Skill Level  2

Relevance:4 Technical Level:2

Page includes consideration of Phenytoin, Meldonium and Lithium

Page Synopsis: It turns out to be healed requires us to do the footwork, relying on doctors for a leadership role or advocacy is not advised


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CFS OCD and pTBI-CF surprisingly have much in common


1) About two-thirds of TBI patients will develop posttraumatic brain injury chronic fatigue (pTBI-CF)
'Factors contributing to chronic fatigue after traumatic brain injury'


2) CFS patients have psychological coconditions, conditions that are statistically more prevalent in CFS include attention deficit hyperactivity disorder, depression, generalized anxiety disorder, eating disorders

'Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus'


Those who report a diagnosis of CFS/ME have increased levels of psychiatric disorder prior to the onset of their fatigue symptoms. When present, this psychiatric disorder typically appears to be depression or anxiety
'The relationship between prior psychiatric disorder and chronic fatigue'

'Beyond tired'

compared with people with other chronic diseases, CFS patients had notably higher PTSD rates


3) CFS causes and may partly be caused by brain damage

'Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study'

The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate


we designed a longitudinal MRI study to investigate long term brain changes associated with CFS over 6 years using optimized voxel based morphometry (VBM) analysis. The purpose of this study is to (1) optimize VBM methodology for analysis of longitudinal images using simulated atrophy, (2) investigate longitudinal brain changes in patients with CFS, (3) detect brain structural differences between CFS and NCs, and (4) identify correlations in CFS between structural differences and disease severity measures


Compared with NC, CFS patients also showed decreased GM volume and increased T1w and T2w signal intensities near the contralateral ILOF. The absence of corresponding longitudinal findings in the right hemisphere may be a result of lower sensitivity in longitudinal studies and/or because the changes in CFS occurred soon after onset (before the first scan) and did not progress appreciably thereafter. The increased T2w signal intensities suggest possible decreased blood volume in these regions.31 Indeed, previous studies have found decreased regional cerebral blood flow in frontal and temporal lobes32 and decreased frontal oxygenation33 in patients with CFS. Thus, a gradual and chronic hypoperfusion of the brain may contribute to this continuing WM shrinkage

                     3b) CFS causes and may partly be caused by brain damage linksSimilar Brain Damage in Chronic Fatigue Syndrome and Sleep Apnea NHS inform - Scottish health information you can trust | NHS inform Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome | Brain Communications | Oxford Academic Beyond tired Long-Lasting Mental Fatigue After Traumatic Brain Injury – A Major Problem Most Often Neglected Diagnostic Criteria, Assessment, Relation to Emotional and Cognitive Problems, Cellular Background, and Aspects on Treatment | IntechOpen Chronic Fatigue Syndrome (for Teens) - Nemours KidsHealth Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome | PNAS Chronic fatigue syndrome - Wikipedia A unifying theory for cognitive abnormalities in functional neurological disorders, fibromyalgia and chronic fatigue syndrome: systematic review | Journal of Neurology, Neurosurgery & Psychiatry Systematic review and meta-analysis of cognitive impairment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) | Scientific Reports Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management - ScienceDirect COVID brain impact similar to Chronic Fatigue Syndrome Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) - NHS Brain Injury and the Chronic Fatigue Syndrome Brain | CFS Remission JCI - Pathomechanisms and possible interventions in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)  Post-Concussion Syndrome & Extreme Fatigue: Why You’re Exhausted and How to Make It Better Brain injury may cause chronic fatigue - ABC tv - Australian Broadcasting Corporation About the Disease - Solve ME/CFS Initiative 'Chronic Fatigue Syndrome and the Central Nervous System' The Journal of International Medical Research
  Fatigue After Brain Injury: Why It Occurs and How to Overcome It Chronic fatigue syndrome: Gradually figuring out what’s wrong - Harvard Health What is Brain Fog and Clouding of consciousness? The ultimate guide to understanding the symptoms, medical cause, and top treatment options to help reduce or get rid of the fog in your brain Chronic Fatigue Treatment in Chapel Hill | Leigh Brain and Spine Server Not Found chronic fatigue syndrome | Symptoms, Causes, & Treatment | Britannica What does M.E. feel like? | Action for ME What Is ME/CFS? – American ME and CFS Society Chronic Fatigue Syndrome (CFS): An Imprecisely Defined Infectious Disease Caused by Stealth Adapted Viruses Chronic Fatigue Syndrome Article Brain Injury, A Consequence Of Glandular Fever Could Trigger Fatigue Syndrome Neurofatigue / Invisible consequences / Consequences | Braininjury-explanation.com Study finds brain abnormalities in chronic fatigue patients | News Center | Stanford Medicine An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - PMC Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration - PMC ‘The brain injury that could be behind 30,000 case of chronic fatigue’ | Mail Online | 18 May 2014 | The ME Association Brain injury study finds chronic fatigue widely misunderstood | Headway Could ME/CFS be a Chronic, Ongoing Brain and Spinal Cord Injury - That is Exacerbated by Exertion? - Health Rising Brain on Fire: Widespread Neuroinflammation Found in Chronic Fatigue Syndrome (ME/CFS) - Health Rising Chronic fatigue syndrome patients had reduced activity in brain’s 'reward center' -- ScienceDaily Frontiers | Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods | Neurology Study Helps Explain ‘Brain Fog’ in Chronic Fatigue Syndrome Brain - MEpedia Fibro Fog and ME/CFS Brain Fog Overview Chronic Fatigue and Pituitary Dysfunction after Concussion - Casper De Toledo Progressive Brain Changes in Patients with Chronic Fatigue Syndrome: Are our brains starved of oxygen? - #MEAction Network Chronic fatigue syndrome: Changes in brain chemistry found Fatigue and Traumatic Brain Injury | Model Systems Knowledge Translation Center (MSKTC) Chronic fatigue syndrome (CFS) - Better Health Channel Chronic Fatigue Syndrome (CFS) Causes - Who Gets It and Why
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4) CFS patients eventually develop OCD like symptoms, Dr. Naviaux, “ASD and ME / CFS are on the same biological spectrum.”  Dr. Naviaux has encountered teenagers with ASD who develop ME / CFS, and adults with ME / CFS who develop autism-like symptoms of mutism, social withdrawal, sensory hypersensitivities, and OCD-like symptoms".


