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Assessment and Treatment of Cognitive Impairment in Fatiguing Illnesses

Jan 18th 2021 | By Craig Tanio MD, MBA, FACP, IFMCP

neurofeedback image of mind with waves

Dr. Tanio, MD, MBA, FACP, IFMCP at Rezilir Health was recently featured in the December 2020 Townsend Letter, the Examiner of Alternative Medicine, which publishes a print magazine about alternative medicine. It is written by researchers, health practitioners and patients. As a forum for the entire alternative medicine community, we present scientific information (pro and con) on a wide variety of alternative medicine topics.

Cognitive Impairment

Cognitive impairment is a major component of fatiguing illnesses and a significant driver of disability and poor outcomes in these conditions. Cognitive impairment is part of the formal criteria in the 2015 National Academy of Medicine definition of myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS).  A recent review of patients with ME / CFS showed self-reported issues with memory (80%), expressing thoughts (73%), attention (69%), slower thoughts (66%), and comprehension (55%).  Other clinical frameworks used to define fatiguing illnesses such as Chronic Inflammatory Response Syndrome from Water Damaged Buildings (CIRS-WDB), Mast Cell Activation Syndrome (MCAS), and Multiple Systemic Infectious Disease Syndrome (MSIDS) all identify cognitive impairment as an important subset of symptoms.

Treatment of these issues should not occur outside of the context of treating the root cause and entire condition. However, specific interventions to assess and treat cognitive impairment as part of a comprehensive plan is likely to result in improved outcomes. We use the following approach to assess and support cognitive function:

  • Assess current cognitive function using a 3-pronged approach that incorporates subjective patient information, formal cognitive testing, and volumetric brain imaging.
  • Assess and treat cognitive function with particular attention to brain perfusion, sleep/limbic system activation, pacing/glucose metabolism/nutrition, and neuroinflammation
  • Treat the overall fatiguing illness (out of scope for this article)

Assess Cognitive Function with a 3-Pronged Approach

The discerning clinician will notice signs of cognitive impairment from the moment the patient steps in the room. Common issues that may look like problems with adherence include forgetting instructions and suggestions from a prior visit, confusion with complex explanations, and trouble remembering medications. They may have delayed verbal responses to questions that worsen during the time of the visit. Patients may also report cognitive post-exertional malaise (PEM) that occurs in a similar pattern to physical PEM.

We utilize a three-pronged approach to get an objective and practical assessment. The use of all three approaches can allow a clinician to confirm the location and degree of neurologic injury.  

Cognitive testing. The use of validated brain testing software such as CNS VitalsTMis a straightforward way for the clinician to get objective measures of brain function within 30 minutes. Findings often seen include slowing of information processing speed, complex attention, and executive function, as well as changes in verbal and visual memory.

Patient surveys. Detailed brain surveys such as the Brain Function Assessment FormTMare a practical way to correlate symptoms with specific neuroanatomic pathology. Survey information cannot be taken at face value but needs to be confirmed and further explored through the history.

Volumetric imaging. We utilize volumetric MRI imaging if patient survey and cognitive testing are positive.  Volumetrics MRI imaging uses software such as NeuroQuant or NeuroReader to convert 2D segmented images into 3D volumes and compare the images to a control database with reports that show gray and white matter volumes reported out in percentiles. Larger volumetric sizes may reflect neuroinflammation with likely mechanisms including micro-interstitial edema related to incompletely regulated cell danger responses, failed autophagy, apoptosis, possible mast cell activation, and microglial cell activation. Smaller volumetric sizes may reflect neurodegenerative pathology resulting from chronic neuroinflammation, mitochondrial degeneration, reactive oxygen species damage, protein misfolding, and neuronal vascular injury. It is more accurate than a radiologist in assessing atrophy. Volumetric studies of patients with fatiguing illnesses have been plagued by independent small sample studies rather than a collective registry but the types of observations include:

  • ME/CFS – The most consistent volumetric findings have been changes in the basal ganglia including the caudate and putamen
  • CIRS-WDB – Reported volumetric findings include increases in forebrain, hippocampus, and pallidum sizes and decreases in multiple grey matter areas including caudate, forebrain, cortical matter
  • MCAS – Mast cells can be present in the cerebellum, ventral diencephalon, caudate, putamen, and thalamus resulting in increased volumetric sizes

The use of volumetric imaging greatly helps patients who have often been told by previous clinicians that “it’s in their head” to understand that there are clear biologic and neurologic issues. We will review patients’ symptoms and correlate them with the location of their neurologic injury. Understanding the degree of neurologic injury can be motivating to patients at a time when they can take effective action. Finally, all three of these assessment methods can help to document clear improvement over time.

Cerebral Perfusion

The proper circulation of blood and delivery of oxygen, glucose, and other nutrients are critical for good neurologic performance.

