Dr Graham Exelby May 2024
This paper is part 3 of a series looking at the immune dysfunction, causes of cognitive impairment and other problems, and management protocols.
There are a number of ways that Covid can cause cognitive impairment. Severe Covid can be equivalent to 20 years of aging, with studies showing reduced mental capacity up to 2 years after infection. It is worth noting that no such deficits were seen in patients who had full recovery from Covid.(1) Multiple factors thought to contribute to neurological dysfunction in Long-COVID. These include persistent systemic inflammation with cytokine production, immune system activation and production of Reactive Oxygen Species (ROS).
Each patient requires a careful assessment and likely evaluation of the involved pathology. Cognitive impairment is a major symptom in POTS and its co-morbidities, and the combination of autonomic dysfunction, mechanical “drivers” all can contribute to cognitive impairment and other post-COVID symptoms, thus providing the potential for improvements based on these “drivers.”
The underlying causes may be elucidated by looking at previous history and co-morbidities as it can uncover areas where other treatment can be commenced, eg an underlying mechanical causes eg Thoracic Outlet Syndrome or Nutcracker Syndrome, as well as diet, and the multitude of environmental factors such as mould which are detailed in the series of POTS articles. (2)
Management described below is geared primarily towards the common fatigue and cognitive impairment, but also includes those with the marked autonomic instability that characterizes Postural Orthostatic Tachycardia Syndrome (POTS.) The recognized programs as described in the RACGP Guidelines (3) also should be followed, and the suggestions based on DNA findings by Dr Vittone (4) and ongoing research in POTS could be added where considered appropriate. The management of POTS is covered in the POTS series of web-pages.
RACGP Recommended Management Guidelines (3)
“Provide education, support and regular review of rehabilitation goals
Begin rehabilitation as early as possible, include a multidisciplinary team and arrange regular review and reassessment to assess function and new symptoms.
If red flags or serious complications are identified, arrange an emergency assessment or urgent opinion from a specialised service.
For all presentations, optimise the management of comorbidities and monitor and manage lifestyle factors (eg smoking, nutrition, sleep, alcohol use and physical activity).
Develop a management plan with the person addressing their main symptoms, problems or risk factors and access issues in determining location for further treatment or rehabilitation (eg home-based, telehealth or face-to-face options).
Fatigue: use a physical rehabilitation plan involving consultation with allied health professionals for cautious initiation and pacing of activity or movement.
Disturbance of smell and taste: consider smell and taste retraining.
Respiratory symptoms: advise breathing retraining to improve symptoms of dyspnoea.
People with post–COVID-19 condition may be referred to a team including but not limited to physiotherapists, occupational therapists, exercise physiologists, speech pathologists, dietitians, psychologists, rehabilitation physicians and/or geriatricians. Use local and regional protocols or health pathways to determine the optimal referral action.
Work with the individual to support return to pre-injury work or education. People should be encouraged to follow official guidance for vaccination, but explain that it is not known if vaccines have any effect on ongoing symptomatic COVID-19 or post–COVID-19 condition. Vaccination post infection has been shown to provide additional protection against reinfection when compared with natural immunity alone”(3)
“Rehabilitation services can be accessed through community health, rehabilitation programs or post–COVID-19 clinics, where available. Chronic disease planning, mental healthcare or other enhanced care plans may facilitate increased access to multidisciplinary care. Additional support may be required for frail or elderly people, people from Aboriginal or Torres Strait Islander communities and culturally and linguistically diverse communities.”(3)
Management at MCMC-Research
This is a personal management protocol. This may be used as possible suggestions in association with RACGP Guidelines. There are no Cochrane Guidelines at this point, and all treatments are based on research from around the world. Patients need to be made aware of this. As the DNA studies reap more information, the first responders TLR 2, TLR4 and mast cell mutations are likely to be critical in the individual patient response. A decision whether to modulate the TLR4 or microglial sensitization needs to be made, or do you suppress the mast cells or target the TLR2/astrocyte/glutamate pathway, concentrate on diet, mechanical drivers, or all of the above?
