For many years, researchers have studied the role of autoimmunity in Parkinson’s disease (PD) and there is ample evidence that what we know to be drivers of autoimmune disease may very well play a role in this neuromuscular condition. As we have often discussed, there are certain predicating factors including environmental concerns and exposures to toxic elements that can contribute to the dysfunction of our immune system. So, could a neurological disorder like PD be influenced by these same factors? 
 
Let’s look at the research…
 
Scientists have focused on autoimmunity and found it is actively involved in the pathogenesis of PD through several proteins, including alpha-synuclein (α-Syn), DJ-1, PINK1, and Parkin, as well as immune cells, such as dendritic cells, microglia, T cells, and B cells.1  
 
We know that clumps of the damaged α-Syn protein can build up in the dopamine-producing brain cells of patients with Parkinson's disease. As a neurotransmitter, dopamine is especially susceptible to the effects of these clumps that may eventually lead to cell death, presentation of impaired motor processes and cognitive decline.
 
A small synaptic protein and the primary component of Lewy bodies, α-Syn can, if incorrectly modified or misfolded, form soluble or insoluble aggregates and act as the neuropathological hallmark in the brain of patients with either sporadic or familial PD. Equally significant is to note is that the formation and aggregation of misfolded proteins in the central nervous system (CNS) is a key hallmark of not only Parkinson’s disease (PD), but also Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS).2

α-Syn plays a leading role in the initiation and progression of Parkinson-like neurodegeneration because it can induce high neurotoxicity by diverse pathways, such as inflammation, oxidative stress and autophagy abnormalities. Particularly important, studies have provided extensive evidence that indicates “abnormal α-Syn can spread to neighboring brain regions and cause aggregation of endogenous α-syn in these regions as seeds, in a “prion-like” manner.”3  
 
These findings may well point to an underlying autoimmune response that develops before the formation of these prions, further fueling the fire of chronic neuroinflammation.4 As for more evidence? In another recent publication, we learn that it is dysregulation of the immune system in conjunction with genetic mutations and environmental factors are contributing pathogenic factors in the initiation of PD. And we know that high levels of chronic neuroinflammation lead to neurodegeneration. This study demonstrates that subsets and cytokine expression profiles of peripheral adaptive immune cells in patients with early-stage PD show distinct differences compared with HCs matched for age and sex. These peripheral abnormalities may drive PD disease initiation and progression through enhanced infiltration of immune cells and enhanced neuroinflammation in the CNS.5
 
There are many, many factors involved in what we believe may drive autoimmune disease and that should be spotlighted in order to best address overall toxic load and environmental health. As we’ve previously written, it may be that other diseases, such as Alzheimer’s, also prove to have autoimmune origins. So it’s truly in our best interests that we continue to study the autoimmunity aspects of neurological disease in order to identify our risks and develop more efficacious treatments. With new findings comes more hope that doctors will one day have the means to make earlier diagnoses of Parkinson’s disease that subsequently leads to earlier intervention.
 
In health and hope,
Dr. Suzanne Gazda
 
References:
 
1 Jiang T, Li G, Xu J, Gao S, Chen X. The Challenge of the Pathogenesis of Parkinson's Disease: Is Autoimmunity the Culprit? [published correction appears in Front Immunol. 2019 Oct 16;10:2242]. Front Immunol. 2018;9:2047. Published 2018 Sep 27. doi:10.3389/fimmu.2018.02047
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170625/
 
2 Cecilia S. Lindestam Arlehamn, Rekha Dhanwani, John Pham, Rebecca Kuan, April Frazier, Juliana Rezende Dutra, Elizabeth Phillips, Simon Mallal, Mario Roederer, Karen S. Marder, Amy W. Amara, David G. Standaert, Jennifer G. Goldman, Irene Litvan, Bjoern Peters, David Sulzer, Alessandro Sette. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-15626-w
 
