ANTI-VIRALS

Again, there are many here that can be discussed, but two stand out that are specific to those with Down syndrome in light of coronavirus as well. Those are Vitamin A and glycyrrhizin.  

VITAMIN A

The malabsorption study of children with Down syndrome cited above also reported vitamin A among the deficiencies seen. (Abalan 1990) Years later researchers in Spain stated "Children with DS between two and six years old show a significantly lower serum retinol." (Chávez 2010) Before considering vitamin A supplementation it's wise to get a blood test to check for a deficiency and discuss supplementation with a nutritionally trained physician. Overdosing of vitamin A is possible and toxic to the body. "Mental status changes are common following Vitamin A intoxication. In addition, there is a risk for seizures, headache, and blurred vision (due to elevated intracranial pressure). Chronic toxicity can lead to alopecia, anorexia, pruritus, dryness of mucous membranes, muscle and bone pain and hyperlipidemia." (Olson 2019)

Vitamin A given in safe doses can greatly enhance the body's immune response. It's been shown in animal studies to increase serum levels of IgG, IgM, and IgA. (Huang 2018) Levels of these immunoglobulins can be tested in humans, as we often do on our patients. We have found low levels of each of these immunoglobulins in our patients with Down syndrome to varying degrees in each of them.  

A study of 2,774 children in Bogotá, Colombia found "Vitamin A and hemoglobin concentrations were inversely related to rates of morbidity in school-age children." (Thornton 2014) From a global perspective in light of the recent spread of COVID-19 it should be noted that vitamin A deficiency is a major public health problem around the world.(Timoneda 2018) This could likely contribute to more serious complications from COVID-19 in those who are vitamin A deficient given the important role that vitamin A plays in lung health. 

LICORICE (GLYCYRRHIZIN) - EDITED 3/14/2020

​Previously I wrote of the potential benefits of glycyrrhizin, the active constituent of licorice, due to its antiviral properties. As well researchers in Germany tested glycyrrhizin against two clinical isolates of coronavirus (FFM-1 and FFM-2) from patients with SARS. "glycyrrhizin was the most active in inhibiting replication of the SARS-associated virus." (Cinatl 2003) Other researchers in Germany confirmed their findings and stated, "Glycyrrhizin (GL) was shown to inhibit SARS-coronavirus (SARS-CoV) replication in vitro." (Hoever 2005)

In "Potential natural compounds for preventing 2019-nCoV infection" Chen and Du also discussed the use of glycyrrhizin. They pointed out that COVID-19 enters the host lung cells via ACE2 receptors on the surface of the cell. "Targeting ACE2 holds the promise for preventing 2019-nCoV infection." (Chen and Du 2020) They went on to add, "Given the low toxicity of glycyrrhizin, its anti-virus effects on SARS and its potential interaction with ACE2, it’s worthwhile to test its efficacy against 2019- nCoV infection." (Chen and Du 2020)

Despite this, I'm retracting my recommendation of glycyrrhizin based on information that was published February 29, 2020.  A team of researchers and doctors in China reported low potassium levels, hypokalemia, being linked to severity of lab results in patients who contracted COVID-19. "Body temperature, CK, CK-MB, LDH, and CRP were significantly associated with the severity of hypokalemia (P<0.01). 93% of severe and critically ill patients had hypokalemia which was most common among elevated CK, CK-MB, LDH, and CRP." (Li 2020) 

Glycyrrhizin can cause renal potassium loss and subsequent high blood pressure. (Allcock 2015) Given that hypertension is among the co-morbid conditions seen in non-survivors of this novel coronavirus infection, and low potassium is linked to severity of aberrant lab results, it would be wise to avoid glycyrrhizin at this time. It should also be noted that the papers from Chen and Du and Li, et al are in pre-print, which means they have not been peer-reviewed and should not be used to guide clinical practice.

SUMMARY OF TIPS TO DISCUSS WITH YOUR CHILD'S DOCTOR
​

• Anti-inflammatory diet (gluten-free, dairy-free)
• No refined sugar, absolutely none at this time
• B vitamins as warranted and tolerated
• Vitamin D
• Vitamin C
• Quercetin
• Liposomal Glutathione
• Vitamin A (use with caution)​
• Obtain current labs that include CBC, serum B12, serum vitamin A, histamine, glutathione, homocysteine and immunoglobulins. Discuss all potential causes of aberrant results with your child's physician.
• More tips on boosting the immune system can be found by reading Boosting Immunity: Functional Medicine Tips on Prevention & Immunity Boosting During the COVID-19 (Coronavirus) Outbreak​​

Many children with Down syndrome and autism experience gastrointestinal issues. (Chaidez 2014, Holmes 2014) The consequences of this can be a major contributing factor to nutrient deficiencies and cognitive issues that are common in both of these conditions. Low muscle tone that is common in children with both of these conditions is a significant factor impacting gut health.

Let's start by briefly reviewing gastrointestinal anatomy. Basically the gut largely consists of smooth muscle.  It is essentially a muscular organ (Image 1). The interior lining of these muscles, the mucosa, is where the very important task of secretion and absorption occurs. 

If tone in the skeletal muscle of a child is low then the same factors that are causing skeletal muscle tone to be low will also cause low tone in smooth muscles of the intestines as well.  This low muscle tone in the intestines leads to slow gut motility.  When gut motility is slow bacteria and yeast can't be cleared properly and get backed up in the small intestines. This leads to small intestinal bacterial overgrowth (SIBO) and/or yeast overgrowth (Image 3). Researchers at the University of California stated, "Depending on the flow rate and the frequency of contractions, the bacterial density profile exhibits varying spatial dependencies." in their paper titled "Bacterial growth, flow, and mixing shape human gut microbiota density and composition." (Cremar 2016) In other words, the level of bacteria in the gut is dependent on gut flow or motility. How much the gut is able to move plays a significant role on the quantity and balance of healthy bacteria within the gut.

Bacteria and yeast in the gut are very much alive and continuously growing and reproducing.  The rate at which they are growing and reproducing must match the rate at which they are being eliminated from the body through constant sloughing and evacuation of the bowels.  If these rates are not properly in sync with one another due to slow gut motility then a build up of bacteria and yeast within the small intestines can easily occur.  

SIBO can have a significant impact on the overall health of the body.  Nutrient absorption can be greatly impaired by SIBO. Micronutrients like vitamin B12, A, D and E, iron, thiamine, nicotinamide can be depleted due to malabsorption. (Dibaise 2008) Deficiencies in several of these nutrients, especially vitamin B12 and thiamine, can negatively impact nervous system function, which will be discussed for it's role in gut motility below. Malabsorption from SIBO has also been linked to poor growth in children as well. (Donowitz 2015)

Propionic acid is a short chain fatty acid that is produced by bacteria in the gut. Propionic acidemia (elevated levels of propionic acid) has been studied as potential a contributing factor to autism.  Derrick MacFabe, MD has conducted extensive research to support this and discussed his findings in "Autism, Mitochondria and the Microbiome".  Elevated levels of propionic acid have been shown to impair brain function in animal models, corroborating MacFabe's work. (Choi 2018)  Gut motility is a major factor impacting levels of propionic acid. (Prasa 2004) Symptoms of propionic acidemia include frequent vomiting, lethargy, refusal to feed, and hypotonia.  The mechanism behind elevated propionic acid is clear given that this short chain fatty acid is produced by bacteria in the gut, which will be present in higher concentration when gut motility is low.

Because the gastronintestinal tract is a muscular system it is heavily dependent on a healthy nervous system. The enteric nervous system is the division of the nervous system that exclusively controls the gut. It includes mesh-like branches, called plexus, that innervate the muscles of the gut as seen in yellow in Image 7.

Muscles require energy in order to contract in the form of ATP (adenosine triphospate). ATP is generated by mitochondria.  It naturally follows that mitochondrial dysfunction will lead to low muscle tone and slow gut motility. Gastrointestinal symptoms of mitochondrial dysfunction include poor appetite, gastroesophageal sphincter dysfunction, constipation, dysphagia, vomiting, gastroparesis, GI pseudo-obstruction, diarrhea, or pancreatitis and hepatopathy. (Finsterer and Frank 2016) 

Nutrients that support mitochondrial function and therefore support gut motility include:
​

• Carnitine
• CoQ10
• B Vitamins
• ​Ribose
• T3/T2 hormone
• Creatine

Of those compounds listed above the one most noted for it's effects on gut motility is carnitine. Researchers in Japan studied carnitine levels in 27 patients with severe motor and intellectual disabilities. They found that the severity of their constipation correlated significantly with the levels of carnitine found in their blood samples. They supplemented carnitine in those who were deficient and saw a significant reduction in their constipation. (Murata, et al 2014) This has also been the experience of many parents using carnitine to help their child with slow gut motility. 

For a more thorough look at mitochondrial dysfunction, how to test for it and how to treat it you can read Mitochondria - Why They're Important and What They Need to Function

The video below shows how muscles use ATP to contract or essentially shorten.

Slow gut motility (hypomotility) can be seen as early as infancy, especially in the presence of congenital hypothyroidism.  Screening methods to detect congenital hypothyroidism are imperfect and vary from state to state within the United States. Kugelman, et al wisely stated, "Physicians should use their clinical judgment and experience even in the face of normal newborn thyroid screening test and reevaluate for hypothyroidism when there is a clinical suspicion." (Kugelman 2009) Delayed passing of meconium, umbilical hernia, infrequent bowel movements, colic, abdominal distention and reflux should all be clues to the physician to investigate hypothyroidism and the root causes of hypothyroidism in any infant regardless of their genetics.  Schmaltz summarized the signs of hypothyroidism in the newborn in the table seen in Image 9 and included abdominal distention due to hypomotility. (Schmaltz 2009)

Because bile and pancreatic enzymes are essential for digestion and absorption of nutrients, children who experience malabsorption, like those with Down syndrome and autism (Chaidez et al 2014, Abalan et al 1990), may benefit from efforts to increase CCK levels.  One must be careful not to ​increase CCK too much, however, as increased levels have been linked to anxiety due to it's impact on the central nervous system. (Skibicka and Dickson 2013) CCK increases colonic motility (Jun 2011), yet it is also known to induce a delay in gastric emptying.  

Ways to increase CCK:

• Increase fats in the diet, especially olive oil
• Protein with every meal 
• Optimize stomach acid (HCl) production (Image 11)
• Include beans in the diet (Bourdon et al 2001)

Be careful with beans in the diet for those with small intestinal bacterial overgrowth (SIBO) as the fiber and sugars in beans can cause increased gas and bloating. Focus on olive oil and protein. The amount of protein an average child needs is approximately half their weight (lbs) in grams. So, a 40 pound child will only need approximately 20 grams of protein per day.  You don't want to give too much protein to a child with SIBO either as the excess levels of bacteria in the gut can produce ammonia from the protein.

Serotonin (5-HT) is best known for it's impact on mood and low levels being linked to depression.  However, it has other functions within the body, including it's impact on gut motility. After all, 95% of 5-HT is made in the gut. To add to that "Intestinal 5-HT has been found to modulate enteric nervous system (ENS) development and neurogenesis, motility, secretion, inflammation, sensation, and epithelial development." (Terry 2017) 

5-HT is made from tryptophan, an essential amino acid. Essential amino acids are those that our bodies can't make and must be obtained from the diet.  About 90% of tryptophan is used to make nicotinamide (vitamin B3), a cofactor needed for energy production within the body. (Lugo-Huitrón, et al 2013) The other 10% is used to make 5-HT in a process that is dependent on vitamin B6. The availability of tryptophan can therefore influence the production of 5-HT in the body. To learn more about how tryptophan is used to make both nicodtinamide and 5-HT watch the video below.

5-HT is secreted from enterochromaffin cells that are widely distributed throughout the gut. They're a type of neuroendocrine cell that sense pressure and stretch, which is typically from a bolus of food within the lumen of the gut. In response to these sensations they secrete serotonin, in addition to many other hormones needed for optimal digestion, which results in a contraction of the smooth muscles ultimately propelling the bolus of food along. 

One very important factor that can lead to a decrease level of 5-HT within the gut is inflammation.  A disruption in the balance if bacteria and yeast within the gastrointestinal microbiome is a major cause of inflammation within the gut. (Nishida, et al 2018) Researchers in the Netherlands have stated "...in a state of inflammation, not only high levels of proinflammatory cytokines are produced but also altered levels of neurotransmitters, such as serotonin, a derivative of tryptophan metabolism, are detected in the gut." (Waclawiková and Aidy 2018)

So, we have another vicious cycle: disturbed microbiome → inflammation → low serotonin → slow gut motility → disturbed microbiome → etc.

Despite signs and symptoms often being obvious in those with slow gut motility,  testing can be done to detect the level of gut motility in those with more vague signs and symptoms.  Some of these can be done at home and some require the help of a physician.

A simple, at home test involves the use of activated charcoal.  This can be obtained cheaply in capsule form.  Activated charcoal is used often in research to test gastrointestinal transit in animal studies, typically in mice.  Activated charcoal is often used at home and in hospital settings to absorb orally ingested poisons.  It's a good thing to have on hand in any home with small children for this purpose. It's not absorbed by the body and remains in the gut. Due to it's dark color it can be easily detected in stool.  For this reason, it makes for a great tool to measure bowel transit time.  Capsules can be opened or swallowed whole depending on the age and skill of the child.  The number of capsules used will depend on the age of the child.  Adults can use 4-6 capsules, young children can take 2-4 capsules and toddlers can take 2 capsules. Capsules are given all at once right after a bowel movement.  Activated charcoal has almost not flavor, but a slightly gritty texture. It can be mixed in juice to help young children get it down.  It will make the juice pitch black so consider putting it in an opaque cup so the child isn't put off by the color.  Note the date and time the charcoal was given. Inspect every bowel movement under bright light after the charcoal is given, looking for signs of black in the stool.  Write down the date and time the charcoal is first seen.  This is the time it took for the charcoal to pass through the digestive tract. Calculate the number of hours between when capsules were swallowed and when the first sign of black color appeared in the stool. Continue to examine every stool, and note the time and date when the black color has completely disappeared.  An optimal bowel transit time for children and adults is 18-24 hours.  Anything less than 18 hours is considered a fast transit time, more than 24 hours is a sign of slow gut motility.