An initial assessment should include rating scales - which might include:
Central Sensitization Index (CSI) to assess sensitization, the cause of which may be astrocyte/glutamate with microglial/small fibre neuropathy + mast cell activation.(18)
Malmo POTS Severity Score. (19)
Modified Somatic Perceptions Questionairre (MSPQ) for autonomic stability.(20)
Fatigue Severity Scale (FSS) (21)
Bell's Functionality Scale to assess overall level of function (22)
In the POTS patients, especially when it has been triggered by COVID, we have found there is a high percentage that have QT prolongation shown in lying and standing ECGs. This makes the use of H1/H2 blockade with antihistamines and famotidine potentially risky until the prolongation can be controlled (which can be with sympathetic overactivity control with Japanese [Kiiko-Matsumoto in our studies] style acupuncture. In this situation consideration should be given to acupuncture, and/or nigella sativa which has been shown to oppose the spike protein which may be of benefit in early COVID. TLR4 modulation (see below) and/or oral ketotifen, as this may be useful when QT prolongation is present to modulate the mast cell response.
Our protocol supports a general approach that leads to individualised solutions:
Determine the various primary cellular elements involved- microglial, astrocytic or mast cell
Control the inflammatory and microembolic cascade if present
Control the sensitisation that separates these patients from other people with similar mechanical issues.
Control the immune, inflammatory, and dysautonomic responses.
Identify and (if possible) address the underlying mechanical problems that we have found present in all Long COVID patients with POTS, Fibromyalgia, Migraine.
Initial management with diet, mast cell blockade, TLR2, TLR3 or TLR4 modulation depending on history
Improve mitochondrial functioning- diet and consideration for NMN
Encourage DNA testing if not responding to identify individual metabolic pathway abnormalities
Initial management involves a detailed history from birth, to assess likely previous components to symptoms, as well as detailed family history to provide the clues to possible DNA abnormalities, for treatment and appropriate investigations undertaken. Most of the patients with long COVID with POTS or Fibromyalgia have a pattern of previous injury or minor symptomatology that is similar to that in other POTS patients.
There are vital clues in all, eg the head pressure whether lying, seated, standing and sometimes all 3, associated tinnitus, which may be pulse-synchronous or a high-pitched scream, or both, coathanger pain, and post exertional malaise (PEM), postural shortness of breath and ataxia to name a few.
Ultimately, our approach is simple: work out the drivers (especially in the spine and vascular compression), sort out dietary triggers; look at lifestyle, posture, occupational causes, commence mast cell blockade, supplement where necessary, and heal what has been damaged, if this is possible. Dr Vittone can provide the DNA/artificial intelligence assessment for each patient, providing the way to treat the affected metabolic pathways. DNA assessment is very helpful in the complex patients that appear to fail to management plans, This is particularly so in Long COVID.
Mast Cell Blockade- Studies have reported that H1 as well as H2 receptor antagonists, are associated with a reduced risk of infection and deterioration leading to intubation or death from COVID-19. These agents are considered to improve pulmonary symptoms of COVID-19 infection by blocking the histamine-mediated cytokine storm.(5)
The use of H1 + H2 blockade has been expanded in our clinic, using usually fexofenadine or cetirizine for H1 blockade twice daily and famotidine for H2 blockade up to 160 mg daily, and occasionally more subject to tolerance and QT changes, adding H4 blockade subject to response.
Low Dose Naltrexone (LDN) is a H4 blocker, and TLR4 modulator, reducing the cytokine response from TLR4 as well as having positive results with chronic fatigue. It must be emphasized that the results obtained with low dose naltrexone are not in a doctor’s normal TGA-approved formulary, so any patient using these doses are aware they are used without backup from therapeutic guidelines, as all work is still at a research level.(6)
There are a number of other agents that can be used including ketotifen especially if there is QT prolongation.
Famotidine in COVID-19- Mukherjee et al (7) reported that dsRNA virus activated mast cells also trigger innate immune signalling through TLR3, which causes activation of IRF3 and synthesis of interferons.
They found famotidine interferes with the histamine-induced inflammatory signalling and reduces the levels of inflammatory mediators CCL-2 and IL-6 that are triggering cytokine release, and ascribed this effect to the regulation of TLR3 expression by histamine H2 receptors on immune cells.
Brennan et al (8) reported in 2022 that using famotidine 80mg three times daily (240 mg/day) Famotidine was found to be safe and well-tolerated, reducing symptoms by 50% after 8 days.