3 Kumar, S., Thangakani, A., Nagarajan, R. et al. Autoimmune Responses to Soluble Aggregates of Amyloidogenic Proteins Involved in Neurodegenerative Diseases: Overlapping Aggregation Prone and Autoimmunogenic regions. Sci Rep 6, 22258 (2016). https://doi.org/10.1038/srep22258
 
4 Ma J, Gao J, Wang J and Xie A (2019) Prion-Like Mechanisms in Parkinson’s Disease. Front. Neurosci. 13:552. doi: 10.3389/fnins.2019.00552
 
5 Zhaoqi Yan, Wei Yang, Hairong Wei, Marissa N. Dean, David G. Standaert, Gary R. Cutter, Etty N. Benveniste, Hongwei Qin. Dysregulation of the Adaptive Immune System in Patients With Early-Stage Parkinson Disease. Neurol Neuroimmunol Neuroinflamm Jul 2021 8 (5) e1036; DOI: 10.1212/NXI.0000000000001036

Research is revealing that a number of pediatric patients with autism reflect low folate in their brains and that this “cerebral folate deficiency (CFD) may be treatable with certain medications, specifically d,l-leucovorin calcium (also known as folinic acid). ​

Leucovorin is a long-used compound similar to folic acid, which is a necessary vitamin. It also is frequently prescribed in combination with the chemotherapy drugs fluoruracil and methotrexate.

CFD is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood-brain barrier. In some studies when CFD is present, autism spectrum disorder and related symptoms have shown improvements with administration of folinic acid. 
 
Folate and its importance to the brain.
 
Folate is a water-soluble B vitamin that is essential for normal neurodevelopment; folic acid is the synthetic derivation of this vitamin B9. Abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid.1 
 
ASD also has been linked to abnormalities in folate metabolism. Polymorphisms in folate genes may act in complex polygenic ways to increase the risk of developing ASD. Autoantibodies that block folate transport into the brain have been associated with ASD and children with ASD and these autoantibodies respond to high doses of a reduced form of folate known as folinic acid (leucovorin calcium). Some of the same abnormalities are also found in mothers of children with ASD and supplementing folate during preconception and gestational periods reduces the risk to the offspring from developing ASD. These data suggest that folate pathway abnormalities may be a major metabolic disturbance underlying ASD that can be leveraged as biomarkers to improve symptoms and prevent ASD.
 
Treatment and recommendations.
 
In a study, d,l-leucovorin calcium or folinic acid was used  for the treatment of folate pathway abnormalities in children with ASD. Children with FRAs were treated with oral leucovorin calcium in two divided doses (2 mg kg−1 per day; maximum 50 mg per day). Researchers noted that “compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low.”2
 
Study author and renowned autism researcher Dr. Richard Frye, pediatric neurologist and Chief of The Division of Neurodevelopmental Disorders at Phoenix Children's Hospital, noted that mitochondrial support is needed in addressing neurodevelopmental problems. Additionally, he has found that folate positively influenced several aspects of mitochondrial function, including increasing Complex I activity and strengthening the coupling between Complex I and Citrate Synthase. 
 
His recommendations for leucovorin include preparations that ideally are compounded in order for the least amount of additives that can potentially cause sensitivity issues in many children with ASD. 
 
ASD is a heterogeneous neurodevelopmental disorder defined by impairments in social-communication as well as the presence of restricted interests and repetitive behaviors with the prevalence estimated to be about 1 in 54 children in the United States. If we maintain the current trajectory it is estimated that by 2030 one in two children could be born on the spectrum. With these kinds of concerning figures, it is imperative that we identify opportunities not only for treatment, but also to potentially inhibit the development and/or progression of these related disorders. Given that we know folate deficiency to be implicated in other neurological conditions such as cognitive decline and dementia, treatment with appropriate forms of folinic acid could very well be an effective ongoing option that certainly bears further research and review.
 
Click here to view a conversation with Dr. Frye about compounded leucovorin. 
 
