogenesis, pain5Hydroxytryptamine (5HT, serotonin) Polyamines Vasoconstriction, painSpermidine, spermine Secretory granule stability, inhibition of secretionChemokinesIL8 (CXCL8), MCP1 (CCL2), MCP3 (CCL7), Chemoattraction and tissue infiltration of leukocytes MCP4, RANTES (CCL5), Eotaxin (CCL11) CytokinesIL4, IL5, IL6, IL15, IL17, IL31, IL33, TNFEnzymes Immune cell maturation, inflammationArylsulfatases A Lipid/proteoglycan hydrolysisBetahexosaminidase Degradation processesBetaglucuronidase Degradation processesBetaglucosaminidase Degradation processesBetaDgalactosidase Degradation processesCarboxypeptidase A Peptide processingCathepsins B,C, D, E, L Degradation processesChymase Tissue damage, pain, angiotensin II synthesisGrnzyme B Inflammation and preapoptotic effectsKinogenases Synthesis of vasodilatory kinins, painPhospholipases Arachidonic acid generationRenin Angiotensin II generationTryptase Tissue damage, activation of PAR, inflammation, painMetalloproteinases(CPA3, MMP9, ADAMTSS)Growth factors Tissue damage, modification of cytokines/chemokinesbFGF NeovascularizationNGF Nerve growth, mast cell activationSCF Mast cell growth and activationTGFβ Antiinflammatory, profibroticVEGF PeptidesACTH Neovascularization, vasodilationAngiogenin NeovascularizationAngiopoietin NeovascularizationCorticotropinreleasing hormone Inflammation, mast cell stimulus, vasodilationEndorphins AnalgesiaEndothelin SepsisHemokinin1 Inflammation, mast cell stimulus, pain, vasodilationKinins (bradykinin) Inflammation, mast cell stimulus, pain, vasodilationLeptin Food intake regulatorMeltonin Biologic clock regulatorNeurotensin Inflammation, mast cell stimulus, vasodilationRANKL Osteoclast differentiation and activationSomatostatin Mast cell stimulant, antisecretorySubstance P Inflammation, mast cell stimulus, painUrocortin Inflammation, vasodilationVasoactive intestinal peptide Proteoglycans Vasodilation, mast cell activationChondroitin sulfate Cartilage synthesis, antiinflammatoryHeparin Angiogenesis, nerve growth factor stabilizationHyaluronic acid Connective tissue, nerve growth factor stabilizationSerglycin De novo synthesizedChemokinesCCL2, CXCL8, MIP1α, MCP1Cytokines Storage of granule proteasesInterleukins (IL)\1,2,3,4,5,6,8,9,10,13,16,18 Inflammation, leukocyte migration, painIFNα, IFN\ β, IFNγ; MIF; TGFβ; TNF, Growth Factors Inflammation, leukocyte proliferation/activationSCF, βFGF, neurotrophin 3, NGF, Growth of a variety of cellsPDGF, TGFβ, VEGFNitric oxidePhospholipid metabolites VasodilationLeukotriene B4 Leukocyte chemotaxisLeukotriene C4 Vasoconstriction, painPlatelet activating factor Platelet activation, vasodilationProstaglandin D2 Bronchonstriction, pain    \______________________________________________________________________\_Table 5. Microglia Mediators\____________________________________________________________________\_ Cytokines• IL1β• IL6• TNF Chemokines• CCL2• CXCL8 (IL8)• CCL5 (MCP1)\____________________________________________________________________\_   Figure 1. Much evidence suggests that the pathophysiology of ME/CFS is highly associated with alterations in normal energy metabolic processes (Fluge, et al., 2016) and abnormalities in cellular bioenergetics (Fluge, et al., 2016;Hornig, et al., 2015), (Fluge, et al., 2016), (Tomas, et al., 2017)  REFERENCES Abbi B and Natelson BH (2013) Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the 'single syndrome' hypothesis. QJM 106:39.Akin C (2014) Mast Cell Activation Disorders. J Allergy Clin Immunol Pract 2:252257.Alevizos M, Karagkouni A, Panagiotidou S, Vasiadi M and Theoharides TC (2013) Stress triggers coronary mast cells leading to cardiac events. 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9) Hippocampus

 

10) HPA Axis
Much CFS research concerns the HPA axis, the images below show the relation between HPA axis and sleep

 

 

2) Cell Danger Response Theory

 

                       Cell Danger Response Theory 

 

3) Sleep Disorders

 

page 32 CFS > ALLOPATHIC MEDICINES > SLEEP, SLEEP DISORDERS,  APNEA MACHINE AND SNORE SURGERY

page 31

 

Page Table of contents

1) Overview

 

2) Fatigue (customary or chronic)

 2a) Cognitive Fatigue

 2b) Biological Processes Associated With Fatigue

 2c) Diseases associated with fatigue (Disease Hierarchy)

 2e) Fatigue (as Disease), Interaction with Substances

 2f) Gene Interaction with Fatigue (as Disease)

 2g) Molecular Functions Associated With Fatigue

 2h) Pathways Associated With Fatigue

 

3) List of Sleep Disorders

                               International Classification of Sleep Disorders (ICSD), ICSD-3 Sleep Disorder Categories1. InsomniaThe ICSD-3 defines insomnia as "a repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity and circumstances for sleep, and results in some form of daytime impairment."The ICSD-3 groups insomnia into 4 major categories listed below.a. Chronic insomnia disorderb. Short-term insomnia disorderc. Other insomnia disorderd. Isolated symptoms and normal variant 2. Sleep-related breathing disordersThese disorders are divided into those of central origin (characterized by a lack of breathing effort) and those caused by an obstruction of the airways. a. Obstructive sleep apnea disordersi. Obstructive sleep apnea, adultii. Obstructive sleep apnea, pediatricb. Central sleep apnea syndromei. Central sleep apnea with Cheyne-Stokes breathingii. Central sleep apnea due to a medical disorder w/o Cheyne-Stokes breathingiii. Central sleep apnea due to high altitude periodic breathingiv. Central sleep apnea due to medicaiton or substancev. Primary central sleep apneavi. Primary central sleep apnea of infancyvii. Primary central sleep apnea of prematurityviii. Treatment-emergent central sleep apneac. Sleep-related hypoventilation disordersi. Obesity hypoventilation syndromeii. Congenital central alveoloar hypoventilation syndromeiii. Late-onset central hypoventilation with hypothalamic dysfunctioniv. Idiopathic central alveolar hypoventilationv. Sleep-related hypoventilation due to medication or substancevi. Sleep-related hypoventilation due to medical disorderd. Sleep-related hypoxemia disordere. Isolated symptoms and normal variantsi. Snoringii. Catathrenia 3. Central disorders of hypersomnolenceThe ICSD-3 categorizes this class of sleep disorders as those in which "the primary complaint is daytime sleepiness not caused by disturbed nocturnal sleep or misaligned circadian rhythms." a. Narcolepsy type Ib. Narcolepsy type IIc. Idiopathic hypersomniad. Kleine-Levin syndromee. Hypersomnia due to a medical disorderf. Hypersomnia due to a medication or substanceg. Hypersomnia associated with a psychiatric disorderh. Insufficient sleep syndrome 4. Circadian rhythm sleep-wake disordersThese disorders are characterized by a disturbance or disruption to the normal circadian rhythm, which causes patients to experience excessive daytime sleepiness, insomnia, or both.a. Delayed sleep-wake phase disorderb. Advanced sleep-wake phase disorderc. Irregular sleep-wake rhythmd. Non-24-hour sleep-wake rhythm disordere. Shift work disorderf. Jet lag disorderg. Circadian rhythm sleep-wake disorder not otherwise specified (NOS) 5. ParasomniasA parasomnia is an unwanted physical movement or action during sleep. This group of disorders is classified by disorders or arousal from NREM sleep, those associated with REM sleep, and other parasomnias.a. NREM-related parasomniasi. Disorders of arousal from NREM sleepii. Confusional arousalsiii. Sleepwalkingiv. Sleep terrorsv. Sleep-related eating disordersb. REM-related parasomniasi. REM sleep behavior disorderii. Recurrent isolated sleep paralysisiii. Nightmare disorderc. Other parasomniasi. Exploding head syndromeii. Sleep-related hallucinationsiii. Sleep enuresisiv. Parasomnia due to medical disorderv. Parasomnia due to medication or substancevi. Parasomnia, unspecifiedd. Isolated symptoms and normal variantsi. Sleep talking 6. Sleep-related movement disordersThis class of disorders is characterizeed by simple, often repetitive movements during sleep or wake that can disrupt the sleep of the patient, the patient's bed partner, or both.a. Restelss leg syndromeb. Periodic limb movement disorderc.Sleep related leg crampsd. Sleep-related bruxisme. Sleep-related rhythmic movement disorderf. Benign sleep myoclonus of infancyg. Propriospinal myoclonus at sleep onseth. Sleep-related movement disorder due to medical disorderi. Sleep-related movement disorder due to medication or substancej. Sleep-related movement disorder, unspecified 