Below is a video of Dr. Jasmine Zia from UW Medicine explaining the collection process for the hydrogen breath test. One can easily see how conducting this test for small children can be quite difficult. It may, however, be a good option for older children and certainly for adults.

It's important to address the root cause of gut motility issues and not simply use laxatives or diuretics to alleviate the symptoms.  Treatment for slow gut motility should be very individual because the underlying cause can be different in different children. Remember: children with genetic conditions are as individual as anyone else and don't all require the same supplements or treatment.

The main underlying causes to address when considering treatment include:
​

• ACh synthesis
• Micronutrient deficiencies
• Methylation issues (needed for choline synthesis)
• Nervous system function
• Mitochondrial function
• Thyroid hormone function
• HCl, gallbladder and pancreatic function
• Inflammation
• Diet

Herbs

Herbs that improve gut motility can be very helpful to alleviate the symptoms until the root cause can be uncovered and addressed. They can also be helpful to break the vicious cycle of malabsorption secondary to elevated levels of yeast and bacteria. Below are some of my favorite and most effective herbs to help improve gut motility.  

Zingiber officinale (Ginger) is, by far, the one we most often recommend for children due to it's tolerable flavor and high safety profile. Many studies support ginger's long history of use for gastrointestinal symptoms of nausea, vomiting and general dyspepsia.  It decreases gastric emptying time, meaning the stomach empties more quickly after the administration of ginger.  Researchers in Taiwan reported, "...gastric half-emptying time was less after ginger than placebo ingestion." (Wu, et al 2008) Ginger can be used fresh in cooking, made into a tea and sweetened with a little honey, purchased as encapsulated powder or purchased as an alcohol-free glycerite that's then mixed with apple sauce or food.

Iberis Amara (Candytuft) is the main ingredient of Iberogast.  This is a popular herbal formula used in Europe but can also be found in the US. Its often recommended for those with SIBO due to it's ability to increase gut motility. Other ingredients in Iberogast include Mentha piperita L., Matricaria chamomilla, Glycyrrhiza glabra, Angelica archangelica, Angelica archangelica, Silybum marianum, Melissa officinalis and Melissa officinalis. These herbs work synergistically to help optimize digestion and gut motility. German researchers found Iberis amara extract created "clear differences" in the symptoms of IBS over placebo in a multicenter, prospective, double-blind, randomized parallel group comparison. (Reichling and Saller 2002) Ten years later it was stated, "Double-blind and randomized studies versus placebo or active control found statistically significant effects of STW 5 (Iberogast) on patients’ symptoms with a comparable efficacy to a standard prokinetic." (Ottillinger, et al 2012). You can find prescribing information on the package insert here.

Bacopa monnieri (Brahmi) is an Ayurvedic herb that has been used for centuries in children. Adverse effects are rarely reported, but one side effect that it can have is increased intestinal motility. It has acetylcholinesterase inhibition properties, which means it increases levels of acetylcholine within the body.  This ultimately results in improved cognition and improved gut motility. (Aguiar and Borowski 2013)  

Aloe vera juice is a common, safe and effective remedy for constipation. It helps alleviate gut permeability due to it's anti-inflammatory and soothing properties.  One of the key components of aloe is barbaloin which is metabolized to aloe-emodine-9-anthrone by intestinal bacteria. Aloe-emodine-9-anthrone increases intestinal motility. (Hong, et al 2018) 

Foeniculum vulgare (Fennel seed) is more commonly know for it's effects on relieving gas. This makes it a very popular and effective remedy for helping babies with colic. Fennel also has been shown to stimulate the smooth muscles of the small intestines. (Alexandrovich, et al 2003) It can be given as a tea or fennel essential oil that is labeled for oral consumption can be used in very small doses.

Osmotic diuretics

Osmotic diuretics do nothing to optimize gut motility and only act as bandaids to the problem by making stool softer. The most commonly prescribed pharmaceutical agent prescribed to those with slow gut motility and constipation is polyethylene glycol - 3350, known as MiraLAX in the US or Movicol and Macrogol in other countries.  It works by drawing water into the large intestine resulting in softer stool that is easier to pass. It does not improve gut motility and definitely doesn't address the root cause of slow gut motility. Other, safer and more natural osmotic diuretics exist and include magnesium oxide and high dose vitamin C.  We highly encourage our patients to avoid Miralax given the controversy over it's safety. (Welch 2017) Miralax is not labeled for use in those under 17 years of age and is only to be used for occasional, short term constipation. The label clearly states “use no more than 7 days” because it should not be used to address chronic constipation. (Image 11)  My biggest concern with it being used for chronic constipation is it addresses the symptom of constipation yet leaves the underlying cause unaddressed. Several of these underlying causes mentioned above can result in permanent neurological damage to very young children.

Probiotics 

Probiotics should be considered carefully when treating children with gastrointestinal motility issues. In some they can improve gut motility and in others they can aggravate constipation and symptoms of SIBO. Recall that SIBO is an increased level of bacteria in the small intestines, therefore, probiotics can aggravate it. Taking a probiotic with the right strains is extremely important as well. ​

​Bacteria in the gastrointestinal microbiome serve many roles for it's human host. They are involved in nutrient metabolism, vitamin synthesis, short chain fatty acid synthesis that supports the lining of the gut, phenol metabolism, immune system homeostasis and xenobiotic and drug metabolism. (Jandhyala, et al 2015) In 2014 a team of scientist at the Alimentary Pharmabiotic Centre in Ireland reported that neurotransmitter synthesis can also be added to that list. (Clarke, et al 2014) The term endocrine is defined as "Pertaining to hormones and the glands that make and secrete them into the bloodstream through which they travel to affect distant organs" (medicinenet.com) Clarke and his team argue that the gut microbiome acts as an endocrine organ because of it's ability to secrete compounds that act on distal organs such as the brain. They include a list of bacterial strains and the neurotransmitters that are produced by these specific strains seen in Image 12.  Several of these strains listed are considered pathogenic like Klebsiella penumoniae, Hafnia alvei and Morganella morganii.  The presence of these strains within the gut microbiome can result in increased gut motility seen as diarrhea potentially due to their production of serotonin and histamine which can increase gut motility. (Fabisiak, et al 2017)

Studies supporting the connection between the gut microbiome and the central nervous system, aka the gut-brain axis, are numerous. ​We can see a direct link between the brain and the gut with the production of acetylcholine by Lactobacillus plantarum.  The production of acetylcholine, as stated early, not only will support cognition but will also help to optimize gut motility by stimulating the enteric nervous system. L. plantarum should definitely be included in a probiotic given to someone with slow gut motility.

Clinical evidence reveals the eradication of pathogenic bacteria and yeast along with the replenishment of beneficial bacteria within the gut often results in an optimization of gut motility, nutrient absorption, neurotransmitter balance, improvements in mood and behavior, immune system function, cognition and overall health of the host.  This is supported by research and statements from experts such as, "The gut microbiome affects virtually all aspects of human health." (Mohajer, et al 2018)

A comprehensive stool analysis that includes markers like calprotectin, esosinophil protein X, secretory IgA levels, short chain fatty acids, fecal fats, along with the presence of commensal bacteria strains and pathogenic bacteria, yeast and parasites can aide in guiding an appropriate program aimed at improving the gut microbiome.  This task is often not a simple one and in some cases can take years of optimizing diet, supplements, antimicrobials, probiotics and herbal prokinetics. The amount of time and effort it can take to correct gut microbiome imbalance can depend on how extensive the initial cause of the imbalance was, such as number of rounds of oral antibiotics or years of proton pump inhibitor use. The presence of biofilm can slow the process as well if not properly addressed.  We often tell patients, "This isn't a one and done process".  The patients who we see the best results with are those who are able to run functional medical testing like organic acid and comprehensive stool analysis as early as possible and are able to repeat testing at regular intervals (every 3-6 months) to assess the effectiveness of the current treatment program and make necessary adjustments.

Gastrointestinal motility represents one of the major control systems of gut microflora by moving bacteria and yeast out of the body at a rate that is balanced with their rate of reproduction. Gastrointestinal dysbiosis cannot be addressed if gut motility is not optimized. Treating dysbiosis with antimicrobials (herbal or pharmaceutical), probiotics and diet without addressing gut motility will only result in continued ill-health, frustration and money lost on supplements and treatment that don't result in long term effects.

The lumen of the gut can be compared to a river. Environmental biologists know very well that the flow of a river dictates the diversity and health of the river. It's been stated, "A river's flow is its heartbeat. Because we have dammed so many rivers and lakes, our freshwater ecosystems are losing species and habitats faster than any other type of ecosystem." (Internationalrivers.org)  If the river is slowed and becomes stagnant algae and microbes will grow at a rate that is faster than the river moves them along. This will create an imbalance in the ecosystem of that river that chokes out other life, ultimately creating an unhealthy river.

A free flowing river results in less build up of algae, higher oxygen levels, more diversity of life and ultimately a much healthier river.

We couldn't live without acetylcholine (ACh).  It's an important neurotransmitter within the body and, in fact, was the very first neurotransmitter discovered. The moving title of this article was chosen to impress upon the reader the importance of this neurotransmitter to processes within the body that require movement, from skeletal muscle or smooth muscle.  It's also vitally important for brain function, playing a key role in memory, learning and cognition. It functions to relay signals from one neuron to another in the central nervous system and from a neuron to a muscle fiber in the peripheral nervous system. The production of ACh, symptoms and causes of deficiency and how best to treat low ACh will be discussed, but first we'll start with a basic physiology lesson to help you appreciate the function of ACh within the nervous system.

The nervous system is divided into two branches called the autonomic and somatic nervous systems.  The autonomic nervous system is our "automatic" nervous system that we cannot voluntarily control. If you get sweaty when nervous or your heart rate increases when you're excited that's your autonomic nervous system controlling your body's response.  Your somatic nervous system is your "voluntary" nervous system.  This part of the nervous system controls skeletal muscles, like those in my fingers as I type this. You can see from image 1 that ACh is used in both of these branches of the nervous system.

The autonomic nervous system is further divided into the sympathetic and parasympathetic branches of the nervous system. The parasympathetic nervous system is engaged most of the time in a healthy person. The sympathetic nervous system becomes engaged during times of stress or excitement. The sympathetic branch uses ACh to relay messages but also uses epinephrine and norepinephrine. The parasympathetic nervous system relies solely on ACh to function properly. The parasympathetic nervous system is important for proper digestion, gut motility, salivary flow, lacrimation (tears) and bladder function. The nerve fibers of the parasympathetic nervous system originate from the brain stem and sacral region. The parasympathetic nerve fibers originating from the brain stem are cranial nerves III, VII and IX. Cranial nerve X, the vagus nerve, also contains parasympathetic nerve fibers.  A well-functioning vagus nerve is extremely important for all aspects of digestion including stomach acid secretion, pancreatic secretion, bile flow and peristalsis, which is the wave of muscle that moves food through the intestines. (Stakenborg, 2013) The vagus nerve is also very important for regulating heart rate.  ACh creates an inhibitory response to cardiac muscle resulting in a slowed heart rate. This is different than other receptors within the parasympathetic system that result in a general increase in activity.

By reviewing the different functions of the sympathetic and parasympathetic nervous system in image 2 one can already start to get an idea of what a deficiency in ACh might look like.  The symptoms of deficiency are as follows:

Because ACh is so important for nervous system conduction within the brain, a deficiency in ACh has been linked to Alzheimer's disease (AD) and dementia. (Francis, 2005) The enzyme that breaks down acetylcholine is called acetylcholinesterase. Several drugs have been developed for the treatment of Alzheimer's disease that inhibit this enzyme thus increasing ACh levels. These drugs are donepazil, rivastigmie, galantamine. These drugs have not been shown to reverse the effects of AD, they merely stabilize or slow the rate of cognitive decline. As well, some patients don't respond at all to them. (O'Brien, 2010) They also have many side effects due to their systemic effects of increasing ACh levels throughout the body when the goal is to increase ACh in the brain alone. Some of the side effects include nausea, vomiting, diarrhea, muscle cramps, weight loss, headache, insomnia, hallucinations, fatigue, hypertension and frequent urination. (medicine.net)

It's possible that the decline in acetylcholine levels in AD and dementia are due to a deficiency in the precursors needed to make it.  So, let's talk about how acetylcholine is made next.

The synthesis of acetylcholine is actually fairly simple as a whole, yet complex in the details.  To make acetylcholine we need choline and an acetyl group. The preferred source for the acetyl group is acetyl CoA which is derived from pyruvate, the end product of glycolysis. Research showing this dates as far back as 1936 when scientists incubated animal brain cells in various medium and found that glucose, pryuvate and lactate all equally resulted in an increase in ACh production. Oxygen was needed as well. They stated, "We know now, of course, that acetylCoA (AcCoA) is required for ACh biosynthesis and that it must be the substance produced during the combustion of glucose, lactate or pyruvate in the brain that gives rise to ACh." (Quastel, 1936) Their work was corroborated by researchers in 1979 who stated, "Acetylcholine is synthesized from acetyl CoA and choline in the cytoplasm. Glucose and pyruvate are the preferred precursors of the acetyl carbons of acetylcholine in adult mammalian brain." (Gibson, 1979)

The enzyme that cleaves the acetyl group from acetyl CoA and attaches it to choline is choline acetyltransferase (ChAT) as seen in image 3. 