In hope and healing,
Dr. Suzanne Gazda
 
References:
 
1 Frye, R., Slattery, J.C., Quadros, E.V. Folate metabolism abnormalities in autism: potential biomarkers. Future Medicine. (2017) https://doi.org/10.2217/bmm-2017-0109
 
2 Frye, R. E., Sequeira, J. M., Quadros, E. V., James, S. J., & Rossignol, D. A. (2013). Cerebral folate receptor autoantibodies in autism spectrum disorder. Molecular psychiatry, 18(3), 369–381. https://doi.org/10.1038/mp.2011.175

We recently read a brilliant article that sheds more light on the dysregulated immune system that occurs in numerous autoimmune-driven neurological illnesses including:
~ Pediatric acute-onset neuropsychiatric syndrome (PANS)
~ Pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS)
~ Basal ganglia encephalitis (BGE)
~ Autoimmune encephalitis (AE)
~ Movement disorders
~ Other autoimmune driven neurological diseases like multiple sclerosis (MS, neuromyelitis optica spectrum disorder (NMOSD) and a subset of neuropsychiatric conditions from obsessive compulsive disorder to ADHD, depression, anxiety and more.
 
The research and immune responses.
 
In this exceptionally well designed study published in Clinical and Translational Immunology, scientists explored the dysregulated inflammatory response against dopamine-2 receptors (D2R), which are implicated in these movement and neuropsychiatric disorders. Basically, dopamine receptors are involved in many neurological processes; subsequently, ABNORMAL dopamine receptor signaling and dopaminergic nerve function that is triggered by infectious agents are often associated with a number of neuropsychiatric disorders in children and adults.
 
It’s a complicated interaction that starts with the D2R, which is abundantly expressed in the basal ganglia, limbic system and cerebral cortex that are responsible for movement, motivation, learning, emotions and memory. D2Rs are also present on immune cells and work to help modulate the immune system in the peripheral nervous system. Dopaminergic signaling can modulate immunological processes, such as T- and B-cell interactions in antibody production, activation of naïve T-cells, inhibition of stimulated T-cells, suppression of regulatory T-cells, cytokine secretion, as well as cellular trafficking and chemotactic migration or chemotaxis of T cells. Chemotaxis refers to the migration of cells toward attractant chemicals or away from repellents; virtually, every motile organism exhibits some type of chemotaxis.1 Cytokines are the “chemical messengers” responsible for most of the biological effects in the immune system and T lymphocytes are a major source of cytokines. 
 
So, in patients with a dysregulated immune response directed to the DR2R, “the perfect storm” develops that cascades down the road of not only neurological or neuropsychiatric symptoms, but also propagation of neuropathology leading to irreversible and progressive symptomatology.
 
We have in the past discussed DR2-directed autoantibodies and how this blocking mechanism on the receptor can cause a cascade of symptoms as well, but in this study the focus was not on antibodies (there were none), but rather on the autoreactive T-cell response against D2R. These T-cells are associated with a Th1 and Th17 phenotype, suggesting a T-cell-driven immune response. Th1 cells stimulate cellular immune response, participate in the inhibition of macrophage activation and stimulate B cells to produce IgM, IgG1. Th2 cells stimulate humoral immune response, promote B cell proliferation and induce antibody production.  
 
What this study clearly showed was that even in the absence of DR2 receptor antibodies, it is the pathologic immune dysregulation that is driving symptoms and brain pathology. These activated D2R-specific T cells are being fueled by reactions with their antigenic counterpart along with an inflammatory cascade of cytokines and activation of complement systems which are play a major role in the innate immune system. The innate immune responses are the first line of defense against invading pathogens.

Molecular mimicry fueling the fire (again!). 
 
Many believe that these mechanisms are infectious-driven through the process of molecular mimicry whereby cross-reactivity between microbial structures and host proteins results in an immune response misdirected to the host.
 