 3a) Sleep Disturbances and CFS as sleep disorder

 3b) Hypersomnolence, Hypersomnias

 3c) Excessive daytime sleepiness (EDS)

 3e) Sleep Apnea (obstructive or Central)

  3e i) Neurological Effects of Apnea

   3e ia) Treatment

    3e ib) Cpap, Apap, Spap (etc) machinery

    3e ic) Apnea surgery

    3e iii) Dental mold sleep positioner device

    3e iv) CPAP and surgery alternatives

 

4) Sleep circuits, Systems and Regions

 4a) Reticular Activating System

 4b) Ascending Arousal Pathway (ARAS)

  4b i) Ascending Arousal Systems in the Regulation of Sleep and Awakefulness Mediated by the Basal Forebrain

  4b ii) Neuroanatomic Connectivity of the Ascending Arousal System Critical to Consciousness and Its Disorders

 4c) Descending Reticular Activating System (DRAS)

 4e) Hypocretin/Orexin System

 4f) GABA/galaninergic System

  4f i) GABA receptors

  4f ii) Modulation of Vigilance in the Primary Hypersomnias by Endogenous Enhancement of GABAA Receptors

  4f iii) The relationship between sleep and wakefulness may depend on the balance of activity in the GABA/galaninergic systems                   and orexin/hypercretin systems of the posterior hypothalamus

  4f iv) Histaminergic neurons of the hypothalamic tuberomammillary nucleus constitute a major wake‐promoting system

 4g) Somnogen in Cerebrospinal Spinal Fluid of Hypersomnia Patients, and (Endogenous) Enhancement of GABAA Receptors

 4h) Hypothalamus

  4hi) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome as Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus

  4hii) "The sleep switch", hypothalamic control of sleep and wakefulness

 4i) Hippocampus

 4j) HPA axis

 

5) Sleep Medicine

 5a) Histamino‐mimetic drugs such as H3‐receptor inverse agonists could, in fact, become a treatment option not only in patients with narcolepsy (Lin et al., 2008) but also for those with EDS of other origin

 5b) Drugs for narcolepsy

                                                                     Drugs prescribed for narcolepsy

• Adderall
• Provigil
• Xyrem
• modafinil
• Nuvigil
• sodium
• lisdexamfetamine Vyvanse
• Ritalin
• Wakix
• Xywav
• pitolisant
• methylphenidate
• Concerta
• Dexedrine
• dextroamphetamine
• armodafinil
• amphetamine / dextroamphetamine
• Methylin
• amphetamine
• desvenlafaxine Off-label
• Methylin ER
• Zenzedi
• Sunosi
• ProCentra
• Evekeo
• solriamfetol
• calcium oxybate / magnesium oxybate / potassium oxybate / sodium oxybate

  

 5c) Treatment with Flumazenil (GABAA receptor antagonist)

 5e) Sleep aid drugs

 

6) CFS similarities analogy to Hibernation state

 6a) Cell Danger Response Theory

 6b) Best diet for patients affected by CDR

 

7) Fatigue from TBI and Factors contributing to chronic fatigue after traumatic brain injury

 7a) Sleep Disturbance After Traumatic Brain Injury (TBI)

 7b) TBI and hormones

 7c) Changes in Emotions or Sleep Patterns

 7e) Disturbed sleep

        Nocturnia

 

8) Studies done on Sleep Issues (links)

 

9) Miscellaneous

 9a) Sleepiness

 9b) Cortisol Mean, Cortisol Slope, or Abnormal Cortisol Levels Were not Related to  9c) Neurocognitive Symptoms, Psychiatric Status, or Sleep Difficulties (just 1 study)
 9c) Indirectly sleep related

                                                              Indirectly sleep relatedreported deficiencies in the urea and the TCA cycles, (ornithine/citrulline and pyruvate/isocitrate ratios)  reported deficiencies in the urea and the TCA cycles, (ornithine/citrulline and pyruvate/isocitrate ratios), which ultimately result in reduced levels of ATP production in patients with ME/CFS (Yamano, et al., 2016).  Reduced Substrates That enter oxidation downstream of pyruvate dehydrogenase (PDH)  Studies revealed that ME/CFS have reduced substrates that enter oxidation downstream of pyruvate dehydrogenase (PDH), such as glutamine, glutamate and phenylalanine, thus suggesting impaired pyruvate catabolism, which ultimately results in increased utilization of acetyl-CoA-producing amino acids as alternative substrates for fuelling aerobic metabolism via the TCA cycle (Armstrong, et al., 2012), (Armstrong CW, et al., 2015), (Fluge, et al., 2016).  Glutamine  Phenylalanine  Reduced concentrations of amino acids that maintain TCA cycle capacity (suggesting) impaired fuelling of the TCA cycle by pyruvate  Reduced concentrations of amino acids that maintain TCA cycle capacity were detected in patients with ME/CFS (Fluge, etal., 2016), suggesting impaired fuelling of the TCA cycle by pyruvate.  TCA cycle intermediates reduced in Urea and Plasma  Reduced ATP production is associated with increased levels of reactive oxygen species (ROS)  The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia  Increased ROS in CFS and FM, resulting in impaired mitochondrial function and reduced ATP in muscle and neural cells, might lead to chronic widespread pain in these patients. Therefore, targeting increased ROS by antioxidants and targeting the mitochondrial biogenesis could offer a solution for the chronic pain in these patients. The role of exercise therapy in restoring mitochondrial dysfunction remains to be explored, and provides important avenues for future research in this area  Reduced ATP production is associated with increased levels of reactive oxygen species (ROS), which may ultimately lead to mitochondrial damage and the hypometabolic profile of ME/CFS (Naviaux, et al., 2016)&nbsp;(Armstrong CW, et al., 2015)  Mitochondrial Inhibition, Damage and Hypometabolism  ROS (and Ros mediated damage)  reduced levels of ATP or ATP production  Steroidogenic Pathways  Neurosteroidal Systems  Steroid Hormones  T1T2 cycle  DHEA DHEA’s involvement in immune homeostasis is anti-Th2/pro-Th1  steroids cortisol damaging, check oxidatn  noroadrenaline the problemcfs  modulator of [neurotrophic factor receptors  Abnormalities in Cerebral Perfusion  Abnormalities of AMPK activation and glucose uptake  Effect of EPS on AMPK activation, MHC expression and cytotoxicity  