They also showed that H2 blockade caused early recovery from elevated interferon alpha, presumably by modulating inflammation in organ tissues. It must be emphasized that the results obtained with high dose famotidine are beyond normal recommended doses, and that any patient using these doses are aware they are used at a research level.
Amitriptyline is a tricyclic antidepressant (TCA) commonly used to treat depression, neuropathic pain, and other chronic pain conditions. While the primary mechanism of action of amitriptyline is the inhibition of serotonin and norepinephrine reuptake, it has also been shown to have other effects, including anti-inflammatory and immunomodulatory properties. While there is no direct evidence of amitriptyline acting as a TLR4 modulator, it appears to have anti-inflammatory and immunomodulatory effects that could be indirectly related to TLR2 and TLR4 signalling.
Other TLR4 modulators include LDN, doxycycline, Nigella sativa, PEA, NMN, Glutathione, and Sulforaphanes.
A good starting point can be to add H1 and H2 blockade as soon as Tryptase (and sometimes Chromogranin in hyperadrenergic states) have been checked. Ideally heart rate variability assessed (a number of commercially available Holter monitors have this facility, or smart phone applications.) As described by Afrin, “normals” are incorrect. To reduce the histamine response and sensitization, we are using H1 blockade with fexofenadine or cetirizine (occasionally others), along with dietary change as a first-line treatment.(9)
Famotidine (H2 blockade) is then rapidly added, especially if there is any sign of continuing COVID activity in the long-COVID POTS patients. Even is apparent “past” infections, if symptoms of eg fatigue persist, blockade is usually very helpful, often in only a few weeks. Doses used usually are 40 mg twice daily, but may be started at much lower doses to aid tolerance. To be effective, famotidine may need to be increased to 160mg daily, with patient acknowledgement that these are research-based doses and greater than recommended doses. There is a subgroup of patients who are intolerant of this management. DNA profiling is likely to be needed in them. Ketotifen is useful when QT prolongation is present.
The research from Professors Marshall-Gradisnik and Smith’s team from Griffith University (6)(10) discovered mutations in an important TRP pathway (TRPM3 ion channel dysfunction) found Low Dose Naltrexone (LDN) of great assistance, and as it improves glymphatic function the various research pathways start to merge. APO E4 and PEMT (and similar) mutations appears to be a significant addition to risk.
Low dose naltrexone needs to be started at low dose, and increased slowly. Our starting dose is usually 0.5 mg daily in a compounded form, increasing weekly. We usually use 4 .5 mg daily as maximum dose, but benefits usually occur around 2 to 3 mg. The results of LDN may be improved by splitting the dose to every hours, as LDN has a short “half-life” of 4 hours.
The combination of histamine blockade, attention to diet usually improves patients’ well-being, the acupuncture can be added to control the autonomic instability, then the vascular and mechanical drivers need to be attended to. If there is evidence of glutamate disfunction, either in testing, or from co-morbidities (ADHD, ASD, migraine, fibromyalgia) reducing glutamate intake may produce significant improvements. The pure low glutamate diet is seldom effective as so many other issues are usually in place.(11)
Mechanical/ hydraulic “components”
Table 1: Established Co-morbidities and Possible Underlying Causes from Clinic Observations
Chronic Fatigue Syndrome
TLR4 / cytokine /microglial activation
Mast cell activation
Autonomic dysfunction including Intra-abdominal Compression Syndromes
Chronic pelvic pain syndrome/ primary dysmenorrhea
TLR4 / cytokine /microglial activation
Mast cell activation
Pelvic congestion syndrome
Intra-abdominal compression syndromes (especially May-Thurner and Nutcracker Syndromes with probable effects from paravertebral and azygous vein dysfunction)
Temporomandibular joint pain
Upper cervical dysfunction
Post-Traumatic Stress Disorder (PTSD)
Multiple chemical sensitivity
TLR4 / cytokine /microglial activation
Mast cell activation
Periodic limb movement disorder/ restless legs syndrome
Central sensitization (an aspect of increased spinal cord excitability related to impaired modulation by dopaminergic pathways) (12)
TLR4 / cytokine /microglial activation
Intra-abdominal compression syndromes
Mast cell activation
Food intolerance
Migraine /tension headaches
Upper cervical dysfunction (especially C2/3)
Impaired glymphatic flow and activated microglia and astrocytes (13)
Central sensitization
Intracranial Hypertension
CSF flow obstruction (including lymphatics head and neck)
Intracranial venous obstruction -See Intracranial Hypertension, Intracranial Hypotension and Craniovascular Pressure Change (14)
Postural Orthostatic Tachycardia Syndrome (POTS)
See Assembling the Pieces of POTS (2)
Fibromyalgia Syndrome
See Fibromyalgia Syndrome and the Linking with POTS and Chronic Fatigue Syndrome (15)
Many Long-COVID and POTS patients are easily fatigued while sitting at a computer, or reading on their phones, or driving and may even suffer panic attacks while driving. The role of the spine is obvious after whiplash or other spinal injury; but spinal problems can be occupational (e.g., in hairdressers, dentists, and nurses, who work with a rotated spine). This problem is likely to become more common, as people become more dependent on their computers and tablets without attending to their posture.