This could very well be the reason why in PANS and PANDAS (and even in some cases of MS) we may see disease exacerbation when there is an underlying infectious trigger. And this also could explain the negative Cunningham panels we see in some of our PANS and PANDAS patients as it also clarifies more about the other mechanisms driving these “brains on fire.”
 
Summing up the significance of these findings…
 
The results present several key items:
~ Study authors noted the presence of peripheral autoreactive T cells against D2R that were not associated with autoantibodies in patients with neurologic and psychiatric symptoms. 
~ This sheds more light on disease mechanisms and neural signaling issues that better explains the mechanisms of disease.
~ Findings continue to support the enormity of early identification and diagnosis as well as appropriate treatment and intervention – truly, we cannot emphasize this enough!
~ Early treatment utilizing IVIg in some cases of PANS and PANDAS may aid in the “immune response reset” that could dampen or even stop the progression of “brain on fire.” 
 
Bottom line... it is not always streptococcus bacteria at work and ALL potential infectious and non-infectious triggers must be explored. The stark reality is that in many instances by the time patients come to us, the infectious trigger is long gone and it is the immune dysregulation that must be stabilized and improved. And we already know that epitope (the part of an antigen molecule to which an antibody attaches itself) spreading is known to advance disease in MS and in most autoimmune diseases.2 
 
I believe what is missing in most protocols is a well designed and individualized neuroplasticity protocol. And sadly, we are simply getting many of these cases in an advanced state of disease. So we are especially grateful for research that will lead to more patients receiving accurate timely diagnoses and comprehensive, integrative care that is appropriate to their specific health needs. 
 
Let’s hope that the science continues to progress toward providing the best practices resolutions for the wellbeing of all those who struggle with these highly complex and destructive disorders. So many patients and their families are counting on all of us!
 
In health,
Dr. Suzanne Gazda 

References:
1 J.B. Stock, M.D. Baker. Encyclopedia of Microbiology (Third Edition). 2009
 
2 Shivaprasad H. Venkatesha, Malarvizhi Durai, Kamal D. Moudgil. Chapter 4 - Epitope Spreading in Autoimmune Diseases. Editor(s): Yehuda Shoenfeld, Nancy Agmon-Levin, Noel R. Rose. Infection and Autoimmunity (Second Edition) 2015, Academic Press. Pages 45-68. 
ISBN 9780444632692. https://doi.org/10.1016/B978-0-444-63269-2.00003-9.
 
For additional articles about PANS and PANDAS, please see these selections below or use the “search” bar function on our website to explore the library of materials and information.
 
https://www.suzannegazdamd.com/blog/pans-and-pandas-is-making-the-newsbut-what-do-we-really-know
 
https://www.suzannegazdamd.com/blog/why-is-nutrition-so-important-in-pans-and-pandas

About 25% of patients with autoimmune disease will have more than one autoimmune disorder; patients with rheumatoid arthritis (RA), multiple sclerosis (MS), autoimmune thyroiditis, Sjögren’s syndrome or similar conditions carry a markedly increased risk of having another autoimmune disease.
 
For example, the estimated prevalence of MS in the general population is 0.1% but the prevalence of the disease jumps to 0.5% in patients with inflammatory bowel disorder, suggesting a 1.5 to 5-fold increase in the risk of developing MS in patients with IBD.1 There is also a link between RA and IBD, RA, MS, and Hashimotos, Sjogrens and Type 1 diabetes – really, it’s quite extraordinary when you realize there are so many links between just as many of these serious conditions.
   