​

Fatigue

Oxford Textbook of Neurorehabilitation (2 edition 'The impact of fatigue on neurorehabilitation'

https://oxfordmedicine.com/view/10.1093/med/9780198824954.001.0001/med-9780198824954-chapter-26

                      The impact of fatigue on neurorehabilitation IntroductionThough difficult to define, and abstract in conceptualization, fatigue is an experience familiar to all. Consequently, it is not itself pathological but is experienced to an extreme and disabling degree in many neurological conditions. In chronic fatigue syndrome (CFS) extreme fatigue is the central feature of the condition, and the physiological changes and behaviours associated with it probably contribute to the pervasiveness of symptoms and chronicity of the problem. These physiological changes and behaviours likely also contribute to fatigue in other conditions. These often represent potentially remediable factors, and consequently are important to identify and address. An individualized formulation is crucial to achieving this, a principle which will guide the structure of this chapter. First, we will consider how factors innate to neurological conditions and those secondary to them can contribute to fatigue. Then, we will discuss how understanding of these factors can be synthesized in the formulation to guide treatment. This chapter will focus on the commonest neurological conditions in which fatigue is prominent; multiple sclerosis (MS), stroke, Parkinson’s disease (PD), and traumatic brain injury (TBI). The same principles are applicable to fatigue in other neurological conditions General issuesWhat is fatigue? The distinction between ‘normal’ and ‘pathological’ fatigue is unavoidably arbitrary. Nonpathological fatigue would be the experience of being tired after exercise, with energy restored after rest [1] . Definitions of pathological fatigue vary, but that of the MS Council’s is a good example, namely: ‘a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities’ [2]. The subjectivity of fatigue is emphasized in this definition, which is consistent with the description of (poststroke) fatigue as ‘weariness unrelated to previous exertion levels and usually not ameliorated by rest’ [3]. Other definitions, such as Staub and Bogousslavsky’s, emphasize the subjective need for greater effort, which does seem to be a core feature of the fatigue experience in all contexts [4 Though attempts have been made to separate physical and mental fatigue, this is often neither feasible nor useful. Others favour dividing fatigue in to ‘central’ and ‘peripheral’ components. Chaudhuri and Behan (2000) for example, define central fatigue as ‘the failure to initiate and/or sustain attentional tasks and physical activities requiring selfmotivation (as opposed to external stimulation)’, whereas peripheral fatigue is regarded as primarily physical or muscular in nature [5] . Central fatigue would be exemplified by the perception that more effort is required to undertake a task than is normal in the absence of any overt physical disability (i.e. a sensory symptom), while peripheral fatigue might be characterized by the objective documentation that voluntary power declines during a task or on repetition of that task (i.e. a motor sign) [6]. Notwithstanding that neurophysiological testing is crucial in distinguishing the level of involvement of the motor system, in practice the usefulness even of this more considered distinction can be questionable [7]. Perceived levels of central and peripheral fatigue covary, and even in myasthenia gravis, that exemplar of ‘peripheral fatigue’, reports of mental fatigue are common [8 Fatigue is dissociable from sleepiness although there is overlapping symptomatology [9] . Sleepiness is a physiological phenomenon, depending on previous sleep and occurring at regular intervals following a circadian rhythm [10]. By contrast, fatigue describes persistent physical or mental exhaustion, not necessarily accompanied by sleepiness, and which sleep cannot alleviate. A patient may have both, and they are associated with common factors (e.g. the release of proinflammatory cytokines) [11]. Apathy, even harder to distinguish from fatigue, is a feeling of indifference; fatigued patients generally retain an interest in their hobbies and interests, they just do not have the energy to undertake them Recently models of the ‘predictive brain’ from computational neuroscience have been applied to try and provide a unifying theory to understand fatigue. These models conceptualize the brain as constantly trying to minimize ‘surprise’ by predicting sensory input while simultaneously driving behaviour to maintain homeostasis. Within this model, Stephan et al. propose fatigue to be a feeling arisen from a state of chronic dyshomeostasis [12]. Essentially, in the context of a chronic perturbation (which in MS for example could be chronically elevated cytokines or dopamine imbalance due to failure of nonmotor functions of the basal ganglia) there is persistent interoceptive surprise which represents a warning to the brain that it cannot maintain homeostasis. This may underpin the experience of fatigue, which as it is accompanied by metacognitive recognition of the failure of homeostatic control strategies, impacts on selfefficacy beliefs and is associated with discomfort. It may drive rest, but as this does not result in resolution of fatigue, predictions are modified with the expectation fatigue will be an enduring state. Consequently, even if the precipitating perturbation does resolve, this expectation can persist. This prediction alters neurocomputational processes during monitoring and preparation of effortful physical activity which results in the ongoing experience of fatigue [13]; the related changes in behaviour continue, further maintaining the fatigued state Complementing the predictive brain model of perception is the idea that the motor cortex generates predictions of the sensory consequences of its output, this ‘efference copy’ alerting sensory cortices to upcoming feedback and changing their response properties. This efferent copy is experienced as a sensory experience, the force developed by a muscular group being perceived indirectly through the effort necessary to generate it [14]. The active inference theory of sensorimotor control expands on this, postulating that for a movement to be initiated (and sensory predictions to be fulfilled), ascending sensory errors must not be attended to, a process known as ‘sensory attenuation’ [15]. In Annapoorna Kuppuswamy’s words, ‘we have to transiently suspend attention to sensory evidence we are not moving’ [16]. If this process of sensory attenuation is impaired, it is argued, these ascending sensory errors are attended to, which is inferred by the brain as more than the estimated effort being required to perform the muscle contraction [16]. It is this which is experienced as fatigue. As expected by the predictive brain model of fatigue, this memory of effortful activities influences resting state spontaneous neuronal firing meaning that over time chronic fatigue is experienced even at rest How to measure a subjective conceptPeripheral fatigue, as an acute tendency for force generating capacity to diminish during sustained effort, can be fairly easily described and quantified. It is attributed to mechanisms such as the failure of neuromuscular transmission, metabolic disturbances, defects of muscle membranes, or peripheral circulatory failure [5] . Central fatigue is subjective, warranting intervention when a patient endorses the symptom, its importance, and desire for treatment. Many attempts have been made to quantify it. Mead et al. identified over 50 scales used to assess fatigue poststroke [17], some of the more commonly encountered being summarized in Table 26.1. Others have taken a different approach to assessing fatigue. For example, in stroke a semistructured interview has been used, and ‘caseness’ defined as fatigue present most days for >50% of waking hours which interferes with everyday activities [18]. This approach has also been used to define CFS. It is clear however that all cutoffs for ‘caseness’ are arbitrary, and as all assessments rely on subjective reporting they do not differentiate inability to generate or maintain the required effort/force from disinclination to do so [6 Attempts have been made to objectively quantify ‘central’ fatigue. In ‘cognitive’ fatigue, likely best conceptualized as one component of it, these have generally measured performance on tasks requiring sustained attention. Meaningful associations between subjective reports of fatigue and neuropsychological measures have been elusive however [19]. This is perhaps unsurprising given the lack of an association between cognitive complaints and performance on neuropsychological assessment [20]. Though an MS study did report an association between subjective fatigue and performance when executive demands were very high [21], and a stroke study related fatigue to attentional and executive impairment [22], objective measures of central fatigue are currently of little clinical utility Another way of categorizing fatigue is dividing it into perceived fatigue and performance fatigability. Perceived fatigue is defined as subjective sensation and measured by questionnaires. Performance fatigability in contrast is a decline of objective measures of physical or cognitive performance over a discreet period of time and measured by physical or cognitive tasks. Use of this approach has been suggested in stroke [23, 24], PD [24], and MS [25]. In most cases, fatigue and fatigability probably coexist. Systematic review of 19 MS studies (n = 848) showed that there is a significant correlation between fatigue and fatigability (r = 0.31; p <0.001). However, the strength of the association between those two constructs was not high enough to conclude that fatigue and fatigability are the same phenomenon and they should be assessed separately [25]. This has implications for practice, as perceived fatigue and fatiguability may respond to different treatment approaches EpidemiologyCommunity studies report a prevalence of debilitating fatigue lasting at least six months of around 5% [26]. Greater fatigue is weakly associated with increasing age, female gender and, possibly, lower socioeconomic status [27, 28]. The prevalence of fatigue in neurological conditions is increased beyond what would be expected solely on the basis of age and disability, being estimated to affect 30–80% of patients (see Table 26.2) [24]. Patients also often report a qualitative difference in their experience of fatigue after acquiring a neurologic illness, describing it as ‘overwhelming’ and ‘mindnumbing’ [29, 30]. Impact of fatigueApproximately 40% of MS and onethird of PD patients report fatigue as their most