So, how do we then get acetyl CoA from glucose and pyruvate? This is where it gets a little more complicated. Those who have studied and understand the Citric Acid Cycle will recognize this information. For those who haven't studied this: the Citric Acid Cycle is a key process involving many steps by which mitochondria make energy. This process is heavily dependent on B vitamins.  Image 4 shows the many steps and enzymes involved in this process along with the B vitamins that act as cofactors for those enzymes.  The one enzyme I will focus on here is PD that is seen below pyruvate at the top of image 4.  PD stands for pyruvate dehydrogenase.  It's role is to convert pyruvate into acetyl-CoA.

I've discussed pyruvate dehydrogenase before in my lecture "Thiamine Deficiency in Children with Special Needs".  I've posted the whole lecture below for those who want to know all of the details.

Essentially PD is dependent on adequate levels of thiamine (B1), riboflavin (B2), alpha lipoic acid and niacinamide (B3).  In addition, the precursor to coenzyme A (CoA) is pantothenic acid (B5).  All of these B vitamins must be present in adequate amounts in order for acetyl CoA to be made. (Stacpoole, 2012) Particularly noteworthy is the role that thiamine plays in ACh production.  "The role of thiamine as a crucial coenzyme in neuronal metabolism of carbohydrates and neurotransmitters, especially acetylcholine, has been well elucidated." (Hirsch, 2011) The administration of benfotiamine, a form of thiamine, alone has been shown to reverse the symptoms of Alzheimer's disease, which has been linked to low ACh levels. (Pan, 2016)

Deficiencies in these B vitamin cofactors is most often due to gastrointestinal malabsorption. Yeast overgrowth is a common cause of malabsorpton, especially of B vitamins.  The best testing to determine a need for these B vitamins is organic acid testing.  Results like the ones seen in image 5, for example, indicate a significant deficiency in B1, B2, B3 and B5.  These are results for a child who has Down syndrome and is likely also deficient in ACh due to her B vitamin deficiencies, not her extra chromosome.  The deficiencies in this child were due to small intestinal bacterial and fungal/candida overgrowth. Addressing these deficiencies along with the root cause of malabsorption is key to optimizing ACh synthesis.

That leaves us to discuss choline as the other important half of acetylcholine.  Choline is an essential nutrient that must be obtained from the diet. Because it is water-soluble the body does not store it, so daily consumption of this nutrient is important for consistent production of acetylcholine to occur. Some choline synthesis within the body is possible, however the production of choline is heavily dependent on a properly functioning methylation cycle.  Many genetic and environmental variables exist around methylation.

Foods highest in choline include eggs (yolks) and meat, so vegans and vegetarians are at risk for being low in choline.  Supplementation is possible by taking lecithin sourced from soy or sunflower. Lecithin is rich in phosphatidylcholine (PC), which is a precursor to choline. Citicoline and CDP-choline are other forms of choline that have been shown to enhance memory and cogntion. (Gareri, 2015; Fioravanti, 2006) Choline bitartrate should be avoided. It's the most commonly used form because it's the cheapest.  It also is the least reliable form for impacting brain levels of choline (Lippelt, 2016) I prefer PC over other sources of choline because the production of PC is the second largest draw on methylation than all other process that require methylation combined. (Bertolo, 2013) Image 5 shows the production of PC from phosphatidylethanolamine via PEMT (phosphatidylethanolamine N-methyltransferase), a process that occurs in the liver. Because cell membranes consist largely of PC the body is required to make it often to keep up with cellular repair and growth.  By supplying PC as a supplement this eases up on methylation and allows more methyl groups to be used for other methylation dependent processes.

As well, supplementing with PC has been shown to increase acetylcholine synthesis.  Dr. Steven Heizel from the Department of Nutrition, School of Public Health and School of Medicine at the University of North Carolina stated, "Acetylcholine synthesis can be influenced by the availability of choline...its manipulation by changing the diet is likely to be a powerful tool for improving human performance.". (Heizel, 2006)

The stage of life that has been shown to be most dependent on dietary choline is fetal development. Dr. Heizel has written, "Choline is critical during fetal development, when it influences stem cell proliferation and apoptosis, thereby altering brain structure and function." (Heizel, 2006) Researchers recently tested two groups of mothers who were in their third trimester of pregnancy. They supplemented one group with 480 mg of choline per day and the second group received 980 mg of choline per day.  They then followed up by testing the infants at 4, 7, 10 and 13 months old for processing speed and visuospatial memory. Their results showed "maternal consumption of approximately twice the recommended amount of choline during the last trimester improves infant information processing speed." (Canfield, 2018)

Genetic variations in mothers can alter choline requirements as well. Specifically variations in PEMT and MTHFR1 genes can alter endogenous synthesis of choline. Maternal dietary choline intake can influence global gene methylation and ultimately gene expression in the unborn child. (Bennett, 2016). Because not all mothers know their PEMT or MTHFR1 gene status supplementing with choline during pregnancy at approximately 980 mg per day, as was done in the study above, may help to ensure adequate levels are available for proper infant brain development.  In addition, vegans are at high risk for being choline deficient and should definitely consider supplementing.  Vegetarians who eat eggs daily are less likely to be deficient. One egg contains about 150 mg of choline.

Because many people are looking to avoid the side effects from pharmaceutical cholinesterase inhibitors, natural cholinesterase inhibitors have grown in popularity in recent years.  Using such compounds to address ACh deficiency does not address the root cause. The root cause of ACh deficiency is most often rooted in a deficiency in one or several of the precursors needed to make it. The preferred means to address ACh deficiency is to provide the body with necessary precursors in amounts that have been determined to be individual for each person based on diet, labs, history and symptoms. Using cholinesterase inhibitors can include side effects as it's interfering with the body's ability to naturally eliminate excess ACh when needed. I'll list a few of these compounds below, but want to highlight that root cause should be addressed first. In addition, when working with children it's important to use natural cholinesterase inhibitors with the fewest side effects and highest record for safety.

Bacopa monnieri (also known as brahmi, water hyssop, and Herpestis monniera) is one of my favorite nootropic herbs.  It has the lowest chance of creating side effects over other forms of cholinesterase inhibitors. "Emerging research demonstrates several mechanisms of action—acetylcholinesterase inhibition, choline acetyltransferase activation, b-amyloid reduction, increased cerebral blood flow, and monoamine potentiation." (Aguiar and Borowski, 2013)

One side effect that is possible with Bacopa is loose stools. This is likely due to increased levels of ACh.  The dose can be reduced if this occurs. However, Kumar, et al stated "Bacopa in syrup form, equivalent to 1 gm dried Bacopa daily, for three months in 40 school children aged 6–8 years, showed improvement in immediate memory, perception, and reaction performance without any side effects." (Kumar, 2016).

Gotu Kola (also known as Centella asiatica) is another favorite nootropic herb of mine due to the research supporting it's efficacy and few reported side effects.  "Several mechanisms of action of C. asiatica were demonstrated for enhancing cognitive function, such as the inhibition of acetylcholinesterase activity, reduction of phospholipase A2 (PLA2) activity, protection against ß-amyloid formation, and protection from brain damage." (Puttarak, 2017)

Gohil et al report "CA has no known toxicity in recommended doses. Side effects are rare but may include skin allergy and burning sensations (with external use), headache, stomach upset, nausea, dizziness, and extreme drowsiness which tend to occur with high doses of the herb." (Gohil, 2010)

Both Bacopa and Gotu Kola were used in a formula that was tested in children with ADHD. It was not only shown to be effective but "No serious adverse events were reported, and the rate of even mild adverse events among CHP-treated patients was actually less than that of placebo. (Katz, 2010). (CHP is compound herbal preparation.)

Huperzine A is extracted from Huperzia Serrata, a firmoss, which has been used for various diseases in traditional Chinese medicine for fever and inflammation. It has potent cholinesterase inhibition activity. (Wang, 2006) While it has been shown to be effective for improving memory due to mechanisms other than just cholinesterase inhibition (Zhang, 2008), it has not traditionally been used in children and no studies exist reporting it's efficacy or safety in children. Use in children has been deemed "possibly safe" when taken for less than one month. (WebMD)

Potential side effects include nausea, diarrhea, vomiting, sweating, blurred vision, slurred speech, restlessness, loss of appetite, contraction and twitching of muscle fibers, cramping, increased saliva and urine, inability to control urination, high blood pressure, and slowed heart rate.(WebMD)

For these reasons, along with focusing on addressing root cause, I don't typically recommend using Huperzine A in my patients.

Because choline has been shown to optimize brain development and methylation is necessary for optimal choline synthesis, choline supplementation in the Down syndrome model has been tested. Dr. Barbara Strupp and her team at Cornell University have done some very important and clinically relevant work in this area.  They first wrote about the potential benefit of choline supplementation prenatally in pregnant mothers carrying an infant with Down syndrome in 2016.  In this review article they explain the cognitive deficits related to cholinergic pathways in mice that are engineered to have an extra chromosome (Ts65Dn mice) that correlates with that in human trisomy 21.  They stated, "Using the Ts65Dn mouse model of DS/AD, our group has identified a putative novel therapeutic intervention that holds great promise for improving cognitive outcome and offering neuroprotection to the cholinergic projection system in DS; namely, supplementing the maternal diet with additional choline during pregnancy and lactation." (Strupp, 2016)

They moved on in 2017 with researching actual maternal choline supplementation (MCS) in the Ts65Dn mouse model.  They were able to state, "These results support the lifelong attentional benefits of MCS for Ts65Dn and 2N offspring and have profound implications for translation to human DS and pathology attenuation in AD." (Strupp, 2017)

In 1986 a report of supplementing phosphatidylcholine in a 2.5 year old child with Down syndrome was published.  They reported no other supplements given.  After 7 months "The child showed a definitive increase in speech and language skills as well as general motor skills which exceeded same aged Down Syndrome peers experiencing like training programs." (Cantor, 1986)

Thiamine supplementation at 50 mg given three times per day has also been shown to improve speech, mood, energy and cognition in adults with Down syndrome. (Reading, 1979) The mechanism behind these changes are likely due to an increase in ACh as well as the many other benefits thiamine supplementation provides.

If you've given your child with Down syndrome a natural cholinesterase inhibitor and seen improvements in gross motor skills, cognition, speech and overall energy levels it's likely related to an underlying deficiency that has not been properly addressed. This can happen even when giving a multivitamin that contains the cofactors necessary for ACh synthesis if the levels are not high enough for your child's specific needs or malabsorption has not been addressed.  If an underlying deficiency goes undetected and untreated other biochemical needs of the body can go unaddressed.  Thiamine deficiency, for example, is something I've detected in many of my patients with Down syndrome. It's function in ACh synthesis is just one of many ways thiamine supports brain function and overall health.  Thiamine is essential for glucose metabolism, which must be optimized for proper brain function. Optimal glucose metabolism is needed in the brain for more than just ACh synthesis (Mergenthaler, 2013)

Remember, every child with Down syndrome is unique. Some may have a significant need for addressing ACh deficiency and some may not.  "With full trisomy, intuitively it might be assumed that expression levels of triplicated genes are 1.5-fold that of the euploid population. However, this is not so." (Strydom, 2016)

People with Down syndrome (DS) have an extra copy of chromosome 21, which is the location for the APP gene. This gene codes for a protein called amyloid precursor protein. The leading theory of the cause for Alzheimer's disease (AD) is that plaques in the brain made from amyloid protein causes the symptoms of cognitive decline that define AD. The science behind this theory is not settled, despite the push for drug development to address amyloid protein deposition in the brain as the only means to address Alzheimer's disease. 

Morris, Clark and Visser, researchers in Australia, write about the importance of gaining a better understanding for the cause of AD before more drugs are developed. (Morris 2014) They explain further why the amyloid hypothesis has failed clinically based in the failure rate of the five anti-amyloid drugs that have been approved by the FDA. Other theories for the cause of AD include (Armstrong 2013):

1. Exacerbation of aging
2. Degeneration of anatomical pathways
3. Exposure to aluminium
4. APOE gene
5. Mitochondria dysfunction
6. A compromised blood brain barrier
7. Immune system dysfunction
8. Infectious agents

Armstrong further explained that AD is multifactorial, which is restated by many other authors:

• Alzheimer Disease, a Multifactorial Disorder Seeking Multi-therapies - Igbal 2010
• The multifactorial nature of Alzheimer's disease for developing potential therapeutics.- Carreiras 2013
• The Complex and Multifactorial Nature of Alzheimer’s Disease -Alkadhi 2010
• Toward a multifactorial model of Alzheimer disease - Storandt 2012​​

Amyloid plaque is estimated to occur in 100% of those with DS by the age of 40, some even younger. However, not all of them experience the dementia symptoms associated with AD. (National Institute of Aging) That fact alone should make it clear to the research and medical community that more than just the APP gene and amyloid protein is involved in the development of AD. This is an important concept, so I'll restate it. If AD was only caused by amyloid protein and the plaques that are made from it then 100% of those with DS would experience the clinical symptoms of AD. This is not the case. This same phenomenon is also seen in those without DS as stated by researchers in Cambridge, "It has been hypothesized that Aβ accumulation is the primary cause of pathogenesis in AD, yet there is a weak correlation between Aβ plaque density and the severity of dementia." (Treusch 2009) More evidence against the amyloid plaque/APP gene theory was just published this month by a team of researchers from the UK and USA. They used a mouse model to triplicate chromosome 21 without the APP gene. These mice still developed amyloid plaques. "Here, we report for the first time that triplication of chromosome 21 genes other than APP, increases amyloid-β aggregation, plaque formation, and cognitive deficits in a novel Down syndrome–Alzheimer’s disease (amyloid-β deposition) mouse model." (Wiseman 2018)

I'll review here factors other than amyloid protein and the APP gene that have been proposed as contributing factors to AD and how those same factors are experienced by people with DS. The management and treatment of these factors, many of which are lifestyle related, can greatly reduce the chances of anyone developing AD, even those with DS. Those factors are:
​

• Low T3 (active thyroid hormone)
• Impaired glucose metabolism
• Thiamine deficiency
• Sleep apnea
• Aluminum
• Mitochondria dysfunction

The thyroid hormone process within the body is very complicated and involves many steps. A problem in any one of these steps can create a state of hypothyroidism.  A key step that is often not recognized as clinically relevant and therefore missed by many physicians is the conversion of T4 (thyroxine) hormone to T3 (triiodothyronine) hormone.  This conversion is undertaken by an enzyme called deiodinase that removes an iodine, hence T4 (containing 4 iodine) and it's conversion to T3 (containing 3 iodine). (Image 1) T3 is considered to be "active" thyroid hormone because it is the most important form of thyroid hormone that has cellular activity. T4 is lacking of any major cellular activity. The activity of this deiodinase enzyme is very sensitive to stress, inflammation, nutrient deficiencies, oxidative stress, gastrointestinal issues and several other states of ill-health within the body. (Mancini 2016, Hidal 1988, Vierhapper 1981, DePalo 1994)

As it turns out low levels of T3 hormone have been found in those with Alzheimer's. (Karimi 2011) Researchers from Harvard Medical School reviewed this same connection in "Thyroid Function and Alzheimer's Disease". (Tan 2009) The mechanism behind this possible connection is that T3 hormone, as it's considered a transcription factor that effects genetic expression, down-regulates (turns off) the APP gene.(Latasa 1998, Blandia 1998, Belakavadi 2011) This last point should be of great interest to parents, doctors and researchers working with those with DS.