Cognition can be readily impaired by cerebral perfusion deficits due to orthostatic intolerance (OI). OI and Postural Orthostatic Tachycardia Syndrome (POTS) can be practically demonstrated through a NASA 10-minute “lean test” that assesses postural changes in blood pressure, heart rate, and symptoms.  Addressing orthostatic intolerance directly through electrolytes, hydration, compression stockings, and mineralocorticoids can often improve symptoms. At times, alpha-1 receptor agonists or low dose beta-blockers may be required.

A recent study shows that patients with myalgic encephalomyelitis can have significant changes in cerebral blood flow even in the absence of hypotension or tachycardia. This may be mediated by changes in cytokines such as Vascular Endothelial Growth Factor (VEGF) with resulting changes in capillary perfusion. Physical examination can often show peripheral changes in capillary perfusion in hands and feet such as cold hands and feet that can be objectively measured by a laser thermometer.  The use of hyperbaric oxygen can be a particularly helpful modality in these situations, where there can be clinical improvement in peripheral perfusion and neurologic symptoms evident after the first treatment.

If there is atrophy on the NeuroQuant, clinicians should look for evidence of coagulopathies as an additional contributor to diminished blood flow and oxygenation. Abnormal biomarkers can include antiphospholipid antibodies, elevated fibrinogen split products, elevated d-dimer, and abnormalities in von Willebrand Factor among others. These markers often improve with correction of the underlying inflammation.  

Sleep and Recovery

Unrefreshing sleep is a hallmark of myalgic encephalomyelitis, and the most consistently reported symptom. This can include insomnia, sleep disturbances, daytime sleepiness, and irregular sleep cycles. Polysomnography often reveals abnormal sleep architecture with delayed onset of sleep, fragmented sleep, increased alpha waves, and decreased delta waves. The glymphatic system becomes much more active during sleep than during wakefulness in order to remove cellular debris. Therefore, restorative sleep is one of the most effective strategies to reduce neuroinflammation. 

sleep therapy

Good sleep hygiene such as avoiding caffeine, alcohol, and stimulants, avoiding brain activating activities before bed, removal of electronics, use of black out curtains and a consistent sleep ritual is critical. Avoidance of pain amplification, sensory amplification and post-exertional malaise can reduce disturbances of normal sleep.  Magnesium Threonate, L-Theanine, Taurine, 5-HTP, and Valerian all have good safety profiles. Melatonin may be especially helpful for these patients as it has anti-inflammatory properties, preserves the blood-brain barrier and activates BDNF.  Chronic use of pharmaceuticals for insomnia is discouraged due to their tolerance and dependence.  Patients who do not respond to initial measures for sleep should have a sleep study to rule out sleep apnea. We find the use of biomonitors such as the Biostrap and Oura ring to be an excellent aid to track progress.

A significant subset of patients with unrefreshing sleep will also show signs of limbic system activation. This can range from signs of increased sympathetic activity such as anxiety, being easily startled, light sensitivity, tachycardia, or difficulty relaxing to signs of reduced parasympathetic activity such as dry eyes, dry mouth, or slow bowel movements.  Patients can have a high score on the Adverse Childhood events score and show high volumetric sizes in their amygdala, hippocampus, cingulate, and thalamus. Their “flight or fight” response is consistently on.

While the literature on the efficacy of treatments for limbic system activation is not robust, in our experience it is a considerable roadblock for patients that needs to be overcome early in treatment. Interventions can range from mindfulness training, meditation, Heart Math, and ice baths to full limbic system retraining programs such as the Dynamic Neural Retraining System or the Gupta program.  Herbs including baicalin, tribulus, and ginger can have salutary effects on reducing sympathetic activity.  Measuring improvements in heart rate variability through the Apple Watch or other similar biometric devices along with surveys are a good way to monitor changes in a “N of 1” trial of such programs.

Pacing, Sugar, and Nutrition

The notion of cognitive pacing is similar to physical pacing for patients with ME/ CFS. Pacing is an individualized approach to managing physical, cognitive, and emotional energy within a patient’s specific limits.  Symptom journals and activity markers can help patients understand triggers of setbacks and where their tolerance limits are. Studies have shown that acute exercise can impair cognitive performance and affect brain function in ME/CFS patients as measured by functional MRI. Clinicians need to teach patients about how to pace and manage their energy envelopes and to not overdo it. Behavioral strategies to manage cognitive impairment include selecting of the best time of day to complete cognitive tasks, minimizing interruptions, and reducing sensory input to the brain through sound-reducing headphones and reducing screen glare.