disabling symptom [31, 32]. Fatigue imposes significant socioeconomic consequences, including loss of work hours and may be the most important factor in loss of employment [33, 34]. Fatigue was identified as one of the top ten research priorities relating to life after stroke, as agreed by stroke survivors, caregivers, and health professionals [35 Aetiology and associationsA combination of biological, psychological, and social factors contributes to fatigue in all patients.Though the relative contribution of each varies between diagnosis and patient, failure to consider each sphere can lead to suboptimal treatment in all. Obvious examples are failure to consider depression in an individual who has prominent fatigue following a stroke, or overlooking medication side effects in a patient with CFS. Psychosocial issues, including unhelpful health beliefs, are particularly important to identify in neurological disease, as these may be the most modifiable maintaining factors. Though divisions are fluid, in this section potential contributions to fatigue will be separated into ‘primary’ and ‘secondary’ factors. The former are directly attributable to the neurological disease process, while the latter are physiological, psychological, or behavioural changes occurring as direct or indirect consequences. CFS is an example of a condition in which extreme fatigue exists in the absence of overt neurological pathology, but the presence of immunological and endocrine abnormalities is well established. This demonstrates both the arbitrary separation between ‘primary’ and ‘secondary’ factors and the potentially profound impact that the latter can have. Effective treatment for CFS suggests what may improve fatigue in other conditions. Primary factorsDirect brain pathologyNeurological disorders are due to abnormalities of the structure or function of the nervous system. Those associated with fatigue affect diverse brain regions however, and fatigue is also prominent in medical and psychiatric conditions in which brain structural abnormalities are subtle or absent. Consequently, fatigue is unlikely to be localized to a discrete brain region  Structural MRI studies of MS have reported associations between fatigue and volume loss [36], with atrophy in the striatum, thalamus, frontal, and parietal cortex particularly highlighted [37, 38]. In a 2009 crosssectional study poststroke fatigue was more common in stroke than transient ischaemic attack (TIA) patients, suggesting at least some poststroke fatigue might be attributable to brain damage [39]. Systematic review found no association between fatigue and white matter lesions or brain atrophy however, though some studies did report an association with infratentorial or basal ganglia stroke [40]. No TBI studies examine correlations between structural abnormalities with fatigue, but clinical markers of injury severity do not predict fatigue [41]. A study in patients who had had penetrating TBI found that fatigue was associated with ventromedial prefrontal cortex damage [42]. Reduced grey matter volume is reported in CFS [43], with increased prefrontal cortex volume following treatment with cognitive behavioural therapy (CBT) [44]. In summary, when structural abnormalities are identified they implicate involvement of frontal and subcortical brain regions in fatigue  As fatigue likely involves distributed brain regions, functional imaging may provide greater insights into its mechanisms. These approaches generally support the concept that fatigue is associated with damage to cortical–subcortical circuitry, particularly circuits involved in attention and executive function. In MS there is decreased regional glucose metabolism in the frontal cortex and basal ganglia of fatigued patients [45]; in TBI brain activity is increased in the middle frontal lobe, basal ganglia, and anterior cingulate during a speeded cognitive task [46]; in PD decreases in frontal lobe perfusion are greater in patients with fatigue than those without (which was associated with executive function impairments) [47]; and CFS patients had differing patterns of activation of prefrontal cortical regions compared to healthy controls [48]. Functional imaging studies of fatigued stroke patients have not been undertaken, but poststroke fatigue has been related to attentional and executive impairment [22]. Fatigue in PD could be associated with a reduction in serotonergic function in the basal ganglia and limbic structures and insular dopaminergic dysfunction [49  In summary, convergent data across neurological conditions suggest dysfunction in the striatalthalamicfrontal system is important in fatigue. These impairments may necessitate higher levels of mental effort for complex tasks, which increases subjective fatigue. In conditions with damaged brain structure (e.g. MS, TBI) recruitment of expanded pools of cortical neurons likely reflects brain plasticity unmasking latent pathways. Though adaptive, it may be energy intensive, excessive use of neuronal pools resulting in fatigue [50]. Returning to the predictive brain model of fatigue, metacognitive detection of such a general slowing and inefficiency of cognition, may lead to a similar sensation of fatigue as when caused by bodily dyshomeostasis [12]. In CFS disruption again seems present but likely arises through different routes, which may include mechanisms such as sustained abnormalities of attentional focus. Impairments in regulation of bodily states important in maintaining fatigue may be the consequence rather than cause of beliefs about low allostatic selfefficacy. Inflammation and endocrine factorsInflammation is associated with fatigue, as evident from the lethargy of acute infections. This is mediated by proinflammatory cytokines, which act on the brain to result in drowsiness, loss of appetite, decreased activity and withdrawal from social interaction [51]. It is thought that these cytokines drive the enzyme indole2,3dioxygenase (IDO) to transform tryptophan into kynurenine; this means that less tryptophan is available for generation of serotonin (levels of which are reduced), but also results in accumulation of kynurenine [52]. Kynurenine is further catabolized into neuroactive metabolites such as kynurenic acid and quinolinic acid which are neurotoxic and believed to lead to dysfunction of frontostriatal networks and ultimately sickness behaviour [53  The association between treatment with interferon alpha (IFNα) and fatigue (which is dissociable from depression) is of course well recognized [54]. As inflammatory degenerative disorders, elevated cytokines are particularly relevant to fatigue in MS and systemic lupus erythematosus. Serum levels of TNFα, IFNγ and IL6 have all been shown to be elevated in fatigued versus nonfatigued MS patients [55–57]. Cytokines are however also elevated poststroke and TBI [58, 59], in CFS [60], and even in PD [61], and depression [62], likely also contributing to fatigue in these conditions  Alterations in the hypothalamicpituitaryadrenal (HPA) axis are among the most replicated findings in CFS, mild hypocortisolaemia being consistently reported and attributed to enhanced negative feedback in the HPA axis [63]. This contrasts with the increased HPA axis activity and raised cortisol levels seen in depression [64]. Whereas hormonal changes are relatively subtle in MS and CFS, in TBI, they can be gross and necessitate replacement treatment; this is the case most obviously in pituitary stroke. In TBI these abnormalities are not restricted to the acute phase, with as many as 25% of longterm survivors showing one or more pituitary hormone deficiencies [65]. As well as hypocortisolaemia and hypothyroidism being obvious causes of fatigue, an association with lowered growth and sex hormone levels following TBI has been reported [66, 67  Pituitary dysfunction is common after TBI and stroke, especially subarachnoid haemorrhage (SAH). According to Booij et al., up to 85% of stroke survivors have some degree of pituitary dysfunction [68]. Growth hormone deficiency was most common and was found in nearly half of patients after TBI or SAH. Data on the association between fatigue and pituitary dysfunction are scarce however and more research is needed  Genetic polymorphisms. Most studies examining the relationship between genetic polymorphisms and fatigue have been in CFS. Proposed generelated contributors to fatigue include neurotransmitter dysregulation, changes in activity of the HPA axis, immune dysregulation, and abnormalities in muscle metabolism. Wang et al. recently reviewed associations between single nucleotide polymorphisms (SNPs) and fatigue in CFS, cancer and other medical conditions [69]. SNPs in regulatory pathways of neurotransmitters and the immune system were associated with fatigue in all three groups, with several reports of associations with SNPs in regulatory pathways of the serotonergic system and HPA axis in CFS. One study reported that SNPs could be used to predict CFS with 72–76% accuracy, but to our knowledge this has not been replicated [70  Associations between genetic polymorphisms and fatigue in neurological disease have received little attention. Of six serotoninassociated genes examined, ChoiKwon et al. found a relationship with poststroke fatigue only with a polymorphism associated with low monoamine oxidase A activity—and this association was present only in women [71]. A small, exploratory, poststroke study of two genes involved in inflammatory processes reported that specific genetic polymorphisms associated with higher circulating inflammatory biomarkers (such as IL1β and C reactive protein) were associated with greater selfreported fatigue [72]. Intriguing though these findings are however, the reality is that studies tend to be small and are generally unreplicated; at the present time genetic testing generally has no direct clinical application to fatigue management. Secondary factorsOther medical problemsThe possibility of additional medical pathology must be remembered. There should be blood screens for common haematologic and metabolic conditions and thyroid dysfunction. Recommended investigations to aid diagnosis of CFS, exclude other conditions and ‘red flags’ for alternative diagnostic explanations are shown in Box 26.1 [73]. In MS vitamin D deficiency is common. An association with fatigue has been found in the general population and a randomized controlled trial (RCT) has reported fatigue improved on treatment with cholecalciferol [74]. Though an RCT found cholecalciferol did not reduce fatigue in patients with relapsing remitting MS being treated with IFN, patients were not selected on the basis of vitamin D deficiency [75]. In fatigued patients it seems reasonable to consider checking 25hydroxy vitamin D levels, initiating treating if low. Infections can worsen fatigue and should be excluded [76]. An MS exacerbation may present as fatigue prior to clinical manifestation [77]. Medication side effects Medications frequently causing fatigue include antispasticity agents (e.g. Baclofen or Tizanidine), narcotic analgesics, sedative hypnotic, or anticonvulsant agents, sedative antidepressants or anxiolytics and antihypertensive medication [78]. Patients often report increased fatigue with interferon therapy, though fatigue often improves with time on interferon [79]. Pretreating with nonsteroidal antiinflammatory may improve IFN associated fatigue [78]. Hypertension or hypotension secondary to excessive antihypertensive use may be associated with poststroke fatigue, though whether there is a causal relationship is uncertain [80]. It is unlikely that poststroke fatigue could be a mere side effect of medications, but polypharmacy can certainly increase the likelihood of it developing [81  Mobility issues and environment In stroke, TBI and MS ambulation can be compromised by spasticity and weakness. Gait can be inefficient, requiring excessive energy expenditure that quickly fatigues the patient [82]. This will reduce physical activity causing physical deconditioning. The oxygen cost of breathing is increased in PD patients, meaning they require more energy simply to breath [83]. Energy loss with tremors and dyskinesias has also been demonstrated [84].  