Shoulder pain is just so common. Often, it is not improved or is even made worse by normal shoulder treatments. Yet as one retraces the history of the injuries, there is often a thread implicating an injury to the thoracic outlet rather than to the shoulder itself. But as the rotator cuff wears anyway, the patient ends up as a diagnosis of rotator cuff syndrome or subacromial bursitis, as scans show worn rotator cuffs. Thus, the real problem is missed, and the patient’s treatment fails. An easy clue to TOS is the frozen shoulder, which appears to be a localised autonomic response, although there is no objective proof.
Cytokine-induced central sensitisation is the key to understanding why patients with POTS and long COVID are so ill whereas many people with similar mechanical issues (e.g., TOS) have few if any symptoms. Once the cytokine-induced sensitisation is controlled, symptom control may be seemingly simple (e.g., correction of posture during computer use, avoidance of the use of backpacks, correction of rotated thoracic spine or sustained neck flexion, especially at an angle affecting C2/3 that triggers a cascade of symptoms which are quite difficult to explain). Misguided physiotherapy and manipulation are common problems here.
We try to “turn off” the sensitisation before adding “Kiiko Matsumoto” acupuncture (which targets the ANS, to stabilise the autonomic instability) and appropriate physiotherapy to deal with the mechanical factors that can be corrected.
Cardiovascular deconditioning is a potential consequence of COVID-19, as periods of prolonged bedrest can lead to resting tachycardia, reduced exercise capacity, and a predisposition to orthostatic intolerance.
Deconditioning alone, however, does not explain the many other symptoms present in POTS, including cognitive impairment, gastrointestinal upset, sleep disturbances, and neuropathic pain. In many POTS patients, reconditioning programmes can lead to improvement, but they rarely lead to complete resolution of symptoms. The same has been found in post-COVID syndrome.
Addressing the patient’s deconditioning is a major part of managing POTS, regardless of the cause of the POTS, and usually requires a skilled exercise physiologist, physiotherapist often in combination with a lymphatic therapist or osteopath. Experience has shown the older concepts of pushing exercise even though it increases symptoms is counterproductive. The programme must be tailored for each patient and must be graded very slowly.
Patients with arterial Thoracic Outlet Syndrome (TOS) may need to be referred to vascular surgeons for assessment—for formal MRI angiography and other imaging and possible surgery. Patients with venous and neurogenic TOS generally go to our physiotherapists for assessment. Our programme is evolving, as there is no one-size-fits-all. Diagnosis is difficult in patients with EDS, hypermobility, C0/1/2/3/4 neck trauma, or other spine injuries, especially in the sacrococcygeal area.
The onset of intra-abdominal compression syndromes, is not uncommon after COVID. These may include Median Arcuate Ligament Syndrome (MALS), Superior Mesenteric Artery Syndrome (SMA) and Nutcracker Syndrome. Management of the Intra-abdominal compression syndrome is complex and difficult. Symptoms are often quite pronounced, and many are labelled as “eating disorders.”