In addition, researchers in Italy found elevated levels of reverse T3 in the cerebral spinal fluid of patients with AD. (Sampaolo 2005). Reverse T3 is a form of T3 hormone created by a different form of deiodinase enzyme that is a sign of aberrant thyroid hormone metabolism. (Biano 2013)  Researchers in Japan found that, "Serum rT3 level was a more sensitive parameter than serum T4 or T3 for evaluating thyroid dysfunction." (Shimada 1983) It's also been my experience that reverse T3 levels are elevated in my patients, particularly infants less than one year old as outline here in my research proposal.

The role that hypothyroidism plays in the phenotype of DS has been debated ever since the extra chromosome was discovered as the cause of DS in 1958. To this day only one study exists that investigated free T3 and reverse T3 levels in those with DS. They reported no difference in free T3 levels from those in their control group. (Toledo 1997) This has not been my clinical experience. I often see low free T3 levels along with high reverse T3 levels in my younger patients. The majority of my patients I've seen in my practice are aged 3 months - 3 years old.  The age range of patients in this study they used was 3 months - 20 years old. That's a significant span in life stages. Thyroid hormone metabolism and the factors that impact it can vary greatly depending on the age of the patient. Much more research is needed that explores the full extent of the thyroid hormone process in those with DS. This research could extend to a better understanding of the role that thyroid hormone plays in the development of AD.

Of all the organs in the body the brain is the largest consumer of glucose. When at rest, about 60% of the glucose used by the entire body is used by the brain. This is due to it's high rate of metabolism needed for the constant activity including neurotransmitter synthesis, maintaining appropriate electrical charge across the cell membranes and removal of cellular waste and toxins. Many studies exist supporting the connection and likely cause that impaired glucose metabolism has to AD. 

• The Alzheimer's disease-related glucose metabolic brain pattern. (Tuene 2014)
• Brain glucose metabolism in Alzheimer's disease. (Swerdlow 1994)
• Sugar and Alzheimer’s disease: a bittersweet truth (Iadecola 2015)
• Abnormalities of glucose metabolism in Alzheimer's disease. (Hoyer 1991)
• Brain fuel metabolism, aging, and Alzheimer's disease. (Cunnane 2011)
• Abnormal Glucose Metabolism in Alzheimer's Disease: Relation to Autophagy/Mitophagy and Therapeutic Approaches. (Banerjee 2015)
• ...and many others

Researchers at the Imperial College of London stated, "The impaired glucose metabolism in the brain of subjects with AD is a widely recognized early feature of the disease". (Calsolaro 2016)

Impaired glucose metabolism is common in children and adults with DS as well. Research corroborates this, especially impaired glucose metabolism in the brain where glucose is needed the most. (Azari 1994, Pietrini 1997, Labudova 1999) ​Symptoms of this include excessive hunger, excessive thirst, frequent urination, blurred vision, fatigue, frequent infections, tingling in hands and feet. Even the slightest sign of any of these symptoms in those with DS should be taken seriously as they are clues to potentially early stages of glucose metabolism issues. Those who carry extra weight are at even greater risk due to the additional effect this has on insulin resistance.

For a further review of glucose metabolism and the brain I recommend reading "Sugar for the brain: the role of glucose in physiological and pathological brain function".

Thiamine (B1) is heavily involved in the metabolism of glucose. As well, the nervous system is exquisitely sensitive to a thiamine deficiency. Given the recognized connection between impaired glucose metabolism and AD, thiamine has become a likely candidate in the treatment of AD. Gibson, et al have stated, "In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory." (Gibson 2013) In 2010, a more bioavailable form of thiamine, benfotiamine, was given to mice that were genetically altered to create more amyloid protein. They found, "...in the animal Alzheimer's disease model, benfotiamine appears to improve the cognitive function and reduce amyloid deposition via thiamine-independent mechanisms".(Pan 2010) The same research team reported improvement in MMSE (Mini-Mental Status Exam) scores in their subjects with AD who were given benfotiamine. (Pan 2016) They also assessed amyloid deposition and revealed that significant elevations in amyloid deposition occurred despite improvements in cognitive function. This fact reveals that the cognitive deline in AD is due to factors outside of simply plaque deposition. The number of subjects in this study was small but the findings were significant. 

The enzyme complex pyruvate dehydrogenase (PDHC) is a key step in glucose metabolism. The cofactors for this enzyme are thiamine (B1), riboflavin (B2) and alpha lipoic acid.  PDHC activity was found to be reduced in AD and Huntington's disease indicating a deficiency in one or all of these cofactors. ​​(Sorbi, 1983)

A five year study of 76 elderly patients with mild AD being given benfotiamine is currently underway at Cornell University and will be completed in 2019. (National Institute of Aging) Given the positive results seen in previous studies the results are likely to be positive for some of these patients. 

In addition to it's vital role in glucose metabolism, thiamine is needed for the production of NADPH that is a cofactor the the iodotyrosine deiodinase enzyme (Image 2). This enzyme is found within the thyroid gland itself and scavenges or picks up iodine so it can be recycled to make more thyroid hormone. Low thiamine levels will lead to low NADPH production which will reduce the thyroid glands ability to make thyroid hormone. In addition researchers in Japan found that NADPH also plays a role in T4 to T3 conversion (Sato 1981).

To say my experience using high doses of thiamine in the form of benfotiamine in my patients with DS has been interesting is an understatement. While I have not published these findings, I'll report here that many of my young patients and some of my adult patients with DS are experiencing improvements in speech, cognition and gross motor skills at a rate that is much faster than was occurring before benfotiamine was started. I highlight the stories of two patients and explain some of the history and science behind thiamine deficiency in the video linked below if you want to hear more about my experience.
​

​Two published clinical trials exist using thiamine in two different forms in people with DS. The first one was conducted in 1979 and included three adult subjects with DS. While the size of this trial was small the results were significant. Although not clearly stated, the form of thiamine used was likely thiamine HCl or thiamine mononitrate as these are the more common forms used. They gave 50 mg three times a day. The results are recorded in the center column of Table 2 below. (Reading 1979)

Despite the significant results from this small trial no further research into the effectiveness or use of thiamine was conducted until 28 years later when another form of thiamine, tetrahydrofurfuryl disulfide (TTFD) was used in a clinical trial. This trial included 22 children with DS between the ages of 8 and 16 years old. They, too, used 50 mg three times per day and included a control group that did not receive TTFD for the first 6 months of the experiment. Their conclusion was, "This study did not reveal any dramatic response in any of our 22 subjects. Although 5 of them did demonstrate some increase in IQ ratings, there was little change in the behavior to encourage the parents in most cases". (Lonsdale 2007) It's possible that TTFD simply isn't the ideal form needed for those with DS.

Again, my experience with using thiamine is in much younger children,  and with benfotiamine as the form. To this day a clinical trial investigating the use of benfotiamine (that is non-toxic) in those with DS has not been conducted. My hope is that it would include young children ages 1-3 years given the sensitive nature of brain development at this age.

There's no denying the negative effects that hypoxia (low oxygen) has on the brain. Because the brain uses so much glucose it also has a high demand for oxygen.  Glucose cannot be optimally used for energy without a sufficient supply of oxygen to match.

​Our bodies generate energy from glucose in two ways, aerobic respiration (with oxygen) and anaerobic respiration (without oxygen). Aerobic respiration is the preferred form of energy production because it involves the mitochondria and makes a significantly higher amount of energy. In the absence of oxygen pyruvate (made from glucose) cannot enter the mitochondria.  Pyruvate is then converted to lactate and mitochondria sit unused. You can watch the video below to learn more about anaerobic and aerobic respiration.
​

So, in the absence of oxygen the brain can experience elevated levels of lactate, also known as lactic acid.  This is the same lactic acid that creates sore muscles after a strenuous workout.  A person can feel like they've had a hard workout just from experiencing hypoxia due to obstructive sleep apnea (OSA) at night without the benefits of the strenuous workout. Anyone who as experience with sleep apnea has an increased chance of also experiencing muscle pain. Researchers in Turkey found a "55.4% prevalence of chronic widespread pain in patients with obstructive sleep apnea". (Aytekin 2015) This pain is often due to a build up of lactic acid within muscles.

This same lactic acid can build up in the brain as well and is very toxic to brain cells due to it's acidic nature.  In fact, research exists linking elevated lactic acid to amyloid plaques and AD. Researchers at the University of Florida found elevated levels of lactic acid in cerebral spinal fluid of patients with AD. (Xiang 2010) A team in Italy found the same thing in 2015. (Liguori 2015) 

The level of hypoxia experienced during OSA varies from patient to patient. Researchers in India measured serum lactate and uric acid levels in patients wit OSA and their conclusion reads, "Both serum UA and lactate were positively correlated with the degree of hypoxia in OSAS. The plasma UA levels in patients with OSAS did not show an overnight rise. However, the plasma lactate levels were higher in the morning. The measurement of serum lactate level was a better marker of oxidative stress among patients with OSAS." (Hira 2012) Earlier in 2009 a research team in Turkey found elevated arterial lactate levels in patients with sleep-related breathing disorders. (Ucar 2009)

The rate of sleep apnea, both obstructive and central, is extremely high in those with DS. Many go undetected and untreated because they experience silent sleep apnea. This form of sleep apnea has no symptoms unless a sleep study is done. The rate of sleep apnea in those with DS has been shown to be as high as 78%. (Fan 2017)

My experience of running more than 500 organic acid tests on children with DS has revealed many things. One of the most significant things it has revealed is the high prevalence of elevated lactic acid in these children, especially with those who are struggling the most in areas of gross motor skill and speech development. An organic acid test is conducted on a first morning urine sample in order to get a more concentrated urine sampe that is the furthest from food consumption that can interfere with results. A first morning urine sample also assesses changes in physiology that occur during sleep.

​An elevation in lactic acid can indicate several things: thiamine deficiency, riboflavin deficiency, hypoxia from sleep apnea or other causes of impaired glucose metabolism.  I most often see improvements in lactic acid levels after high dose benfotiamine has been started and the test is repeated. I've included three images of lactic acid results from my patients with DS below as examples, but have seen this many more times.

This is one of the oldest and most widely studied theories as the cause of AD.  As with all other causes of AD it's also controversial despite the research to support it. The leading world expert on aluminum research is undoubtedly Dr. Chistopher Exley. He is a PhD in ecotoxiclogy of aluminum. He only studies aluminum. He has stated, "Quite simply, all biologically available aluminium in the brain is neurotoxic". (Exley 2016) Researchers in Germany agree with him, writing "Aluminum’s neurotoxic effects in humans and its embryotoxic effects in animal models have been proven." (Klotz 2017) Many others in the scientific community agree and aluminum is now widely accepted to be a neurotoxin.

The main route of aluminum exposure in the body is through digestion as aluminum is the most abundant metal in the earth's crust. Aluminum present in soil eventually makes its way into the food and water we ingest. Fortunately, the lining of our digestive tract creates an effective barrier to the absorption of most consumed aluminum. Unfortunately, this barrier can be disrupted in states of ill-health and increased gastrointestinal permeability, aka leaky gut.  Studies have shown that increased aluminum absorption through the GI tract occurs in those with AD.(Moore 2000) Citrate is another factor that can increase aluminum absorption.(Taylor 1998) I often recommend avoiding supplements like magnesium citrate to my patients for this reason.