Hyperthermia contributes to fatigue during exercise in healthy people [85], but the strong association between heat and symptom exacerbation (Uhthoff’s phenomenon) is a particular characteristic of MS. It affects 60–80% of MS patients and is attributed to increased body temperature inducing conduction block in vulnerable axons [86]. Deconditioning can result through avoidance of exercise/activity to prevent symptom exacerbation [87]. Psychiatric conditionsFatigue and depression after stroke have a bidirectional association (i.e. patients with fatigue are more depressed and patients with depression are more fatigued) [88]. Fatigue is a core feature of depression, present in around 25% of people with neurological disorder [89]. Depression severity correlates with fatigue severity [90], and should never be dismissed as simply ‘an appropriate reaction to a serious illness’. Indeed, rather than being ‘secondary’ to neurological conditions its aetiology is often not clearly separable from the neurological disease process itself. A positive correlation has also been reported between anxiety and subjective fatigue [91].  Identification of depression in neurological conditions is complicated by many symptoms (e.g. fatigue, reduced attention and concentration, disturbed sleep) being features of the diseases themselves. Consequently, greater emphasis should be placed on cognitive than somatic symptoms, the presence of guilt, worthlessness, hopelessness, and suicidality strongly suggesting depression. The pattern of fatigue observed in depression is rather different from that in neurological conditions. Fatigue in depression tends to be worst in the morning, improve as the day goes on, and not be relieved by sleep; MS fatigue by contrast is best in the morning, worsens as the day goes on, and rest gives some relief. Substance misuse is strongly associated with fatigue and should always be considered.  Anxiety is less studied than depression, but in the Nottingham Fatigue After Stroke study (which excluded participants with high levels of depressive symptoms) was found to be strongly associated with fatigue at both 4–6 weeks and 6 months poststroke [92, 93]. It is clearly conceivable that anxiety, with its associated increase in threatrelated attention, could both intensify the perception of fatigue and drive avoidance and deconditioning. Sleep disordersIn neurological disorders fatigue has a consistent relationship with broken sleep. Correlations with daytime sleepiness however, though present in TBI and PD, are surprisingly weak in MS [94–96]. Nonetheless, patients reporting daytime sleepiness should be screened for potential sleep disorders, including obstructive sleep apnoea, narcolepsy, and restless leg syndrome/periodic limb movement disorder. The latter are actually very common in MS [97], while sleep disordered breathing is a particular issue after stroke [98], and various sleep disorders are core features of PD [99]. Initial insomnia in the absence of obvious medical cause suggests anxiety, while early morning waking with inability to get back to sleep is more characteristic of depression. Other diseaseassociated problems such as pain, spasticity, and nocturnal micturition also impact on sleep and require specific interventions. Pain Pain is common and can be difficult to treat. Robust correlations between pain and fatigue are reported in various neurological conditions [100, 101]. It is speculated that pain may contribute to fatigue through a reduction in central motor drive [102]. If associated with activity it will encourage activity avoidance. About 10% of patients after stroke present with triad of pain, fatigue, and depression and 20% pain and fatigue [101]. Poor nutritionAs 50–80% of inhospital stroke patients have one or more eating difficulties related to neurologic deficits, it is unsurprising that 50% of stroke inpatients are malnourished [103]. Westergren reported that six months poststroke poorer nutritional status was closely related to a lack of energy [104]. Effects are likely bidirectional, giving rise to a vicious circle. DeconditioningDeconditioning is a complex physiological process in which the lack of use of the body’s cardiovascular, neuromuscular, biomechanical, and musculoskeletal systems leads to a decrease in their functional capacity, and the body’s efficiency [105]. This reduces the capacity for exercise and increase the perception of effort required for a given level of activity. Though evidence of significantly reduced physical fitness in CFS compared to sedentary controls is conflicting, a systematic review concluded that there was reduced physiological exercise capacity in CFS and that deconditioning is a perpetuating factor [106]. Though other factors likely contribute too, some evidence for the presence of deconditioning is provided by the proven efficacy of graded exercise programmes in reducing symptoms of CFS [107]. Neurological conditions are associated with substantial reductions in activity, and deconditioning has been reported in MS, stroke, TBI, and in PD [108–111]. Beliefs about activity/cognitive style Cognitive factors believed to contribute to the maintenance of CFS include a tendency to focus on fatigue and perceive it as a negative experience (which consequently amplifies its perception), beliefs of having a very limited ability to be active (leading to very low levels of activity) and expectations of chronicity (which fits with the ‘predictive brain’ model of expectation determining perception) [112, 113]. In CFS a strong belief in a physical cause of the illness, a strong focus on bodily sensations, and a poor sense of control over symptoms contribute to fatigue severity and functional impairment [114]. The importance of fear of symptom exacerbation in CFS was elegantly demonstrated in a cycling task. It was a more important determinant of distance travelled than physical symptoms, physical disability, mood, and other illness perceptions [115].  It is likely that similar cognitions and attentional biases magnify fatigue in some with neurological disorders. Beliefs about the dangers of activity may be expected in MS, given that elevated body temperature or prolonged exertion exacerbates symptoms [78]. Focusing on personal emotions, selfblame, and maladaptive coping (e.g. denial and selfdistraction) have been associated with poststroke fatigue [116]. Though unstudied, it is likely that after a catastrophic event such as stroke fears of provoking a further stroke inhibit engagement with exercise in some patients. It has been reported in MS that a sense of control, (often referred to as selfefficacy), reduces feelings of fatigue, whereas focusing on bodily sensations aggravates it [117]. MS patients who catastrophize about experiencing symptoms (expecting the worst possible outcome), who are embarrassed about symptoms, or who believe symptoms are always a sign of physical damage are more likely to be fatigued [118 A systematic review incorporating studies in cancer, CFS, MS, fibromyalgia and healthy individuals confirmed a significant association between catastrophizing and fatigue [119]. Other cognitive styles also influence fatigue and activity levels. For example, a qualitative study examining what determined whether people resumed previously valued activities after stroke identified ‘allornothing’ thinking as a barrier [120]. ‘Allornothing behaviour’ (i.e. overdoing things when feeling better then needing to rest for prolonged periods to recover) is associated with fatigue in MS [118]. Preinjury factors and response to stressorsPersonality is assumed to influence vulnerability to CFS, but crosssectional studies confound state and trait effects. A prospective study did however report that higher emotional instability (an individual’s tendency to experience psychological distress) and selfreported stress were risk factors for the condition [121]. Acute physical or psychological stress might trigger the onset of CFS, it being shown that severe stressful events or difficulties are more common in the period prior to onset of the illness than in population controls [122].  