Details on these treatable causes are detailed in the POTS articles.(2)
Mitochondrial repair
Deal with the mitochondrial dysfunction largely responsible for fatigue, cognitive impairment, low energy and memory loss
Keto /low histamine diet (low histamine major importance if has HNMT, Dao enzyme defect). If there is evidence of glutamate sensitization, this needs to be suitably modified. A frequent starting point is avoidance of soy and processed foods, plus any food the body perceives as a threat.
Nicotinamide adenine dinucleotide (NAD+) or precursor Nicotinamide mononucleotide (NMN) is a crucial coenzyme involved in cellular processes including energy metabolism, DNA repair, and regulation of cellular aging. While there is no direct evidence that NMN specifically modulates Toll-like receptor 4 (TLR4), it may have indirect effects on TLR4 signalling and inflammation through its role in enhancing NAD+ levels and sirtuin activation.
The phytochemical sulforaphane (in nature seen in cruciferous vegetables), eg EnduraCell is being utilized to activate Nrf2 (nuclear factor erythroid 2-related factor 2,) seen as an activator of cellular defence mechanisms to induce the expression of a battery of cytoprotective genes and help repair mitochondria, induce mitochondrial biogenesis and activate Beta oxidation in the mitochondria to clear and transform fatty acids into ketone. Ketones like BHB beta hydroxybutyrate are a critical signal in the brain that upregulates Brain-derived neurotrophic factor, critical for neuroplasticity and brain health.
Diet change can produce major improvement in symptoms, especially pain and fatigue. While criticized by many dieticians, the change to a low histamine ketogenic diet has sound scientific research.(16) Ketosis yields ATP through the catabolism of ketone bodies. During ketosis, ketone bodies undergo catabolism to produce energy, generating twenty-two ATP molecules and two GTP molecules per acetoacetate molecule that becomes oxidized in the mitochondria. Keto alone is helpful in many patients.
Nicotinamide mononucleotide (NMN) is a molecule naturally occurring in all life forms. At the molecular level, it is a ribo-nucleotide, which is a basic structural unit of the nucleic acid RNA. NMN is the direct precursor of the essential molecule nicotinamide adenine dinucleotide (NAD+) which is an essential coenzyme for various physiological processes including energy metabolism, DNA repair, and cell growth.(17) NMN and NAD+ down-regulate STAT3 mutations (also associated with rheumatoid arthritis and some malignancies.) They should be avoided if there is any malignancy present.
NAD+ is an essential coenzyme required for life and cellular functions. Enzymes are catalysts that make biochemical reactions possible. Coenzymes are ‘helper’ molecules that enzymes need in order to function. NAD+ is the most abundant molecule in the body besides water, and without it, an organism would die. NAD+ is used by many proteins throughout the body, such as the sirtuins, which repair damaged DNA. It is also important for mitochondria, which are the powerhouses of the cell and generate the chemical energy that our bodies use.(17) NAD+ plays an especially active role in metabolic processes, such as glycolysis, the TCA Cycle (AKA Krebs Cycle or Citric Acid cycle), and the electron transport chain, which occurs in our mitochondria and is how we obtain cellular energy. (17)
In its role as a ligand, NAD+ binds to enzymes and transfers electrons between molecules. Electrons are the atomic basis for cellular energy and by transferring them from one molecule to the next, NAD+ acts through a cellular mechanism similar to recharging a battery. A battery is depleted when electrons are expended to provide energy. Those electrons can’t return to their starting point without a boost. In cells, NAD+ serves as that booster. In this way, NAD+ can decrease or increase enzyme activity, gene expression, and cell signalling. (17)
Physical Rehabilitation (RACGP Guidelines)
All post-COVID needs a progressive return to physical activity and exercise as deconditioning causes deterioration- start assessment at 6 to 8 weeks post infection. Same as POTS deconditioning program -needs good exercise physiologist if there is significant impairment
References:
1. The Lancet. Long COVID: 3 years in. Lancet. 2023 Mar 11;401(10379):795. doi: 10.1016/S0140-6736(23)00493-2. PMID: 36906338; PMCID: PMC9998094.