Disorders in sugar and insulin metabolism can contribute to fluctuating cognitive performance, especially with changes in focus, concentration, and processing speed. With ideal blood sugar function, a patient’s energy and mood are level between meals and this should be the target outcome. We favor a brain-healthy diet based on the principles outlined in the Wahls protocol with an emphasis on high amounts of brightly colored vegetables, gluten-free, lower carbohydrate, low grains/ vegetable oils, and brain-healthy fat.  If patients have been on an unhealthy diet, often frequent meals are necessary until carbohydrate metabolism is improved. An evaluation for HPA-axis dysfunction, thyroid, sex hormone, insulin resistance and reactive hypoglycemia can be necessary.

Given that there can be central nervous system issues with insulin resistance even without demonstrable peripheral insulin resistance it is worthwhile to do a trial of intermittent fasting and ketosis for most patients in the course of their treatment once their metabolism can handle this challenge.  

Even with a healthy diet, there can be relative nutrient deficiencies. Nutrients that are particularly important to brain function and where there are often clinical deficiencies with a healthy diet include Vitamin D, choline, DHA, and butyrate.  Another less recognized issue are patients who have a double variant of Transcobalamin 2 (TCN2) which is a gene for a protein that facilitates transportation of Vitamin B12 into the cell, particularly in the brain and spinal fluid. These patients can have relative B12 deficiency in the brain with normal B12 levels. A trial of injectable B12 in these patients is warranted, if responsive they should continue on B12 replacement. The literature on the contribution of genomics variants to neurocognitive impairment is rapidly expanding and genomics testing can be helpful in select patients.


Most patients with fatiguing illnesses will have some degree of neuroinflammation. At the root of neuroinflammation are microglial cell overactivation and chronic stimulation of the innate immune system. Increases in blood brain barrier permeability can continue to stimulate microglial cells through ongoing exposure to antigens, toxins, and mast cells.  Blood brain barrier permeability can be increased by inflammatory cytokines such as MMP-9 and TGF-beta which can create a vicious positive feedback loop.

Low dose naltrexone can be very useful in addressing microglia cell activation. It can block TLR 4 receptors from activation microglia, increase endogenous opioid growth factors, and decrease inflammatory cytokines including TGF beta. The effects often can take 1-2 months. Palmitoylethanolamide (PEA) can take 2 to 4 weeks to fully realize anti-inflammatory effects.

For patients who need a more rapid anti-inflammatory action, we will use a nasal spray compounded formula of Synapsin (ginsenoside RG3 and nicotinamide riboside) which can decrease microglial cell activated inflammation and neural cell apoptosis. 

The combination of Resveratrol and Curcumin has been shown to increase NRF2 and to decrease TGF-Beta and MMP-9.  Specialized pro-mediators, Vitamin D, and bioflavonoids such as luteolin can also reduce neuroinflammatory markers. Cytoquel®, is a useful nutraceutical blend containing curcumin, resveratrol, tocotrienols, n-acetylcysteine, and epigallocatechin gallate which has been associated with a reduction of multiple inflammatory markers including MMP-9 and fibrinogen.

In patients where toxins (e.g., mold, heavy metals) are a contributor, there can be clinical exacerbation of neurologic issues if there is a significant blood-brain barrier permeability while they are being detoxified. Blood-brain barrier permeability can be directly assessed through a serum S100B (available through Mayo Clinic Labs) or a Cyrex 20.

A common co-morbid contributor of neuro-inflammation that is often overlooked is iron overload which can be measured with ferritin and iron / TIBC. In a study of patients with cognitive issues over the age of 60, more than 10% had iron overload issues. Therapeutic phlebotomy is effective at addressing this issue.

If patients are not responsive to treatments for neuroinflammation or the patient demonstrates concurrent psychiatric symptoms a work-up for neurologic autoimmunity may be in order. Mayo Clinic Labs has a very thorough autoimmune encephalopathy panel and an alternate option is Cyrex 5. Neurologic antibodies themselves can be destructive to neurons unlike most autoimmune antibodies.

Neurodegeneration and atrophy are the cumulative result of neuroinflammation and mitochondrial insults (e.g., prolonged antibiotic treatments). Treatments to address hypometabolism and mitochondria efficiency will often get better results if other issues are addressed first. For example, the use of Vasoactive Intestinal Peptide is reserved until the end of the Shoemaker protocol for CIRS.  Other mitochondrial support protocols such as NADH, CoQ10 will usually get improved results if saved for the end.


Dr. Craig Tanio

Neurocognitive slowing, reduced executive function, cognitive fatigability, and cognitive post-exertional malaise may be the most limiting aspects of fatiguing illnesses. It is a primary reason why patients with these conditions are unable to succeed in school or sustain employment. Specifically assessing and treating these impairments as part of a comprehensive plan for the fatiguing illness is likely to result in improved outcomes.

              Dr. Craig Tanio


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