Having a severe neurological disorder is a significant stressor, and dispositional differences in response to stress must contribute to fatigue in at least some patients. Though prospective studies are lacking, crosssectional data reports higher emotional instability is associated with greater fatigue in MS and cancer [123, 124] and neuroticism and fatigue after stroke [125]. An association between fatigue and perceived stress has also been reported [126]. In a cohort which excluded participants with substantial depressive symptoms, prestroke fatigue increased the risk of poststroke fatigue; indeed (together with having a spouse or partner, lower Rivermead Mobility Index score, and higher depressive and anxiety symptomatology), prestroke fatigue accounted for approximately 47% of the variance in Fatigue Severity Scale scores at 4–6 weeks poststroke [92]. Assessment of prestroke fatigue is obviously retrospective and susceptible to recall bias, however [127], and the picture further complicated by fatigue itself being a risk factor for stroke [127  TreatmentThe multifactorial nature of fatigue is captured by a biopsychosocial formulation, which facilitates an individualized understanding of maintaining factors and guides multidisciplinary management. A model formulation is depicted in Fig. 26.1. Unfortunately, the evidence base for the treatment of fatigue in neurological conditions is poor. Most research on fatigue treatment has been in CFS and MS, so evidence will often be extrapolated from these conditions. The absence of overt neurological pathology in CFS means this must be done with caution. However, as discussed earlier, there is considerable overlap between biological, psychological, and behavioural findings in fatigued individuals across diagnoses, which provides some justification. ‘Secondary’ factors certainly contribute substantially to fatigue in neurological conditions, and being generally more modifiable than the disease process itself are important treatment targets. Review treatment of neurological condition and directly related problemsThough fatigue is a side effect of some immunomodulatory agents used to treat MS, diseasemodifying drugs can actually reduce fatigue. This is reported even with IFNβ, but the effect with Glatiramer Acetate is significantly greater [128]. A crosssectional casecontrolled study suggested Natalizumab may have greatest effect [129]. There is not strong evidence that teriflunomide or dimethylfumarate improve MS fatigue, though patient ratings with both treatments compare favourably to IFNβ [130, 131]. PD drugs are implicated both in exacerbating and reducing fatigue. Pramipexole has been associated with increased subjective fatigue in several RCTs [132], while Carbidopa–levodopa reduced muscle fatigue in experimental studies [133]. Two RCTs reported a beneficial impact of the MAOB inhibitor rasagiline on fatigue in patients with PD [134, 135]. That of Stocchi et al. was by far the largest (n = 1176) and reported less progression of fatigue in recently diagnosed PD patients treated with rasagiline 1 mg or 2 mg when compared to placebo over 9 months [135]. The study evaluated the agent as a diseasemodifying drug and the authors caution that reducing progression of fatigue does not necessarily equate to ‘treatment’. Assessing subjective fatigue is further complicated in PD by whether the patient is in an ‘on’ or ‘off’ sate. Stroke and TBI do not currently have ‘direct’ treatments, but some symptomatic or secondary prevention interventions are associated with fatigue  Identify and treat medical comorbidity and full medication reviewComorbid medical conditions are common in neurological disorders, and are almost universally associated with fatigue Sleep and nutritionSleepSpecific sleep disorders should be identified and treated. Sleep phase disorders are addressed by entraining a regular sleepwake cycle, and melatonin and/or light treatment may assist. CBT has good evidence in treating insomnia in the nonneurological population, with positive studies in TBI and MS [136, 137]. Though hypnotics and sedative antidepressants can be helpful, the high incidence of side effects (falls, hallucinations, sedation, cognitive deficits, bowel and bladder problems, etc.) necessitates caution. Personal experience suggests trazodone and mirtazapine as sedative antidepressants associated with fewest problems, and if they must be used short acting hypnotics (used short term) are preferable to long acting ones. First line treatment of periodic limb movement disorder (PLMD) is reassurance, though dopamine agonists or levodopa can help if treatment is required [138]. Marked relief with ropinirole or pramipexole is reported in poststroke restless leg syndrome (RLS) [139], though ferritin levels should always be checked (and iron deficiency corrected) before starting treatment. Though significant depression must be treated, remember that antidepressants can aggravate RLS and PLMD [98]. Deep brain stimulation has been recommended for the treatment of insomnia in advanced PD [140]. NutritionAll patients should be supported in having a balanced, healthy diet. Even skipping breakfast has been associated with fatigue [141]. In MS, RCTs report adherence to a low fat, low cholesterol diet supplemented with olive oil capsules significantly reduce fatigue [142], but vitamin D or omega3fatty acids do not [143, 144].  Carnitine contributes to cellular energy metabolism, and deficiency may reduce energy production through impaired fatty acid oxidation. An RCT of fatigued elderly individuals without current significant medical morbidity found 4 g a day of acetyl Lcarnitine for 180 days reduced physical and mental fatigue compared to placebo [145]. In an open label randomized study in CFS acetylcarnitine and propionylcarnitine both reduced fatigue, though improvement was reduced with combined treatment [146]. A small crossover randomized trial found acetyl Lcarnitine 2 g daily was associated with greater reduction in MS fatigue (measured by the Fatigue Severity Scale (FSS)) than amantadine 200 mg [147]; in a subsequent study however only amantadine performed better than placebo [148]. Despite reported benefit in various medical conditions, the impact of carnitine on fatigue has not been examined in other neurological conditions. Physical aids and interventionsPhysical aids Use of orthoses or functional electrical stimulators can improve gait mechanics, promote energy conservation, and improve the safety of walking [78], but evidence they reduce fatigue is lacking. Temperature controlGiven the association between heat stress and MS symptom deterioration, simple strategies to minimize heat exposure, such as performing work or exercise during the early morning or late evening when it is cooler, seem sensible. Observational studies report benefit from simple cooling strategies such as cold showers, applying ice packs, and drinking cold beverages [87]. Precooling, essentially immersing the lower limbs in cool water, was shown to have some benefit in terms of walk performance and fatigue ratings [149]. In an RCT, cooling garments demonstrated subjective reductions in fatigue in thermally sensitive MS patients, though blinding of patients was not achieved [140]. Anecdotal evidence suggests 4Aminopyridine limits worsening of MS symptoms during heat exposure or exercise [87]. Treatment of psychiatric conditionsIdentification and treatment of depression and anxiety is crucial, but beyond the scope of this chapter. If insomnia is a major problem sedative antidepressants may be preferable, whereas energizing antidepressants, (such as selective serotonin reuptake inhibitors), may be first choice if fatigue is prominent but initial insomnia not a major issue [150]. Unfortunately, and likely reflecting the multifactorial nature of fatigue, cancer research shows that antidepressant treatment may not improve fatigue even when it treats depression [151]. There is no evidence antidepressants improve fatigue in the absence of depression [152]. Exercise and energy conservation strategiesExercise Exercise improves exercise tolerance and reduces fatigue in healthy individuals as well as those with longterm conditions [153]. Benefit is however not limited to the physical dimension of fatigue, as exercise also improves mood, reduces anxiety and fear [154], and improves cognitive performance [155]. These benefits are likely consequent to associated physiological and anatomical changes, such as increased production of growth factors, increased efficiency of the cerebral vascular system, enhanced hippocampal neurogenesis, and regulation of the immune and endocrine systems [1] . Understanding of how this occurs is fast increasing, a recent study showing voluntary wheelrunning induced gene expression in the mouse hippocampus [155]. As well as addressing deconditioning through these overtly neurobiological mechanisms, exercise gradually allows patients to experience mastery and restore selfefficacy and likely influences effort perception  Andreasen et al. categorized exercise interventions as endurance training (ET), resistance training, combined training (CT), and ‘other’ training modalities (OT) [156]. In general ET, or aerobic exercise, is most consistently beneficial. Walking is especially recommended, but swimming or cycling may also be appropriate [157]. Exercise programmes must be properly planned, gradually building levels of activity to promote increasing stamina and prevent unhelpful ‘boombust cycles’ occurring. This means regular exercise sessions start from a level that does not result in postexertional malaise, with the length and frequency of the exercise sessions progressively increasing. The CFS literature shows that, compared with a symptomcontingent approach, a timecontingent approach leads to greater improvements in fatigue and physical functioning [157]. A measurement (time, distance walked, etc.) rather than symptom experience should determine whether a session ends, this likely underpinning the superiority of graded exercise over adaptive pacing [107]. Though patients may be anxious about undertaking an exercise programme, there is no reason why graded exercise carried out under appropriate professional supervision should be harmful. Research on the efficacy of exercisebased interventions in specific conditions will be discussed next  Chronic fatigue syndromeA 2011 metaanalysis of five RCTs supported the efficacy of graded exercise in the treatment of CFS [158]. Since this the results of the PACE trial, the largest (n = 640) and most important trial of graded exercise therapy (GET), CBT, and adaptive pacing in CFS have been published. It reported that CBT and GET both had an odds ratio for trial recovery compared to standard care or adaptive pacing of around 3.5, and concluded they ‘can safely be added to specialist medical care to moderately improve outcomes for CFS’ [107]. Concerns about the safety of GET are not evidence based [159]. The underlying principle of gradually increasing activity may be applicable to cognitive activity too, implying CFS sufferers should be encouraged to undertake gradually more challenging intellectual tasks, starting from a tolerable level [157  Multiple sclerosisA recent systematic review evaluated the impact of various psychological interventions on fatigue; these including CBT, relaxation, and mindfulness. CBT was found to significantly reduce fatigue, this effect being evident compared to both treatment as usual (five studies, SMD: −0.32; 95% CI: −0.63 to −0.01) and active controls (three studies, pooled SMD −0.71, 95% CI: −1.05 to −0.37) [173]. Interestingly, though a pilot study, of the studies comparing CBT to treatment as usual the largest effect was actually seen with a telephonesupported internetbased version of this intervention, suggesting this may be a viable costeffective option [174]. The CBT model utilized in the three studies with an active comparator could be rather eclectic, but the largest combined explanation of the cognitive behavioural model of fatigue, activity scheduling, sleep hygiene, and changing unhelpful cognitions