A secondary source of aluminum that bypasses the gastrointestinal barrier is aluminum hydroxide that is the most common adjuvant used in vaccinations. Exposing the body to aluminum in this way completely bypasses the body's natural means of eliminating it. Aluminum, even in low levels, is a well-established neurotoxin. (Banks 1989, Joshi 1990, Krishnan 1988) As well, there is evidence for aluminum retention within the brain increasing the risk of neurotoxicity with multiple exposures. (Kumar 2014, Gherardi 2015) Dr. Exley and his team tested several commercially available aluminum based adjuvants, including Alhydrogel®, the most commonly used aluminum based adjuvant. This aluminum based adjuvant is in the form of aluminum oxyhydroxide. They revealed that this adjuvant "is most pre-disposed to migration away from the injection site..." to other areas of the body including the brain. (Exley 2016)

There is a growing body of evidence implicating mitochondria dysfuntion as the means by which aluminum causes neuronal damage. (Marchi 2004, Murakami 2004, Niu 2005)  It has specifically been shown to interfere with isocitrate dehydrogenase (IDH) that is a NADPH dependent enzyme within the citric acid cycle (Image 5).(Murakami 2004) A decrease in this enzyme makes cells more sensitive to lipid peroxidation and oxidative mitochondria DNA damage. (Kim  2003, Lee 2002)

Aluminum can be a contributing factor to AD for those with DS. It's been shown that those with DS have an increase in gastrointestinal absorption of aluminum. (Moore 1997) It's likely due to the higher incidence and under-recognized rate of SIBO (small intestinal bacterial overgrowth) and gastrointestinal candida overgrowth. (Riordan 2002, Kumamoto 2001)

Mitochondria are rod-shaped organelles that can be considered the power generators of the cell, converting oxygen and nutrients into adenosine triphosphate (ATP). ATP is the chemical energy "currency" of the cell that powers the cell's metabolic activities. Recall from above that the brain is the most highly metabolic organ of the body, so it's the organ that is most sensitive to impaired mitochondria function.

The evidence pointing to mitochondria dysfunction in AD is strong and growing as well. I've pointed out several means above by which mitochondria function can be impacted. "Mitochondrial function is deregulated in AD and there is growing interest in understanding how altered mitochondrial function may be targeted to inhibit neurodegeneration." (Onyango 2016)

The most basic fuel that mitochondria need to make energy is oxygen and glucose. The process is similar in some ways to the burning of wood to create energy in the form of heat and light from a flame. Glucose in the wood is in the form of cellulose. Wood (glucose) also requires oxygen to burn. The same is true for our bodies. However, because the creation of energy within our bodies is tightly controlled by enzymes it's a bit more complicated than that. Those enzymes that control mitochondria energy production require B vitamins, particularly B1, B2, B3, B5, B6, B7, B9, B12...well, all of them. For those who are familiar with the citric acid cycle and how energy is generated from it, Image 5 shows how extensively the B vitamins are needed for it to operate. To learn more about mitochondria function you can read "Mitochondria - Why they're important and what they need to function".

It now becomes clear how all of the topics discussed above come together to essentially support mitochondria function. They are truly key players in brain health. Supporting mitochondria function from all angles (sleep, diet, exercise, B vitamins, breathing, avoiding toxic substances, etc) will do a great deal to support brain health and prevent the development of AD in all individuals, including those with DS.

Many studies exist supporting the presence of mitochondria dysfunction in those with DS. Coscun and Busciglio do a thorough job reviewing the role that mitochondria dysfunction has on the phhenotype of those with DS. (Busciglio 2012) In it they state, "Besides oxidative damage, mtDNA mutations and mitochondria dysfunction emerge as important modulators of DS phenotypes." Supporting mitochondria function in those with DS could greatly impact their risk of developing AD.

People with DS are being used as guinea pigs to test the safety and efficacy of a new vaccine, ACI-24, designed to stimulate the immune system in a way that it will then destroy amyloid plaques within the brain.(ClinicalTrials.gov) It sounds good on the surface. But when you break it down, they're testing the safety of a previously unused vaccine on people who have a strong history of discrimination and marginalization in order for those without DS to benefit, not to mention the profits that will be made from the creation of such a vaccine. They're testing the safety. This means they don't know if it's safe in humans. Mice studies have been conducted to test the safety and efficacy of ACI-24. (Muse 2007) They tested for signs of inflammation as an indicator of safety. They found no significant elevations in the markers of inflammation. It's unclear how much time lapsed between the end of the injections series and testing for inflammation.

While ACI-24 may indeed create an immune response in the body that attacks amyloid plaque. Is it addressing the real underlying cause of the plaque? What are the consequences to the body if the underlying cause isn't addressed? Let's take thiamine deficiency for example. Thiamine deficiency in a mouse model has been shown to "greatly exacerbate plaque formation" (Gibson 2016) and you now know how thiamine can help prevent and possibly treat AD in humans. So, if we remove the plaque but don't address the thiamine deficiency will the brain and the rest of the body still struggle? It absolutely will. In addition, researchers from Cambridge, MA reviewed the possible protective role that amyloid plaque plays in protecting the brain in "Amyloid deposits - Protection against toxic protein species?". (Treusch 2009). Clearly, more information is needed about the nature of amyloid plaque before a drug or vaccine designed to remove it is developed.

Informed consent is an important and essential part of every ethical human study. Many parents hold guardianship over their adult children with DS and can sign consent for them to receive the experimental vaccine. As well, many adults with DS are perfectly able to understand the implications of, rate of and importance of preventing AD in DS when signing such a consent. However, are parents and those with DS getting all of the information about the yet undetermined cause of AD? Are they being shown or seeing research that supports alternatives to the amyloid plaque theory? Are they truly informed when they sign a consent? I fear not.

Research on human subjects must pass rigorous ethical standards. Guidelines for informed consent have been established by the Office for the Protection of Research Subjects. A full list of the basic elements  for informed consent can be found in "Informed consent: Issues and challenges". (Nijhawan 2013). A key aspect of informed consent that should be highlighted here is "A disclosure of any appropriate alternative procedures or courses of treatment that might be advantageous to the subject". Based on what you've read here so far you can see that alternatives do exist. It's likely that subjects and their guardians or parents are not being told of the research supporting alternative means to prevent AD. 

The DS population does hold a lot of information about the etiology of AD. However, it's not due to their genetics alone. The metabolic differences experienced in DS hold many clues as well. Researching the effects of addressing these metabolic differences would go a lot further and be much less costly than developing a vaccine that only addresses amyloid plaque.

A disease with a multifactorial cause requires a multifactorial approach.  The work of Dr. Dale Bredesen is the epitome of how this works. ​​​It's not likely that I'll be able to fully explain the importance and full breadth of the work being done by Dr. Bredesen.  He first published his findings using a multifactorial approach to treating AD in 2014 in his ground-breaking report "Reversal of cognitive decline: A novel therapeutic program". (Bredesen 2014) I was very excited to see that the work he was doing reflected almost exactly what I had been doing to help my patients with DS. It was a very Naturopathic approach that addressed diet, lifestyle, sleep, breathing and supplements. Table 1 below is taken directly from his report and outlines the program he used. While this may seem like a lot at first, it's all actually part of a very healthy lifestyle. There's also a lot of cross-over that occurs between each of these items.

​Dr. Bredesen went on to publish The End of Alzheimer's in 2017. I cannot recommend reading this book more highly. It explains the concepts behind his work in terms that can be understood by lay people as well as appreciated by the medical community. He includes information about the very important APOE gene that has been linked to the increase rate of AD in those with DS as well. "When ApoE4 (ε4) is present in DS, the risk for AD is even higher." (Castro2017​) If you're looking to prevent AD in your child or loved one with DS you'll miss a great opportunity to help if you simply wait for a vaccine to become available. 

​Parents are being misled when they're made to believe that the only way to prevent AD in their child or loved one with DS is to target amyloid plaques that are generated from the APP gene. This only serves to perpetuate the idea that those with an extra copy of chromosome 21 are somehow genetically broken and little can be done to help them other than impacting their defective genetics. Many reading this already know that I wholeheartedly don't believe that people with DS are inherently broken based on their genetic make up. What they need in order to prevent AD is the same thing we all need: a healthy diet, prevention of sleep apnea, avoidance of aluminum and optimization of glucose metabolism.

I'll close by modifying an analogy made by Dr. Bredesen in his book that he calls "36 holes in the roof." The problem of neurodegeneration and dementia in AD is analogous to the problem of a house with many holes in the roof. Some holes are larger than others. Ideally, all holes would be fixed in order to keep the house dry. If a few small holes were left we might be able to manage and keep the house fairly dry inside. Let's imagine that the home owner is convinced that one of the larger holes is the only problem. He works diligently to repair only that hole while standing right outside his front door is a team of people willing to help repair the other holes. The home owner chooses to ignore this team of people and focus only on the one hole.  This scenario would be frustrating to witness would it not?

Low muscle tone in an infant or child is not a symptom to ignore. It can indicate significant pathology that is effecting the health of the child in other areas including brain development.

Signs and symptoms of low muscle tone:

• Head lag
• Fatigues quickly
• Poor posture
• Increased flexibility, increasing susceptibility to injuries
• Poor persistence to gross motor tasks
• Lack appropriate body awareness feedback
• Avoids chewy foods
• ​Feeding difficulties
• Preference to engage in sedentary activities

An example of an infant with low muscle tone is seen in the video below. (This video may be difficult to watch but this exam is being conducted by a very experienced physician. We don't recommend that you attempt a head lag test on your own child with low muscle tone.)

Treatable Causes:

• Hypothyroidism
• Mitochondrial dysfunction
• Methylation issues
• Thiamine (B1) deficiency
• Other B vitamin deficiencies
• Carnitine deficiency
• Creatine deficiency

Physicians should conduct a thorough physical exam that includes assessment of deep tendon reflexes, cranial nerves, eye movement, hearing, feeding, gross motor skills and general observation of the infant's movements. A physician trained in understanding the root cause of low muscle tone will also be able to detect signs and symptoms of other vitamin or nutrient deficiencies that are contributing to low muscle tone.

Dismissing low muscle tone in a child or infant with Down syndrome as simply caused by the presence of the extra copy of chromosome 21 will lead to a missed opportunity to detect a secondary treatable cause of low muscle tone. Negative consequences of low muscle tone are mostly seen as slow gut motility resulting in a vicious cycle that ultimately leads to nutrient deficiencies that further decreases muscle tone (Image 1). Another physical consequences of low muscle tone includes stressed joints. Malalignment of vertebral bones and subluxation can lead to further impairment of the nervous system, headaches and jaw pain.

Labs to be done in order to detect the underlying cause:
​

• TSH, free T4, free T3, reverse T3
• homocysteine 
• acylcarnitine profile 
• amino acids (plasma and/or urine)
• organic acids in urine
• creatinine

This is not an exhaustive list as there are many other labs to consider depending on the history and presentation of the patient.  Other labs to consider are vitamin D, ferritin, CBC and histamine. For more information about urinary organic acid testing please see our web page devoted to information about this very informative and important testing method: Organic Acid Testing. Naturally, lab results will guide appropriate treatment.

Physicians should be aware of all causes of low muscle tone and seek out appropriate testing in order to best treat it. Often children are referred for physical therapy and orthotic braces alone and no biochemical cause is pursued, especially when the child has a known genetic condition. While therapy and orthotics are often helpful they do not address the underlying cause of the low muscle tone. When any one of the causes listed above is missed this can greatly impact brain development, cognition and the overall health of the child. 

Can something as simple as a sore throat lead to changes in the brain that result in significant negative behaviors, loss of speech, restricted eating, and loss of fine motor skills?  As it turns out, the answer is "yes". This doesn't happen in all children, but for a certain subset of children it can, especially those who are at increased risk of developing autoimmune disease or those who already have an autoimmune disease. Children and adults with Down syndrome are among those who carry an increased risk of autoimmune disease including autoimmune thyroid disease, type 1 diabetes and Celiac disease. (Chistiakov 2007​) The autoimmune reaction to strep bacteria that leads to neurocognitive changes is called Pediatric Neuropsychiatric Disorder Associated with Strep or PANDAS for short. It is also referred to as autoimmune encephalitis by some. PANS is another broad term for this condition that stands for "Pediatric Acute-onset Neuropsychiatric Syndrome".

Symptoms of PANDAS include:

• Acute onset (may be absent if onset was a long time ago)
• Obsessive compulsive behavior (often absent in patients with Down syndrome)
• Generalized anxiety
• Aggression, irritability, emotional lability
• Hyperactivity, restlessness
• Loss of speech (especially in Down syndrome)
• Hypersensitive to light and sound
• Regression in potty training 
• Loss of academic abilities
• Restrictive food intake
• Overall developmental regression
• Change in fine motor skills or handwriting

The CDC reports that 20-30% of all sore throats in children are caused by Group A strep. (CDC 2016) When the body is exposed to strep bacteria antibodies specific for that bacteria are created that send signals to other immune cells within the body to attack the bacteria. The antibodies don't do the work of killing the bacteria their job is to identify the foreign invader and signal others cells to attack.  The only way the other cells, typically macrophages, know to attack something is based on the presence of antibodies on the surface. Antibodies are generally shaped like the letter "Y" as seen in Image 1. This is only one part of our immune system, called the antibody-mediated immune response or humoral immunity. It's a very complex system that is dependent on a healthy gastrointestinal microbiome as well as optimal levels of vitamins A, D, B12 and others. ​

This extremely important and complex part of our immune system can lead to problems in certain individuals for reasons that are still not fully understood.  When antibodies are generated in response to a bacteria, virus or other foreign invader additional antibodies to tissues of the body can be made at the same time.  The other theory is that the antibodies created for the bacteria or virus happen to be shaped just right for receptors on the surface of cells within the tissue of the host.  This concept is called molecular mimicry. (Cusick 2013) When these antibodies that match tissues of the body come into contact with these tissues then immune cells do what they're designed to do and attack that tissue of the body. This is called autoimmunity.  Some examples of tissues and organs that can be effected by an autoimmune reaction include thyroid gland, adrenal gland, microvilli in the gastrointestinal tract, pancreas, joints, soft tissue, myelin, hair, blood vessels and brain.

Despite PANDAS being a condition recognized by the NIH it is still considered to be controversial by many pediatricians. While many physicians continue to refuse to recognize the mere existence of PANDAS, we include ourselves with the small, but growing, group of physicians who are actually helping patients in significant ways by treating it. If you hear any physician telling you that PANDAS is "controversial" don't waste your time with them. If they aren't even convinced that it exists in the first place you're likely not going to get any help with treatment from them.