These relationships clearly present as a case of a mistaken and activated immune system and, if the immune system already follows the same autoimmune pattern, there is subsequently a higher possibility as well as probability that there will be another target. There have been reports as well of central nervous system (CNS) demyelination that suggests a triggering or exacerbating effect in demyelination diseases such as MS that may very well be induced by treatment with anti-TNF-α.2 TNF-α (tumor necrosis factor alpha) is a well-known pro-inflammatory and immunoregulatory cytokine. Elevated levels of this cytokine are locally and systemically in patients with inflammatory disorders like arthritis. Drugs that block the effect of TNF-α modulate the activity of many autoimmune diseases. Depending on their mechanism of action, anti-TNF-α drugs are divided into monoclonal antibodies (Infliximab, Adalimumab, Golimumab, and Certolizumab) and soluble TNF-α receptors (Etanercept).3
 
I feel as if we go around and around with the concept of an increased risk of shared autoimmune disease in our patient populations. But we must be aware that there is an increased risk of MS developing in those patients who are on TNF-α inhibitors that are sometimes used to treat other autoimmune problems such as RA. Other examples report an increased risk of MS, optic neuritis, Guillain-Barre syndrome, and transverse neuritis developing in patients on TNF alpha inhibitors.4 So I feel that physicians must be cautious when prescribing anti-TNF-α in patients with a family history of MS and also to reconsider the risk of MS in patients being treated for autoimmune diseases. 
 
And still more…
 
One published report additionally linked the use of rituximab for treatment of lymphoma with the initiation of IBD in certain elderly patients. Authors noted that "The association of rituximab and ileocolitis suggests a protective effect of CD20 + lymphocytes in the gut, and implicates their depletion to the development and exacerbation of inflammatory bowel disease." There have also been additional instances of other disease initiation including rituximab-induced psoriasis, finding that "B cell-depleted environment may induce abnormal T cell responses, possibly provoked either by subclinical infection or by the removal of mechanisms whereby B cells regulate T cells."5 We should expect this to be a possible side effect with any of the B cell depleting therapies (Ocrevus and Kimsimpta). So, if your patient is on a B cell blocking drug, this medication will likely need to be stopped or  it may be hard to control the Crohn's or other resulting condition.   
 
No doubt the advancement of biologics therapies has been profoundly helpful in the treatment of various autoimmune diseases. But sometimes our immune modulating therapies can come with unexpected penalties. 
 
Could IVIG be a therapeutic alternative?
 
Many patients with Crohn's disease are on immunosuppressive therapies. However, there have been case reports of progressive multifocal leukoencephalopathy (PML), an infection that damages the material (myelin) that covers and protects nerves in the white matter of the brain, in these patient populations.
 
Therefore, it stands to reason we must consider in some instances alternative treatments for these conditions to potentially decrease the risk of developing additional disorders. Intravenous immunoglobulin (IVIG) has been used for years in Crohn’s and could be a good choice in some patients, especially those who have more than one autoimmune disease, in order to target therapies in the safest way possible. Published findings noted that “A review of the evidence identified indicates that IVIG can induce a rapid and significant improvement in aminosalicylate- and steroid-resistant CD, often within days of the initial administration."6 
 
Immunoglobulin has been employed as a safe and effective protocol in many autoimmune disorders, but without the same degree of treatment “fallout.” We’ve written about the use of IVIG therapies not only for neurological diseases, but as we are now seeing, it also has applicable benefits in treating COVID 19. IVIG does not target the virus, but is used to help calm the overactive immune response seen in the disease by decreasing the instance of multiple cytokines at one time.7 In its use for treatment of autoimmune disease, IVIG has a multimodal method of action (MOA). A number of studies have shown the benefits of IVIg and its anti-inflammatory effects as well as an ability to regulate immune balance. IVIg additionally has the capacity to eliminate clinical autoimmunity, restore a state of tolerance, and reinstate physiologic homeostasis.8
 
There is still much to be learned and better understood about how conventional treatments for neuroimmune and autoimmune conditions may impact disease initiation in some patient groups. But we do know that IVIG has been extremely well tolerated and yielded excellent results as part of a comprehensive program. It’s well advised to consider this in any patient who presents with a preexisting condition if there are concerns about employing medications. Communication is also critical, between any clinicians participating in patient care, as well with the patient themselves and any supporting family members. Together, we can arrive at a more successful treatment plan unique to the individual and their health needs…and that is the basic tenet and very real benefit of integrative medicine.
 