about fatigue [175]. It reported that fatigue decreased with both CBT and the relaxation control, but reductions were greater with CBT (effect size 3.0 vs. 1.8). Changing perceptions of fatigue (e.g. perceiving it as more controllable, as time limited and as having less serious consequences) mediated the decreases in fatigue [176]. The same metaanalysis reported that compared to nonactive controls, relaxation training (specifically progressive muscle relaxation) reduced fatigue (two studies, n = 110, SMD = −0.90; 95% CI: −1.30 to −0.51); it is worth noting however that in one of these small studies it was actually outperformed by reflexology [177]. In a relatively large study (n = 150) mindfulness training reduced fatigue [178], a finding replicated in two subsequent RCTs [179, 180]. Mindfulness aims to reduce stress through teaching a nonjudgemental awareness of momenttomoment experience. StrokeAs discussed Zedlitz et al. reported that, though CBT alone had beneficial effects, reductions in poststroke fatigue were greater when cognitive therapy was augmented with graded activity training [164]. The cognitive component was delivered in small groups and emphasized pacing, improved planning of activities and relaxation, with rather less focus on challenging unhelpful cognitions than CBT in the CFS and MS trials. A subsequent small RCT of more ‘typical’ CBT (n = 15), but including input from an exercise physiologist, also reported a positive effect [181]. These results need replication, but do emphasize the importance of exercise/graded activity accompanying any cognitive intervention for poststroke fatigue. A small uncontrolled pilot study suggested mindfulnessinformed CBT was associated with a reduction in poststroke fatigue [182], with a subsequent small RCT (n = 29) of mixed stroke and (severity unspecified) TBI patients also suggesting benefit for mental fatigue [183]. Parkinson’s diseaseA small RCT (n = 28) of computerized CBT found that thought it did benefit the target symptom, insomnia, there was no reduction in fatigue as measured by the FSS [184]. Multidisciplinary rehabilitationMultidisciplinary rehabilitation aims to reduce symptoms, increase independence, and maximize participation in society [185]. It is generally coordinated by a specialist doctor, delivered by a team of different therapists, and not protocolized, being tailored to individual needs and goals.  Several uncontrolled studies suggested multidisciplinary rehabilitation is beneficial in CFS [186]. Though impact on fatigue was not a specific focus in Khan et al.’s Cochrane review of the efficacy of multidisciplinary rehabilitation in MS, the review does summarize outcomes on this measure [185]. On the basis of two positive RCTs of outpatient rehabilitation they report there is limited evidence that high intensity programmes can provide shortterm benefit in fatigue, and insufficient evidence that a lower intensity programme can reduce fatigue. A homebased intervention had no impact on fatigue compared to standard care, and the only study comparing inpatient rehabilitation to standard care was negative. This review is being updated [187]. We identified one subsequent relevant RCT which found that outpatient multidisciplinary team input (consisting of physiotherapy, occupational therapy and/or social work input) was not associated with improvement in fatigue relative to the control condition of MSnurse consultation in chronically fatigued MS patients [188]. As the authors acknowledge however advice from MS nurses overlapped with that from therapists, was often quite intensive (mean input 163 minutes vs. 280 minutes) and more medication changes were made in the control group (in 39% vs. 19% of patients). A mediumsized RCT (n = 122) in CFS reported that outpatient multidisciplinary rehabilitation outperformed CBT on assessments performed both after treatment completion and at 26week followup [189]. Though benefits of multidisciplinary rehabilitation have been reported in other neurological conditions, specific effects on fatigue have not been examined.  The potentially modest impact of multidisciplinary rehabilitation on fatigue in MS is initially surprising, as it likely includes elements of exercise treatment and cognitive interventions known to have good effect. This may reflect however that it is the delivery of evidencebased interventions directed at specific areas of need that is important rather than simply access to a variety of professionals [190]. MedicationDrugs such as antidepressants have proven benefit in treating secondary conditions common in neurological disease which contribute to fatigue. This section will focus on drugs used specifically to treat fatigue. AmantadineA recent metaanalysis reported that amantadine did reduce fatigue as measured by the FSS (SMD −1.09, CI −1.30 to −0.87), though levels of heterogeneity between included studies was high (I2 = 91%) [191]. It is the only pharmacological treatment for MSrelated fatigue recommended by the UK National Institute for Clinical Excellence [161]. The standard dose is 100–200 mg morning and early afternoon [150]. It is generally well tolerated but side effects can include hallucinations, vivid dreams, nausea, hyperactivity, anxiety, insomnia, constipation, and rash. We could identify no published trials examining the effects of amantadine on fatigue in stroke and TBI, but it was reportedly well tolerated (and effective) when trialled for irritability in the latter [192]. It did not reduce fatigue in a PD study which assessed this as a secondary outcome [193]; the risk of inducing psychotic symptoms is markedly elevated in PD. ModafinilModafinil is a nonamphetaminelike drug approved for the management of narcolepsy which has been used for daytime fatigue in other conditions. A metaanalysis of data from five RCTs (n = 303) showed that modafinil was superior to placebo in patients with MS according to Multidimensional Fatigue Inventory (MFI), while for the FSS there was no significant difference [194]. A small RCT reported improved poststroke fatigue as measured by the FSS (but not the MFI, which was the primary endpoint) [195]. A subsequent large RCT (n = 232) reported significant reductions in poststroke fatigue as measured by both scales after 6 weeks’ treatment with Modafinil 200 mg [196]. Two small RCTs examined the impact of Modafinil on PD fatigue. Though both did not report significant change on any of the FSSs used, one did report improvement in clinical global impression of fatigue [197]; no safety concerns were raised. A metaanalysis of two RCTs (n = 115), showed a therapeutic effect of modafinil on fatigue in TBI (measured by the FSS with a mean difference of –0.82 (95%CI –1.54 to –0.11 p = 0.02, I2= 0%) [198]. Modafinil is generally well tolerated, but serious, lifethreatening skin reactions, psychiatric adverse reactions (such as suicidal thoughts, depression, psychotic episodes) and cardiovascular adverse reactions (e.g. hypertension) have been reported [150]; these, together with the conflicting evidence of benefit, led the European Medicines Agency to conclude in 2011 that the benefits outweighed the risks only for narcolepsy. NICE does not recommend it for MS fatigue [192  Other pharmacological agentsTwo RCTs in MS did not separate effects of Pemoline from placebo [150]; this, together with potential for liver toxicity, mean it is rarely used. Prokarin is a proprietary blend of histamine and caffeine, administered as a cream. A single small MS RCT suggested it reduced fatigue compared to placebo [199]. A single small RCT reported that Methylphenidate 10 mg three times a day significantly reduced fatigue in PD and was well tolerated [200]. It has not been evaluated in other neurological conditions. Lack of replication of this study together with the fact it is a controlled drug, may worsen motor function and quality of life in PD, has a potential for abuse, and can cause insomnia, hypertension, and anorexia, have limited its use. An unreplicated randomized placebocontrolled crossover trial showed benefit from aspirin, daily dosage of 1300 mg, on MSrelated fatigue [201]. 4aminopyridine (Fampridine) does not seem to have a significant impact on MSrelated fatigue [202], despite the fact that good quality studies do report a beneficial impact on walking speed [203]. In a small pilot study (n =12) 10 mg at night of Doxepin, a tricyclic antidepressant, decreased fatigue as measured by the FSSS [204]; this study did not correct for multiple comparisons however, and any benefit could have been driven by improvements in insomnia. Other interventionsSeveral studies have examined the impact of transcranial direct current stimulation (tDCS) on MS fatigue. The most robust of these, targeting the left dorsolateral prefrontal cortex (DLPFC), reported benefit for performancebased measures of cognitive fatigue (it eliminated fatiguerelated increases in reaction time), but no effect on subjective fatigue ratings [205]. Claims have been made for acupuncture in MS fatigue, but the poor quality of studies make this difficult to recommend [206]. Morning treatment with 45 minutes of blue light therapy was found to reduce fatigue in a small RCT of TBI patients (n = 30); improvement was also seen in daytime sleepiness, which may have driven the effect [207]. Benefit was not seen with yellow light therapy and effects were lost on cessation of treatment. Though bright light helped daytime sleepiness in PD, improvements in fatigue were not seen [208]. A pragmatic approach to treating fatigue in neurological conditions This is detailed in Fig. 26.2. Exercise has the best evidence and should be encouraged in all patients. Ideally individually tailored programmes would be provided (e.g. the Exercise After Stroke programme delivered in some UK leisure centres). If not available, but mobility is reasonable, regular walks starting from a modest base are a good option. If there seem to be barriers/reservations about exercise, clinicians must explore what these are and correct any misunderstandings about the perceived dangers of activity/ exercise. CBT has reasonable evidence, but availability is limited. Additionally, many neurological conditions are associated with significant cognitive impairment, which likely reduces the benefit of CBT. Though evidence for pharmacological treatments is weak, amantadine and modafinil have been used. Given the position of the European Medicines Agency and NICE recommendations for the treatment of MS fatigue, the former should be regarded as first choice, though with particular cautions in PD. Carnitine may hold some promise, but further trials are wanted ​ ​ ​ ​  ​                                                                                                                          click here to closeback to top of article