So, what's driving this autoimmune reaction? Why do some children create these auto-antibodies and some do not? The short answer is: "It's complicated". The longer answer involves several areas of health to address when working to reverse autoimmunity in the body, which is possible!  The list below includes several areas of health that a well-trained physician will address in order to reverse the effects of a autoimmunity.

The topics I'll highlight from the list above in the following two cases are gut health, removal of initial infection and removal of co-infections. We also addressed nutrient deficiencies (which can ultimately effect methylation and sulfation), as well as reduced inflammation. While the two children in these case reports do have Down syndrome, it's likely that these same concepts apply to all children. 

Case # 1: Parasites and PANDAS:
(name has been changed)

Sally is an 11 year old female who presented for a follow up appointment via telemedicine in September of 2017 after having been seen in November of 2016 for chronic ear infections.  Sally happens to have Down syndrome, has a G-tube for previous issues with oral feeding that is now only used for medication and supplements and has limited verbal skills.  The mother reported in Nov 2016 that she had an ear infection that had not fully cleared for 6 months despite the use of Amoxicillin by her local pediatrician. Her symptoms included signs that she was in pain as covering her ears and pointing to her head. The mother also reported an increase in anxiety, sadness and sleeplessness.  Her ear fluid was finally cultured by her local pediatrician which indicated staph as the source of the infection. The pediatrician was "not worried about that", according to the mother. Sally had also recently been experiencing urinary incontinence despite having been potty trained many years prior.

I recommended xylitol-saline nasal spray to help treat the staph and potential for biofilm, in addition to some diet recommendations and other basic naturopathic support for ear infections.  We reviewed her organic acid test results during this appointment as well that did not indicate any significant nutrient deficiencies, mitochondrial dysfunction or gastrointestinal issues. I recommended she follow up in two months with results from labs I recommended that included anti-DNase antibodies and anti-streptolysin O antibodies (ASO), as I knew that PANDAS needed to be ruled out. At the time of this appointment I was just beginning to learn about PANDAS and knew enough at the time to simply check for it.  

Ten months later the mother made a follow up appointment in September of 2017 that included the results from the labs I requested. I saw that her ASO was elevated at 320 IU/mL (normal is <200 IU/mL) before the appointment. The mother broke into tears within the first few minutes of her appointment stating she had "lost" her daughter. Sally was no longer engaged, completely non-verbal, had lost all potty training skills, no longer did crafts which she previously loved to do, was aggressive and combative at times, had increased anxiety and unusual posturing when they were able to get her to have a bowel movement on the toilet.  Her behavior was worsened whenever the doctors prescribed antibiotics. My chart notes include this: "was sweet and loving until 2 years ago - disappeared".  They were in what many of us call "PANDAS hell".  

I knew this was NOT "just Down syndrome", as many other doctors had told the mother.  Something had to be done.  By this time I had learned more about PANDAS and had been helping several other patients with it.  The first step was to find the strep within her body in order to eliminate it.  So, I recommended a GI Effects Comprehensive Profile from Genova Diagnostics.  I knew this would be helpful at detecting any other abnormalities in her digestion and microbiome that might be impacting her as well. I also referred the mother to a physician who was listed on a PANDAS website and was local to her.  Given that I was only seeing her through telemedicine, I wanted her to have more local support. 

The results of Sally's stool analysis came back in January of 2018. Images from those results are listed below.  You can click on each image to see a larger version of it. 

 

I immediately messaged the mother to inform her that her daughter's stool results revealed the presence of three! parasites in addition to excess candida, gamma haemolytic Streptococcus and Klebsiella pneumoniae.  She also had a very high secretory IgA level indicating her immune system was reacting to the infections. Her propionate percent was also elevated. This is a short chain fatty acid that has been linked to autism (MacFabe 2015) I advised that she show these results to her local pediatrician and the physician she had seen for help with the diagnosis of PANDAS.

The mother did see that "PANDAS expert" physician and despite her symptoms, history, her labs revealing an elevated ASO and her stool analysis results she was told that her daughter was only experiencing the effects of her extra chromosome. I was livid when I heard this. If I had more time I would have written a letter to this doctor explaining how he had practiced discrimination against my patient, not to mention malpractice. It was a clear example of diagnostic overshadowing that so many of my other patients with Down syndrome experience.

The mother was now in great despair and felt helpless.  She messaged me and I recommended she make an appointment so we could discuss her options. I was shocked to hear her story. Although I shouldn't have been since it is a story I've heard from many other patients. This was just the most egregious example of diagnostic overshadowing and medical neglect I had heard.

We had that appointment in March of 2018. We discussed treatment options for all of her gastrointestinal infections.  We chose herbal formulas as they have the advantage over pharmaceuticals in situations where multiple infections exist.  Their antimicrobial properties can be effective against yeast, parasites and bacteria. In many cases they are more effective than pharmaceutical alternatives.  Here is a portion of the exact plan I wrote in her chart:

Pumpkin seed oil treatment 

• Pumpkin seed oil  - 1 Tbsp first thing in the morning before breakfast.  2 hours later give another 1 Tbsp.  Another 2 hours later give castor oil 
• Castor oil - 1 Tbsp 

Follow with:

• Black walnut/Wormwood - 1 mL 2-3 times per day for 10 days only 

Use for 2 months following pumpkin seed oil treatment: 

• Biocidin - 7 drops twice a day, empty stomach is best (before breakfast and before dinner), start slowly with 1 drop on the first day and increase by 1 drop each day after that
• LactoPrime - 1 capsule at bedtime
• S. Boulardii - 2 capsules twice a day (at bedtime and during the day between Biocidin doses if possible)

Biocidin is a powerful antimicrobial herbal formula that is very effective at treating yeast, parasites and bacteria.  I chose this for a longer treatment option for her to continue after the initial treatment that was targeted for parasites. I advised that she follow up in 3 months with a repeat stool analysis and blood labs that were to be ordered from her doctor.  

Pumpkin seed oil contains a substance called cucurbitin that treats worms and other parasites by paralyzing them so they can be expelled from your body. (Grzybek 2016) Black walnut and wormwood are herbs that specifically treat parasites but also have anti-fungal properties as well.

I signed her chart and moved on to helping other patients. I had to wait with much anticipation for her follow up appointment to hear how she responded to this plan. The results from her follow up stool analysis finally came in on August 13, 2018 and are below.

Sally's story is an example of how co-infections likes parasites can be the initial cause of an autoimmune reaction for those who experience PANDAS secondary to strep exposure. Ercolini and Miller have stated, "In particular, viruses, bacteria and other infectious pathogens are the major postulated environmental triggers of autoimmunity." (Ercolini and Miller 2009) They discuss and very thoroughly describe how molecular mimicry that is triggered by infection leads to an autoimmune reaction. The following quote is taken from Autoimmunity and the Gut:

Ultimately, checking for co-infections should be part of treatment for every patient with PANDAS and other autoimmune conditions.

Case #2: Yeast and PANDAS
(name has been changed)

Bella is now an eight year old female patient who I had been working with for several years. I helped make recommendations to her dose of thyroid medication in addition to supplements and diet changes to optimize her health. She was overall a healthy young girl who had hypothyroidism and happened to have Down syndrome. Blood work and symptoms were our main guides and we had seen improvements in her health with every adjustment to her plan, but more was needed.

In March of 2017 the mother was able to do an organic acid test through Great Plains Laboratory so we could get an in-depth look at how to best help her.  She had been prescribed several rounds of antibiotics over the years for upper respiratory infections, which increased my suspicion for a disrupted balance of bacteria and yeast within her gut. The organic acid test is something I encourage most of my patients to do. It includes markers that can detect gastrointestinal malabsorption and dysbiosis, mitochondrial dysfunction, fatty acid metabolism, vitamin deficiencies and more.  Bella's test results are below.
​

Her results revealed the following:
​

• Significant yeast overgrowth
• Clostridia difficile (seen as elevated 4-cresol)
• Riboflavin deficiency (elevated succinic acid, 3-methylglutaric acid and glutaric acid)
• Inflammation (elevated quinolinic acid)
• Need for carnitine (elevated adipic acid)

This is a very simplified interpretation of this test. I've left out some details to keep this as straightforward as possible.

The mother and I discussed taking a more aggressive approach to treating her daughter's gut health in addition to her strict following of a healthy diet.  I recommended the following plan:

Gut Treatment for 6 weeks: 

• Biocidin - 3 drops twice a day on empty stomach.  Can be given with thyroid medication.  Start with 1 drop and increase by 1 drop per day until you reach maximum dose. 
• Biofilm Defense - 1 capsule with Biocidin
• Probiotic - 1 capsule at bedtime
• The Candida Diet - do the best you can.

2 weeks after starting Biocidin or when symptoms are better: 

• Carnitine - 1/4 tsp once a day
• Riboflavin - 1/2 capsule once a day
• B Complex - 1/2 capsule once a day with food

There was more to her plan than this, but these were the recommendations made in order to address specifically what the organic acid test had revealed.  I recommended she repeat the organic acid test in 3-6 months and follow up with a blood draw that included strep antibodies due to a recent bout with strep throat and changes in her behavior that included emotional lability and decreased cooperation. Mom reported that she was grumpy overall. She also had a sleep study that revealed moderate sleep apnea that was likely aggravated by her enlarged tonsils. She followed up in December of 2017 with the blood draw results I had requested but was not able to repeat the organic acid test. Her original ASO level is below.

These results along with her symptoms were enough to diagnose her with PANDAS.  She had already been treated for strep with Augmentin and it was not completely effective at eliminating it. Because the tonsils can become quite enlarged, strep can hide deep within them and be very difficult to treat.  While not an ideal solution, I recommended the mother speak with an ENT about the option of removing her daughters tonsils.  The risk of these strep antibodies further impacting her brain function far outweigh the risk in removing her tonsils. Nine of ten children with PANDAS who had a tonsillectomy experienced improvement in their PANDAS symptoms according to physicians at Albert Einstein College of Medicine. (Demesh 2015)

The most recent appointment with this patient I had was in July 2018. The mother had stopped all supplements before repeating the organic acid test and was continuing a whole foods, grain-free diet. Her daughter's tonsils had not yet been removed. The results of her organic acid test are below.

Her yeast markers are greatly reduced as well as her 4-cresol level (c. diff).  She still showed a need for riboflavin and carnitine but those markers were greatly reduced from her previous test.  In addition to the improvements in her organic acid test results her ASO antibodies had also come down to nearly normal. They are posted below.  While still high, they are one third of what they were just 6 months prior. The mother also reported improvements in Bella's behavior and no ear or upper respiratory infections over the previous winter. The decrease in her strep antibodies correlates directly with the reduction of yeast overgrowth as seen on her organic acid test.

We're still working on optimizing Bella's health to further reduce the antibodies and help her immune system be less reactive. The biggest impact to her health has been the incredible diligence the mother has for maintaining a healthy diet for her daughter.  Treating yeast with a very effect herbal formula and probiotic was another significant factor in helping her immune system normalize.

In 2015 physicians in India cultured oral flora of 50 children with Down syndrome compared to 50 control children (without Down syndrome). 74% of children with Down syndrome showed a growth of Candida while only 36% of the control group showed this. Most of these were C. albicans infections. They state in their conclusion, "The Down syndrome subjects run a greater risk of having opportunistic infections with a possibility of systemic spread..." This increased risk of a C. albicans infection is something that is confirmed on a daily basis in my practice. This opportunistic infection does not remain isolated to the oral cavity. A C. albicans infection in the oral cavity is indicative of infection deeper in the gastrointestinal tract. The ramifications of C. albicans overgrowth in the gastrointestinal tract are vast and potentially devastating to their ability to absorb nutrients, not to mention the effects from toxins like aldehyde released from C. albicans.  In addition to these effects, a C. albicans infection also increases inflammation in the gastrointestinal tract. (Kimamoto 2011) Researchers in Denmark have revealed an increased risk of autoimmune disease in those with inflammatory bowel disease. (Halling 2017) Testing to detect C. albicans infections in patients with PANDAS and other autoimmune disease is a necessary part of correcting their immune system dysfunction.

Labs for Diagnosis

The labs we most often run in our patients with previously diagnosed PANDAS or suspected PANDAS are:
​

• Organic acid test
• Comprehensive stool analysis
• Anti-DNase antibodies
• Anti-streptolysin O antibodies

Additional testing to check for co-infections as warranted would include:

• Borrelia burgdorferi antibodies (Lyme disease)
• Epstein-Barr virus antibodies
• Mycoplasma antibodies
• Coxsackie antibodies
• Parvo 19 antibodies
• HHV-6 antibodies
• CMV antibodies
• Anti-Dopamine Receptor D1
• Anti-Dopamine Receptor D2L
• Anti-Lysoganglioside GM1
• Anti-Tubulin

The last four tests on the above list are part of the Cunningham Panel.  This is the only test currently on the market that offers these. It's an expensive test, as it's not often covered by insurance, that doesn't necessarily change the mode of treatment. The root cause of autoimmunity often lies in the gut, so the majority of testing should rely on gut function tests. 

Naturally, if elevated antibodies are revealed from any of the viral or other infectious agents tested treatment specific for those should be undertaken. Lyme disease, for example, requires working with a physician who is specifically trained in treating it.

Closing Thoughts
​
​The rate of PANDAS in Down syndrome has not been studied, but autoimmunity is known to occur at a higher rate in those with Down syndrome than the general population. The likelihood that this is going undiagnosed in children and adults with Down syndrome is high.  We routinely check strep antibodies in our patients with Down syndrome if they experience even one bout with strep. We're detecting these antibodies more and more in many, but not all, of our patients with Down syndrome.