In health and hope,
Dr. Suzanne Gazda 
 
References: 
 
1 Dziadkowiec K N, Stawinski P, Radadiya D, et al. (July 30, 2020) Is Multiple Sclerosis an Extra-Intestinal Manifestation of Inflammatory Bowel Disease? Food for Thought. Cureus 12(7): e9485. doi:10.7759/cureus.9485
 
2 Kemanetzoglou, E., & Andreadou, E. (2017). CNS Demyelination with TNF-α Blockers. Current neurology and neuroscience reports, 17(4), 36. https://doi.org/10.1007/s11910-017-0742-1
 
3 Van Oosten BW, Barkhof F, Truyen L, et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996;47(6):1531–1534) 
 
4 Alnasser Alsukhni, R., Jriekh, Z., & Aboras, Y. (2016). Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature. Case reports in medicine, 2016, 1423131. https://doi.org/10.1155/2016/1423131
 
5 Varma P, Falconer J, Aga A, Prince HM, Pianko S. Rituximab-induced Crohn's disease. Scand J Gastroenterol. 2017 May;52(5):606-608. doi: 10.1080/00365521.2017.1280530. Epub 2017 Jan 27. PMID: 28129697.
 
6 Moshe Rogosnitzky, Rachel Danks, Daniel Hol. Intravenous immunoglobulin for the treatment of Crohn's disease. Autoimmunity Reviews (2012).Volume 12, Issue 2. Pages 275-280.
ISSN 1568-9972. https://doi.org/10.1016/j.autrev.2012.04.006.
https://www.sciencedirect.com/science/article/pii/S1568997212000961
 
7 Suzanne Gazda MD (www.suzannegazdamd.com)
https://www.suzannegazdamd.com/blog/with-more-potential-uses-for-more-diseases-ivig-gains-enhanced-awareness-for-its-multimodal-properties
 
8 Suzanne Gazda MD (www.suzannegazdamd.com)
https://www.suzannegazdamd.com/blog/ivig-in-autoimmune-disease-therapies

Although the function of alpha-synuclein is not well understood, studies suggest that it plays an important role in maintaining an adequate supply of synaptic vesicles in presynaptic terminals. It may also help regulate the release of dopamine, a neurotransmitter that is critical for controlling the start and stop of voluntary and involuntary movements. Alpha-synuclein may also play a role in the movement of structures called microtubules that help cells maintain their shape.1
 
We know that genes are one part of the story, but the even more telling piece is epigenetics. Environmental factors influence gene expression so it is one thing to “carry the gene,” but the most important points we have to consider are the environmental risk factors that help trigger or turn on the genes we carry through life.   
 
What recently has especially come to light is that once started, these neurodegenerative diseases may propagate themselves; misfolding leads to a domino effect as more and more proteins become misfolded and are incorporated into a large, ever-growing abnormal clump of material in the brain. This process is similar to what we know has happened before with prion diseases (e.g. mad cow disease, Kuru, combined immunodeficiency disease), which are considered very rare. However, in recent years, scientists have discovered that similar processes of protein misfolding are at work in many neurodegenerative disorders including Alzheimer’s, Parkinson’s and Lou Gehrig’s disease. Prion refers to abnormal, pathogenic agents that are transmissible and are able to induce abnormal folding of specific normal cellular proteins called prion proteins that are found most abundantly in the brain.2  Research has shown as well beyond a shadow of doubt that Alzheimer’s is a prion disease where the amyloid and tau can also “self-propagate.”3
 
In integrative medicine, we must look to all factors of disease initiation to best understand its likely progression in order to identify the most appropriate treatment protocols. Alpha-synuclein is clearly a factor in neurodegenerative disorders and the more we can learn about its actions will hopefully provide us with the insight to diagnose more patients at an earlier stage.
 