 

Recomended 7 to 8 hours a night, every hour of sleep before midnight is worth 3 hours after 10

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I have long considered CFS a sleep related disorder. Most of my research was focusing on finding the hormonal signal(s) to the brain that tells the body to sleep. It is fascinating to discover, as per the research by Naviaux, that the signal resides not in the brain but in the blood itself!

 

Here I begin this page by examining Hibernation, Torpor, Dauer State and Cell Danger Response as it triggers a switch from aerobic to anaorobic metabolism in chronic fatigue syndrome patients, what induces the signals to the brain for this metabolic switch, and what can be done to switch it back

 

Eliminate the 'dangers' in the environment that trigger Cell Danger Response (CDR), such as:
Environmental stressors and toxins
Psychological and Emotional stressors and triggers

 

Eliminate the 'dangers' in the internal environment that trigger Cell Danger Response (CDR), such as:
Latent HHV6

 

Find a method to induce or encourage a switch back to aerobic metabolism such as:

antipuerinetic medicine
TCM

 

While waiting until such methods are found, to implement the best methods to subsist on anarobic metabolism such as:

High fat diet

Stress reduction

 

Fatigue diagrams

​   click for full size, click 'x' button to close  <>xclick here to close and return to report

 

1) Hibernation

 

                        Hydrogen Sulfide Induces Hibernation State in Chronic Fatigue Syndrome (click to open) ***

 

                       Towards understanding the neural origins of hibernation                    ***

 

                       Takeaways from 'Towards understanding the neural origins of hibernation' ***

 

 

page 32 CFS > ALLOPATHIC MEDICINES > SLEEP, SLEEP DISORDERS,  APNEA MACHINE AND SNORE SURGERY

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