​Elevated strep antibodies in patients with Down syndrome who were experiencing catatonia were reported in 2015 by a group of psychiatrists.  Two of the three patients in their case reports had elevated antibodies to Epstein-Barr, Mycoplasma and Streptococcus. They stated, "Though immune disorders are significantly more common in DS...than in the general population, the significance of these co-occurring immune disorders and reactions is unclear." (Ghaziuddin 2015) The treatment of choice for these patients was ECT (electroconvulsive therapy) and benzodiazepines. No mention of gastrointestinal function testing was made in these reports. The reason behind the increased rate of autoimmunity in those with Down syndrome is due in part to genetics but mostly due to the very common and often undiagnosed gastrointestinal issues they experience.  Parasites and candida overgrowth along with small intestinal bacterial overgrowth are just a few of the gastrointestinal issues we detect and treat in our patients with Down syndrome.

If you suspect PANDAS in your child or loved one with Down syndrome find a doctor who will listen and not just dismiss their symptoms as "normal for Down syndrome". Hopefully that same physician will not only check for strep antibodies to confirm the diagnosis they will also work to uncover the root cause of the autoimmune reaction. Reversing an autoimmune process is not simple and often not remedied quickly. Be patient. Don't give up. The work often pays off eventually and is worth every hug and smile you get in return.

There are many factors that impact growth in children. All factors must be optimized in order for optimal growth to occur. Focusing on one factor, like growth hormone alone, will not always result in optimal growth and will leave other underlying causes unaddressed that can have detrimental impacts to other areas of the child's health. Addressing only one factor that alleviates a symptom happens often in medicine. The problem with this model is that many other factors will get missed and contribute to issues in other areas including cognition. I will discuss here the top seven factors that impact growth in children. Remember to optimize growth you must optimize all of them. 

Delayed growth has been generally accepted to be part of the phenotype of Down syndrome. In fact, they have their own separate growth chart. This fact is maddening to me. Here's the logic behind it: Let's take a symptom of a pathological process (poor growth) measure it in children with Down syndrome, show that they tend to have significantly shorter stature than their peers without T21, give them their own separate growth chart then call it "normal for Down syndrome".  I'd like to make a suggestion. How about we try to uncover the underlying cause for their slowed growth? I don't recommend referring to these growth charts that are specific for Down syndrome. I never use them in my practice. Children with Down syndrome can experience issues in any or all of the follow seven factors. The good news is we have tools to improve all of these issues.

Dr. John DiBaise explains how SIBO causes malabsorption of Vitamins B12, B1, B3, A, D, E, and iron as well as a decrease in amino acid and protein precursor uptake in "Nutritional Consequences of Small Intestinal Bacterial Overgrowth". (4) Proteins and amino acids are the main building blocks needed for muscle and skeletal growth. 

​The microbiome consists of trillions of microbial cells on and in the human body, the majority of the microbiome is found in the gut. The human microbiome also consists of the genes these cells harbor. Kunc, et al review very thoroughly how the microbiome in the gut can impact thyroid hormone, growth hormone and other hormones of the endocrine system in "Microbiome impact on metabolism and function of sex, thyroid, growth and parathyroid hormones​". (5) Among many other things they discuss the role that lipopolysaccharides (LPS) have on the endocrine system. LPS is a toxic compound produced by gram-negative bacteria as part of their outer membrane. Elevated levels of LPS in the gut can have a number of negative effects on the endocrine system including thyroid and growth hormone, not to mention it's role in inflammation. 

Children with Down syndrome experience a higher rate of and far too often under-recognized inflammatory bowel disease. The root of these gastrointestinal issues often lies in gut motility issues, untreated hypothyroidism, higher rate of c-section, higher rate of formula feeding and much higher rate of antibiotic use in infancy. The latter three lead to an imbalance in the gut microbiome in ways that extend into adulthood. (6)

While research exists supporting a beneficial role ketosis can have on brain function in some children, particularly those with seizures and autism (10,11) optimizing glucose metabolism would benefit the brain more as glucose is the brain's preferred source of energy. I'll explain more in the glucose metabolism section below. 

Children whose diet is high in sugar and grains, particularly refined grains like white bread, white crackers and white rice can experience decreased growth due to their diet lacking of nutrients and protein. Another means by which such a diet can impact growth is the negative effect it can have on the microbiome of the child which has far reaching effects on the child's overall health as well. A diet that is high in sugar and grains can lead to yeast overgrowth in the gut, especially in a child who has received antibiotics. Children who eat diets that are high in refined grains are typically low in fiber. Soluble fiber is one of the main food sources for healthy bacteria in the gut. Conlon and Bird have written a comprehensive review of the impact that diet can have on the gut microbiome and overall health in 2015. They stated, "Dietary means, particularly the use of a range of fibers, may be the best way of maintaining a healthy gut microbiota population." (12)

A lot happens in our bodies when we sleep. It's during this time that our body cleans up waste, repairs, rebuilds and for children it's when they grow. There's a lot that's involved in supporting healthy sleep architecture. Neurotransmitters in the brain like, GABA and glycine are involved. Certain nutrients like zinc, magnesium, vitamins B1, B12, vitamin D and iron are all involved in optimal sleep. Several studies exist supporting restless sleep in children being associated with low iron levels, for example.(13,14) Ideally ferritin should be at or above 50 ng/ml to prevent restless sleep. 

The way we breathe at night can have a big impact on the quality of our sleep. Mouth breathing at night can contribute to and even cause ADD/ADHD.(15) Mouth breathing actually changes facial structure in children as well which makes it even harder to nose breathe later in life. (16) Ensuring nasal passages are clear before going to bed either by blowing the nose, gently cleaning the nostrils with a moist q-tip, using saline nasal irrigation or spray can help increase the ability to nasal breathe. Enlarged adenoids can make nasal breathing difficult. Consult your child's doctor if you suspect enlarged adenoids which can lead to chronic ear infections, sinus infections and mouth breathing during the day.

Researchers in Sweden studied hormone levels in 37 snoring men and found that IGF-1 (a marker for growth hormone) increased after one month of using a nostril dilator to prevent snoring. About half of the men reported being less tired in the morning as well.(17) This study highlights the direct connection that breathing pattern and quality of sleep can have on growth.

Symptoms of poor sleep quality or not enough sleep in children are irritability, ADD/ADHD, behavioral issues, low energy, excessive yawning, falling asleep easily in the car and poor growth. Symptoms of sleep apnea include the same symptoms but might also include gasping and snoring at night that you would only hear if sleeping near your child. Sleep apnea can be silent in many children as well. If you're suspicious that your child may have sleep apnea it's best to speak with your doctor about getting a sleep study done. However, I have mixed feelings about sleep studies. On one hand, it's important to know whether a child is experiencing sleep apnea or not and on the other hand will it change any of the treatment that is already being taken to address underlying cause of suspected sleep apnea? 

Thyroid hormone has many functions in the body. It works by interacting with our DNA. It's considered to be a transcription factor, which means it functions by attaching itself to certain genes in every cell of our body resulting in those genes either being turned on or turned off. Thus, it's a major controller of cellular function. Every cell of our body relies on optimal levels of active (T3) thyroid hormone being present at the cellular level. T3 hormone helps to regulate body temperature, cellular energy production, brain function, gut function, immune function and so much more. In children it takes on an additional role. T3 hormone is the main driver of growth and development in children. An example of the impact T3 has on development is seen in the metamorphosis a tadpole experiences when developing into a froglet and then on to an adult as seen in image 3. 

T3 hormone is the main trigger for the dramatic changes seen in this metamorphosis. (19) Thyroid hormone works much the same way in humans as described by Bucholz in 2015.(20) The many changes that occur in the body of an infant and toddler including fontanelle closure, tooth eruptions, bone growth and facial development are all driven by thyroid hormone.  

The cascade of events that occurs in order to get optimal levels of active T3 hormone within the cells of the body is complex. I review it briefly in my blog post "Pediatric Thyroid Reference Ranges". Many parents may believe that their child's thyroid hormone levels are normal or managed when in fact they are not optimal because the physician has not done complete thyroid labs which include TSH, free T4, free T3, reverse T3, TgAb and TPO. Management of hypothyroidism is complex and outside the scope of this blog post. For some patients thyroid hormone replacement therapy using natural desiccated thyroid hormone is warranted. We strive to treat the root cause of hypothyroidism in all of our patients if they are receiving hormone replacement therapy or not, because no one experiences just hypothyroidism. There is always an underlying cause that should not be missed.

Growth Hormone (GH) is a protein hormone, secreted by the anterior pituitary gland. GH secretion is pulsatile, secretory bursts occur especially at early hours of sleep and throughout the night. GH has no specific target organ. It effects all organ systems of the body. It's secretion from the pituitary gland is stimulated by GHRH (growth hormone releasing hormone) that comes from the hypothalamus. Researchers at SUNY-Health Science Center in Brooklyn found normal pituitary function but hypothalamic dysfunction in a group of children with Down syndrome.(21)

​Some children do experience remarkable strides in growth, strength and even cognition after receiving growth hormone injections. After all, growth hormone has been shown to improve cognition as well as fine and gross motor skills in children who are growth hormone deficient. (22) Researchers in Sweden studied the effect of GH on adolescents with Down syndrome (Ds) in 2010 and saw that those who received GH performed better on the motor tests than the children with Ds who did not receive GH.(23) In 1999 another team of researchers in Sweden had studied the effect of GH on a group of children with Ds and found it resulted in normal growth velocity but had no effect on mental or gross motor development.(24) The research on the benefits of growth hormone use in children with Down syndrome is mixed. Perhaps because the other factors that are impacting growth occur to various degrees in each child with Ds and more than growth hormone alone is needed.

Several compounds have been studied for their effect on growth hormone secretion. These include glycine, taurine, glutamine, ornithine, vitamin B12, niacin and arginine. Arginine is actually one of the agents used in the growth hormone stimulation test due to it's well-known effect on increasing growth hormone secretion from the pituitary gland. Researchers in The Netherlands used a combination of glycine, glutamine and niacin in middle-aged and elderly subjects and found that it did increase GH secretion, but not IGF-1 levels. However, some subjects did experience increased IGF-1 levels and those subjects also experienced increased memory and vigour.(25) In 2014 a large group of international researchers came together to show the importance of taurine, whose synthesis is dependent on vitamin B12, in growth hormone regulation. They were able to show that taurine increased GH-dependent IGF1 synthesis in the liver. (26)

I want it noted that I'm not opposed to the use of growth hormone in children with Down syndrome when warranted. I simply want to ensure that all processes that impact growth are being explored and nothing gets missed in my patients.

This topic is the most exciting to me as it relates directly to brain function as well as growth. If glucose metabolism is impaired, meaning our brain and body can't get energy from glucose, then cognition is sure to be impacted. Our brain is our most metabolically active organ and therefore the highest consumer of glucose in the body. It's been estimated to use as much as 60% of our daily glucose intake.(27)

Growth hormone is well-known for it's positive impact on glucose metabolism. (28) It's role in glucose regulation is to raise blood sugar levels in times of hypoglycemia (low blood sugar). It does this by triggering gluconeogenesis in the liver. This is a normal process the body undergoes in the presence of hypoglycemia. Hyperglycemia (elevated blood sugar), therefore has the opposite effect. A negative feedback loop exists between blood sugar levels and the pituitary gland. The body adjusts growth hormone secretion based on it's need to tightly control blood sugar levels. Therefore, hyperglycemia leads to a decrease in growth hormone secretion. Other hormones involved in blood sugar control are glucagon, catecholamines and cortisol. 

Hyperglycemia occurs in those with insulin resistance. Insulin is a hormone secreted by the pancreas that is necessary for moving glucose into the cell. Insulin resistance occurs when insulin receptors on the surface of the cell no longer work resulting in low levels of glucose within the cell and high levels of glucose remaining in the blood. Chromium has been shown to alleviate insulin resistance.(29) Insulin resistance has been linked to low intracellular magnesium levels in patients with Type II Diabetes.(30) As well, supplementing with magnesium has been shown to increase insulin sensitivity in non-diabetic patients.(31) Maintaining a diet that is low in sugar and processed grains will help to prevent insulin resistance and hyperglycemia.

Thiamine and riboflavin deficiency can also lead to hyperglycemia.(32,33,34) These two B vitamins, along with alpha-lipoic acid are co-factors, meaning they are absolutely necessary, for the function of the enzyme pyruvate dehydrogenase. This enzyme shuttles the breakdown product of glucose (pyruvate) into the mitochondria where it can be used for energy. If this enzyme doesn't work the whole mechanism backs up and glucose levels increase in the blood. In my practice I pick up deficiencies of these two B vitamins often in my patients with Down syndrome. Deficiencies in these vitamins, sometimes severe, can be seen using an organic acid test. Not all patients with Down syndrome experience these deficiencies as they are more often seen in those who have malabsorption secondary to gut issues.

There are few areas of the body not effected by the nervous system.  When an organ, tissue or cell isn't optimally connected to the nervous system it can't work properly. Signals from the nervous system send directions from the brain and spinal cord to tissues and organs of the body telling it how to respond to internal or external stimuli.  

Bones are no exception when it comes to communicating with the nervous system.  The skeletal system is very dynamic, especially in children.  It's constantly receiving signals from the rest of the body to breakdown bone and build new bone in a process called remodeling and modeling. You can view the video below to learn more about this process.

The nervous system is divided into two parts, the central nervous system (brain and spinal cord) and the peripheral nervous system (all nerves outside of the central nervous system).  Peripheral nerves make direct contact with bone via the periosteum (outer covering of bone), however no direct contact between nerves and osteocytes (cells within bone) have been found yet.(35) The nervous system communicates with bones via neuropeptides, which are chemical messengers released from nerves in the area of osteocytes.