Both, he believes, are caused by a failure of the cell danger response (CDR) to shut down normally after a chemical or biological injury has been healed or cleared. Both disorders lead to abnormalities in metabolism that he has characterized using a laboratory tool called mass spectrometry and metabolomics

'Treating Autism and CFS: Could One Drug Help Both'


5) Cytokines are however also elevated poststroke and TBI, in CFS, and even in depression, likely also contributing to fatigue in these conditions


CFS patients had differing patterns of activation of prefrontal cortical regions compared to healthy controls

Oxford Textbook of Neurorehabilitation 2nd Edition
'The impact of fatigue on neurorehabilitation'


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 factors Inflammation 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



From: Reviving the Broken Marionette: Treatments for CFS/ME and Fibromyalgia

Phenytoin is believed to act by modulating glutamatergic transmission. It has been in clinical use as an anticonvulsant for over 50 years, but it is also an antiarrhythmic similar to lidocaine and mexiletine. It has analgesic, anxiolytic and mood stabilizing properties. Jay Goldstein has used it to treat CFS/ME and fibromyalgia in a low dose of 100 mg a day.62 He reports synergistic effects from combining it with gabapentin.


Phenytoin may also help tinnitus.63


Phenytoin is generally thought to have adverse effects on cognition, but this may only apply to the large doses used to treat epilepsy. Smaller doses have even been shown to positively influence cognition.64 In one study phenytoin was found to cause a significant increase in right brain volume in patients with PTSD.65


The most common side effects include tiredness, nausea, ataxia (impaired coordination), nystagmus, dizziness and tremor. Phenytoin may reduce the blood levels of folic acid, biotin, calcium, vitamins B1 and B12, vitamin D, vitamin K and carnitine, but folate also decreases blood levels of the drug. Phenytoin can also interact with a number of different medications, including many antibiotics, anticoagulants, azoles, opiates, benzodiazepines, other anticonvulsants and oral contraceptives.


Phenytoin is available virtually everywhere and it is very inexpensive. It can be used topically as an analgesic, but this form is not commercially available and must be compounded


What is meldonium and why was it banned


Meldonium is used to treat ischaemia: A lack of blood flow to parts of the body, particularly in cases of angina, chronic heart failure, cardiomyopathy and other cardiovascular disorders.The drug also helps to adjust the body's use of energy and can boost stamina and endurance. It increases blood flow, which improves exercise capacity in athletes and increased blood flow means more oxygen to muscle tissue

Lithium side effects can include fatigue. In some patients it has shown to combat fatigue. There are two types of medicinal Lithium Lithium is prescription and Lithium is otc. It may help CFS (page 3), TBIcf alttherapy (59) and OCD (68), supplements (8

Psilopcybin and neuroplasticity is a topic I will review and update the site with

For even more medicines and potential therapeutics, please visit links page




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