2. Exelby,G. Assembling the Pieces in POTS. 2023 https://www.mcmc-research.com/post/assembling-the-pieces-in-pots-part-1
3. RACGP. Caring for patients with post-COVID-19 conditions. 2022. https://www.racgp.org.au/clinical-resources/covid-19-resources/clinical-care/caring-for-patients-with-post-covid-19-conditions/introduction
4. Vittone,V, Exelby, G. DNA Mutations that Underpin POTS and Long Covid. 2023. https://www.mcmc-research.com/post/dna-mutations-that-underpin-pots-and-long-covid
5. Kakavas,S. et al. The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19. 2021 Nutrients. https://doi.org/10.3390/nu13103458
6. Eaton-Fitch N, Du Preez S, Cabanas H, Muraki K, Staines D, Marshall-Gradisnik S. Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients. J Transl Med. 2022 Feb 16;20(1):94. doi: 10.1186/s12967-022-03297-8. PMID: 35172836; PMCID: PMC8848670.
7. Mukherjee, R. et al. Famotidine inhibits toll-like receptor 3-mediated inflammatory signaling in SARS-CoV-2 infection. 2021. JBC Research Article. https://www.sciencedirect.com/science/article/pii/S0021925821007250
8. Brennan CM, et al. Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial. Gut. 2022 May;71(5):879-888. doi: 10.1136/gutjnl-2022-326952.
9. Afrin, Lawrence; Weinstock, Leonard; Molderings, Gerhard. Covid-19 Hyperinflammation and post-Covid 19 may be rooted in Mast Cell Activation Syndrome. 2020: International Journal of Infectious Diseases 100, 327-332.
10. Marshall-Gradisnik,Sonya, Eaton-Fitch,Natalie. Understanding myalgic encephalitis. 2022. Science. DOI: 10.1126/science.abo1261. https://www.science.org/doi/10.1126/science.abo1261
11. Exelby, G, Bright, K, Vittone, V. Low Glutamate Diet. 2023. https://www.mcmc-research.com/post/low-glutamate-diet
12. Gemignani F, Melpignano A, Milioli G, Riccardi S, Parrino L. Restless legs syndrome: a new entity of neuropathic pain? Treatment with prolonged release oxycodone/naloxone combination. Research and Reviews in Parkinsonism. 2016;6:23-27https://doi.org/10.2147/JPRLS.S77560
13. María Toriello, PhD, Vicente González-Quintanilla, PhD, Sara Pérez-Pereda, MD, Noelia Fontanillas, PhD, Julio Pascual, PhD, The Potential Role of the Glymphatic System in Headache Disorders, Pain Medicine, Volume 22, Issue 12, December 2021, Pages 3098–3100, https://doi.org/10.1093/pm/pnab137
14. Exelby,G. Intracranial Hypertension, Intracranial Hypotension and Craniovascular Pressure Change. 2024. https://www.mcmc-research.com/post/intracranial-hypertension-intracranial-hypotension-and-craniovascular-pressure-change
15. Exelby, G. Fibromyalgia Syndrome and the Linking with POTS and Chronic fatigue Syndrome. 2024. https://www.mcmc-research.com/post/fibromyalgia-syndrome-and-the-linking-with-pots-and-chronic-fatigue-syndrome-part-1
16. Sajoux I, Lorenzo PM, Gomez-Arbelaez D, Zulet MA, Abete I, Castro AI, Baltar J, Portillo MP, Tinahones FJ, Martinez JA, Crujeiras AB, Casanueva FF. Effect of a Very-Low-Calorie Ketogenic Diet on Circulating Myokine Levels Compared with the Effect of Bariatric Surgery or a Low-Calorie Diet in Patients with Obesity. Nutrients. 2019 Oct 4;11(10):2368. doi: 10.3390/nu11102368. PMID: 31590286; PMCID: PMC6835835.
17. NMN. https://www.nmn.com/
18. The Central Sensitization Inventory. https://www.emdr-training.net/wp-content/uploads/2019/09/CSI_Inventory_and_Scoring.pdf
19. Malmo POTS Score. https://potsfoundation.org.au/wp-content/uploads/2023/03/Malmo-POTS-Score-vFinal.pdf
21. Fatigue Severity Scale (FSS). https://www.sralab.org/sites/default/files/2017-06/sleep-Fatigue-Severity-Scale.pdf
22. Bell's Functionality Score. https://fibromyalgiaaustralia.org.au/wp-content/uploads/BellsFunctionalityScore.pdf
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