​A complete understanding of how the nervous system controls bone growth has yet to be developed by the scientific and medical community. However, some research does exist. Orthopedic physicians from Greece have written a review article outlining the role the peripheral nervous system plays in bone growth in children. In it they state, "Bone growth...has a very complicated regulation... Starting from the genetic factors, growth factor, insulin-like growth factor 1 (IGF-1), triiodothyronine, thyroxine, androgens, Indian hedgehog, fibroblast growth factors, bone morphogenetic proteins (BMPs), vascular endothelial growth factors (VEGF) are some of them which affect positively the bone growth." (36) They go on to discuss several other factors that implicate the nervous system in bone growth. One of these factors is CGRP (calcitonin-gene regulated peptide), one of several neuropeptides that was discovered only 30 years ago. It works to increase osteoblast activity. These are the cells of the bone that increase bone mineralization. CGRP is primarily released from sensory nerves and is a strong vasodilator.(37) CGRP also inhibits osteoclast (bone dissolving cells) activity. 

Interestingly, CGRP levels were found to be low on blood spot tests of newborn infants with Down syndrome.(38) However, delayed bone growth and development in children with Down syndrome is clinically often recognized as simply due to them having Down syndrome. It's likely that supporting nervous system function in infants and children with Down syndrome can ultimately improve growth as well.

Signs and symptoms of peripheral neuropathy include:

• Muscle weakness
• Cramps
• Muscle twitching
• Loss of muscle and bone
• Changes in skin, hair, or nails
• Numbness
• Loss of sensation or feeling in body parts
• Loss of balance or other functions as a side effect of the loss of feeling in the legs, arms, or other body parts
• Emotional disturbances
• Sleep disruptions​

A team of physicians from Loma Linda University reviewed the effects that a traumatic brain injury can have on bone metabolism. They report an increased risk of fracture and osteoporosis secondary to traumatic brain injury, indicating a connection between brain signals and bone health. The hypothalamic-pituitary-adrenal axis, which is reliant on a healthy pituitary gland within the brain has a significant impact on bone growth as well.  Image 7 reveals the many hormones involved in bone formation that originate from the pituitary gland.

When discussing bone growth it's important to consider all bones, not just long bones involved in linear growth. The growth and development of craniofacial bones are also dependent on signals from the nervous system. Adamyeyko and Fried review the close involvement of the nervous system in embryological craniofacial development in "The Nervous System Orchestrates and Integrates Craniofacial Development: A Review". In it they state, "Recently, a growing amount of data has provided a deeper insight into how various cellular sources are coordinated and integrated during craniofacial development. The cranial nervous system, including the developing anterior neuroectoderm, brain, neurogenic placodes and peripheral nerves has appeared as an essential element in a number of regulatory interactions that result in a fully functional complex craniofacial organ." Most important of these nerves involved in facial development is the trigeminal nerve (image 8). One can easily see from this image how this nerve innervates the nasal, maxillary and mandible bones. 

Healthy nerves are heavily dependent on adequate amounts of B vitamins. For example, a B1 (thiamine) deficiency can impair the recurrent laryngeal nerve, resulting in hoarseness. It can also impair cranial nerves manifesting as tongue and facial weakness as well as oculomotor muscle weakness and nystagmus. (40) Impairment of the nerves that innervate these areas can impact facial bone growth as well.

No physician should dismiss growth delay in any child. It can be a sign of significant problems that could only get worse if left unaddressed. Delayed growth in a child can indicate significant underlying pathology that when missed can impact other areas of health and development. My own son had failure to thrive as an infant and was NG tube fed for his first month of life. He also had poor growth, hypothyroidism, low muscle tone, severe constipation (going as long as ten days with no bowel movement at one point), circulation issues indicative of nutrient deficiencies, etc. He is now ten years old and in the 97th percentile on the typical growth chart. He is in a public school classroom and keeping up academically with his 4th grade peers. Sleep is sacred in our house, as is a healthy diet. We've done a lot of work to help heal our son and it literally shows. Poor growth does not have to be part of the phenotype of Down syndrome. Optimizing growth in these children is possible when all of these seven factors are addressed. 

This question comes up a lot online: "What are the optimal reference ranges for thyroid hormone labs in children?" I hope this post serves to help parents and physicians understand optimal reference ranges for children versus reference ranges reported on actual lab results. This is an important topic as thyroid hormone is crucial for brain and global development of infants and children.

Unfortunately, there are no national or international standards for reference ranges that labs use. This has resulted in sometimes huge variations in reference ranges used by different labs.  Ultimately, a well-studied physician should have their own reference ranges that they use when evaluating labs.

The six most important labs to obtain when assessing thyroid function, regardless of the age of the patient, are:

1. TSH
2. free T4
3. free T3
4. reverse T3
5. TPO
6. TgAb

There are others but these are values that assess direct thyroid hormone status. The other labs that are pertinent to thyroid hormone function are CBC, ferritin, zinc, copper and vitamin D. I'll start by reviewing in very simple terms the thyroid hormone cascade.

The most important message to take away from this is that the thyroid hormone process within the body is complicated and involves many steps that include proper pituitary function, thyroid gland function, deiodinase enzyme function, cell receptors and thyroid hormone receptors within each cell of the body.  A problem in any of these steps can result in hypothyroidism.

​Given the negative feedback loop that occurs between TSH and T4, endocrinologists have been using TSH levels only to assess the health of the very complicated thyroid hormone process for their patients. This has resulted in many patients who still experience symptoms of hypothyroidism but are told by their doctor that they don't have hypothyroidism. The result of this for an adult is often continued fatigue, depression, weight gain, dry skin and many other symptoms. Given the critical role thyroid hormone plays in childhood development at key stages that can't be revisited, this same incomplete assessment can result in irreversible lack of optimal brain development. For a thorough review of the important role thyroid hormone plays in brain development please read "Thyroid Hormones in Brain Development and Function" by Juan Bernal, M.D. Ph.D.

As it turns out several studies do exist supporting that the current practice of using TSH only to assess thyroid hormone function is missing a lot of patients with hypothyroidism, including children. One such study was conducted in 2005 by researchers at Athens University School of Medicine (Koutras, 2005). They tested TSH, T4 and T3 levels in 85 patients with hypothyrodism who were taking T4-only medication. They found that these patients had lower T3 levels compared to normal, non-hypothyroid subjects. They concluded that hypothyroid patients may benefit from co-administration of T3 and T4 medication. They also concluded, "TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. " In 2015 a team of physicians collaborated to write "Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment".  They suggest that the use of TSH be "scaled back" and highlight the importance of T3 hormone levels.

​The most important work being done to support the need to use more in-depth labs and assessment when testing patients for hypothyroidism is Dr. Antonio Bianco. The website for his lab is Deiodinase.org.  His lab is doing extensive and valuable work investigating the important role that local cellular control of thyroid hormone plays in the thyroid status of patients. This website contains a wealth of knowledge regarding deiodinase enzymes and I highly recommend Endocrinologists start studying his work.

Although the role TSH levels play in thyroid hormone assessment should be downplayed, an optimal reference range should still be discussed. Many functional medical doctors agree that an optimal reference range for a test result is quite different than reference ranges that have been established by labs.  These reference ranges may be capturing lab values for patients with undiagnosed pathology. The optimal reference range for TSH is generally accepted to be 1.0-2.5 mIU/L.  In 2015 the American Association of Clinical Chemistry published "Thyroid-Stimulating Hormone" in which they state:

As well, researchers in the UK refer to a normal TSH as <2 mIU/L in "Pitfalls in the measurement and interpretation of thyroid function test".

The optimal reference range for TSH in newborns, infants and children varies from those of adults. In addition, there are definite differences in optimal free T4 and free T3 levels in children. The most comprehensive anaylsis of thyroid hormone tests of pediatric patients was done in 2008 (Kapelari, 2008). Researchers analyzed medical records of 414 patients.  Patients were grouped into age ranges of 1 day to 1 month, 1 – 12 months, and 1 – 5, 6 – 10, 11 – 14, and 15 – 18 years, respectively. They state in their conclusion, "Our results corroborate those of previous studies showing that thyroid hormone levels change markedly during childhood, and that adult reference intervals are not universally applicable to children." The images below are graphs from this study displaying their findings. The darkest black line in the graphs represents the 50th percentile (median) lab result.

The conversion of pmol/L to pg/mL, the unit of measurement most often used in the US for free T3, uses the conversion factor of 1.536. The pmol/L number is divided by 1.536 to get pg/mL.  The conversion of pmol/L to ng/dL, the unit of measurement most often used in the US for free T4, uses the conversion factor of 12.9. The pmol/L number is divided by 12.9 to get ng/dL.

The results from Kapelari's study are converted to US units of measurement and summarized in Table 1.

A reference range for reverse T3 in infants and children has not yet been established nor has it adequately been studied. However, some studies do exist. Researchers at UCLA studied levels of T4, T3 and reverse T3 in neonates from 1-30 days old. They found that "high serum rT3 concentration in the newborn becomes comparable to that in the normal adult by 9-11 days of neonatal life." (Chopra, 1975) The same dramatic decrease in reverse T3 in newborns was reported by Dr. Brown and Feingold in 2010 as seen in Image 7. (Brown, 2010) A striking increase in T3 levels after birth was noted by both studies as well. Reference range for reverse T3 in adults has been established to be 10-24 ng/dL. (Endocrine Society Laboratory Reference Ranges) Unfortunately, until further studies are conducted the only information available today regarding reverse T3 in infants is to use that of adults.  

It's of utmost importance to assess signs and symptoms of hypothyroidism in infants and children in addition to lab results when determining their thyroid hormone status and whether thyroid hormone supplementation is warranted or not.  Those signs and symptoms include:

• Dull look
• Puffy face
• Thick, protruding tongue
• Choking episodes
• Constipation
• Dry, brittle hair
• Jaundice
• Low muscle tone (floppy infant)
• Low hairline
• Poor feeding
• Short height
• Sleepiness
• Sluggishness
• Slow growth
• Hoarse-sounding cry or voice
• Short arms and legs
• Very large soft spots on the skull (fontanelles)
• Wide hands with short fingers

Thyroid antibodies should always be checked when assessing thyroid status given the high prevalence of autoimmune induced hypothyroidism. Naturally, these antibodies ideally should be as low as possible. Once again reference ranges vary widely from lab to lab.  The Endocrine Society has determined the reference range for thyroid antibodies to be:

• TPO (Thyroperoxidase) - < 2.0 IU/mL
• TgAb (Thyroglobulin antibodies) - < 4.0 IU/mL

Functional medical physicians are also taught that TPO up to 15 IU/mL is normal. Reversing autoimmune hypothyroidism and lowering these antibodies is possible. The treatment for doing so is outside the scope of this article. I highly recommend working with a physician who is trained in treating the root cause of autoimmunity if you or a loved one has elevated thyroid antibodies.

In short, hypothyroidism should not be missed in any infant or child given the important role thyroid hormone plays in the health and development of children. Signs and symptoms should never be ignored and a complete and thorough check of all thyroid hormone levels should be conducted.

**Please do not write comments that include your child's specific lab values asking for medical advise. We will not be able to give medical advise based on lab values alone and cannot give medical advise in this format. These comments will not be approved for posting. Feel free to contact the office to make an appointment if you would like our help.

Here are some tips to safely manage a fever:

1. Hydrate - encourage drinking of homemade electrolyte replacement drink that can be made into popsicles as well. 
2. Enhance a fever if needed with chamomile, ginger and yarrow tea.
3. Monitor the temperature frequently, especially in a child.  The most accurate way to obtain the temperature in a young child is rectally, but other means can be used as well.
4. Rest - No matter how busy you are you must conserve energy and stay in bed. To keep young children still try putting on their favorite video (an exception to limiting screen time for children).  Often the aches and malaise that come with the fever don't allow for much activity.
5. Observe for signs of dehydration. Babies should urinate at least once every 6 hours, children and adults should urinate at least once every 8-12 hours. Sunken eyes, dry mouth, dark urine, little to no tears when crying, lethargy, dizziness and even confusion are all signs of dehydration.

If your child experiences a febrile seizure:

• Seek medical help immediately, not tomorrow morning. Call 911.
• While waiting for emergency help, keep your child upright and make sure their airway stays open and they are able to breathe.  Watch for changes in your child's breathing and/or color.
• Stay with your child and speak reassuringly.
• Clear the area around your child to prevent injury. Do not try to hold your child down. Restraining a thrashing child can cause additional injury. Try placing a soft pillow or blanket under your child's head. Loosen clothing to prevent injury and ease discomfort. 
• Do not try to force anything into your child's mouth. You might cause choking, or suffer a bite yourself.
• If vomiting occurs, turn your child's head to the side so that there is no risk of your child choking on inhaled vomit. If possible, keep your child's whole body turned on the side as well.

​
To cool a really high fever naturally and help a child or adult with a fever try a wet sheet wrap.  For a small child a pillow case can be used.  Get the sheet or pillow case soaking wet with cold water.  Be sure to wring it out well so that it isn't dripping wet.  Wrap the child very quickly in the sheet or pillow case and cover the wet sheet with a warm blanket, preferably wool.  It's most important to wrap the torso, so their arms can be free if they aren't comfortable being wrapped tightly.  They may object at first to the cold wet sheet, but will soon be comforted by the cooling sensation.  They will most likely fall asleep shortly after being wrapped up.  Let them sleep as long as they can in the wrap; two hours or more is best.  If they will tolerate it all night long that is ideal.  For an adult lay the dry blanket on the bed and place the wet sheet on top of that.  Lay down on the wet sheet and wrap yourself up snugly or have someone help you.  Again, sleep in this for as long as you can tolerate it, preferably overnight.  The sheet will be dry in the morning.  This technique can be used to help "break" a fever. ​​