PANS/PANDAS in Down Syndrome

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. ​

Image 1. Antibody reaction to invading bacteria or virus

(Image source: https://www.aboutkidshealth.ca/Article?contentid=927&language=English)

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.

Image 2. Immune cells attacking due to presence of antibodies on the surface of cells, aka autoimmunity.

(Image source: https://www.aboutkidshealth.ca/Article?contentid=927&language=English)

The current theory behind PANDAS is that antibodies to strep are cross-reactive to certain areas of the brain involved in mood, behavior and motor coordination. The basal ganglia is one area that is currently being studied. The antibodies are able to enter the brain due to increased permeability of the blood brain barrier (BBB), which is the collective junctions between blood vessels of the brain and protective cells of the brain called astrocytes. (Platt 2017)

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.

• Gut health
• Removal of initial antigen/infection causing immune reaction
• Removal of co-infections
• Removal of antigenic foods
• Methylation
• Sulfation
• Nutrient deficiencies
• Reduce inflammation
• Heavy metals

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.

Her follow up stool test revealed the absence of parasites (although this doesn't mean they're totally gone), normal secretory IgA levels and the absence of Klebsiella. The day finally came for her follow up appointment six months after making the above recommendations to treat her gastrointestinal infections in September of 2018 (one month ago from the day of writing this blog post). I am overjoyed to announce that all of her symptoms of PANDAS had resolved. I couldn't type fast enough to keep up with all of the improvements the mother had written down and was reading to me. Here is an exact copy from my chart notes:

Followed parasite protocol - no die off
Started protocol in May saw improvements in 3 weeks
Able to get hair cut and brushed with no fussing
Able to brush teeth
Can have toenails and fingernails clipped
Starting to draw again - big circles
Used to only sit on bottom to go down stairs - now walks down the stairs
Closes car door without reminding
Wants to take care of self more
More curious about what's in the kitchen
Still resistant but a lot less aggressive
Understands a lot more

I consider this a huge success and her PANDAS to be in remission.  The mother wasn't able to get a lab order from Sally's doctor for the repeat ASO, but we're hoping to get that soon.  I will edit this blog post to include the actual results of her antibody levels when they come in whether they are reduced or not.  

I recommended that the mother do additional herbal treatments to ensure that any residual parasites or infection were gone. Given that Sally has a G-tube the mother is able to easily use any antimicrobial substances despite many of them being very unpalatable when taken orally. I recommended she use oregano oil (not essential oil of oregano) for a couple of months, continue probiotics and eventually add in black cumin seed oil. Black cumin seed oil, aka Nigella sativa, has many health benefits as reported by researchers in India, Oman and Saudi Arabia. "Extensive studies on N. sativa have been carried out by various researchers and a wide spectrum of its pharmacological actions have been explored which may include antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial, anti-inflammatory, spasmolytic, bronchodilator, hepato-protective, renal protective, gastro-protective, antioxidant properties, etc." (Ahmad 2013). In addition, researchers in Poland found Nigella sativa as well as oregano to be effective against Blastocystis hominis. They stated, "aqueous extract of Nigella sativa significantly inhibits the growth of Blastocystis isolates...Similarly, supplementation with 600 mg emulsified oil of Mediterranean oregano (Origanum vulgare) daily lead to the complete disappearance of Blastocystis." (Lepczyńska 2017).

We're doing a lot more than I've written here including gallbladder and bile support (due to elevated fecal fats), immune support, diet changes, etc.  What I've written here is the main aspect of her plan that most helped her. We are far from done with her healing journey but she's out of the woods from her experience with PANDAS.  The next steps are to help optimize her health to prevent this from happening again.

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:

"Infectious agents, including bacteria, viruses, fungi, and parasites, are also known to trigger autoimmune disorders through several mechanisms: molecular mimicry, epitope spreading, standard activation, viral persistence, polyclonal activation, dysregulation of immune homeostasis, and autoinflammatory activation of innate immunity. It is important to note that an infection may not necessarily be the inducer but rather the total burden of infections from childhood on that trigger autoimmunity. Moreover, an infection can amplify an autoimmune disease by either exacerbating an ongoing disorder, including a relapse, or by leading to chronic progressive disease."

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.