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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.
Good sleep hygiene such as avoiding caffeine, alcohol, and stimulants, avoiding brain-activating activities before bed, removal of electronics, use of blackout 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, HeartMath, 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 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.