1 U.S. Library of Medicine – The SNCA gene
https://ghr.nlm.nih.gov/gene/SNCA
 
2 Centers for Disease Control and Prevention – Prion diseases
https://www.cdc.gov/prions/index.html
 
3 University of California San Francisco – Alzheimer’s disease and prions
https://www.ucsf.edu/news/2019/05/414326/alzheimers-disease-double-prion-disorder-study-show

Pediatric acute-onset neuropsychiatric syndrome (PANS) is a complex neurological disorder that more scientists are studying in order to learn more about the origins of this illness that along with PANDAS (pediatric autoimmune neuropsychiatric disorders associate with streptococcal infections) is estimated to affect 1 in 200 children.

While PANDAS is thought to occur following an infection, the diagnosis for PANS is a clinical one based on the original working criteria first introduced by Dr. Susan Swedo.*

A recent preprint study, “Hypoferritinemia and iron deficiency in youth with pediatric acute onset neuropsychiatric syndrome" led by Jennifer Frankovich, MD from the Stanford PANS Clinic explored the potential association between hypoferritinemia (low iron storage in the ferritin form) and the development over time of neuropsychiatric symptoms. The authors concluded that in patients with PANS and iron deficiency, “clinicians should consider the possibility of inflammation as the cause especially if iron deficiency cannot be explained by diet and blood loss.” 1

Additional findings released by the investigating team were as follows:
▪ Children with anxiety, depression, tic disorders, attention-deficit/hyperactivity disorder, febrile seizures, breath holding spells, and fibromyalgia, are more likely to be iron deficient.
▪ 1 in 4 PANS patients (27%) had hypoferritinemia.
▪ 75% of those cases occurred during a PANS “flare” (abrupt worsening of neuropsychiatric symptoms.
▪ Patients with hypoferritinemia had worse global impairment, more comorbid inflammatory diseases, and exhibited a chronic course of PANS illness.”
▪ An estimated 3-8% of the PANS patients had iron deficiency. That rate is nearly 2 times higher than healthy subjects.
▪ Out of the patients who had an iron workup, 14% had an iron deficiency. And about half of those patients also had anemia.
▪ The hypoferritinemic group of patients had a higher rate of chronic PANS illness (69% vs. 46%) and higher global impairment scores. (When ferritin levels were measured.)
▪ Comorbid inflammatory diseases were also more commonly seen in the hypoferritinemic group.
▪ Ferritin levels returned to normal for the majority (69%) of the hypoferritinemic patients after they received treatment.
▪ Therapies included IVIG, methylprednisolone, prednisone bursts, NSAID or a combination of these treatments.

Ferritin and its significance.

Free iron, not typically found in large amounts in the bloodstreams, can be toxic as it can act as a catalyst to the formation of free radicals that subsequently damage cells. Ordinarily, our systems draw upon several protective mechanisms to bind iron in various tissue compartments. This way, the iron is stored complexed to protein as ferritin or hemosiderin. Ferritin serum level correlates with the total values of iron stores in organism stores. Low serum ferritin (less than 15 ng/ml for general population with some labs using age and gender-specific norms) is highly specific for iron deficiency.

But we have long known about something called anemia of inflammation (AI), formerly also called anemia of chronic disease or anemia of chronic disorders. This disorder is usually a mild to moderately severe anemia (hemoglobin rarely lower than 8 g/d) that develops in the setting of infection, inflammatory disease or malignancy.2

When the protective mechanisms go awry.
In the study linking hypoferritinanemia and PANS, the pathophysiology involved here includes several systemic actions that result in this low ferritin storage:
▪ Mildly shortened erythrocyte survival (increased destruction) due to macrophage activation by inflammatory cytokines.

▪ Hypoferremia, iron-restricted erythropoiesis from cytokine-stimulated hepcidin increase. The hormone hepcidin, a peptide, is the principal regulator of iron absorption and its distribution to tissues, hepcidin acts by regulating the iron delivery to plasma from macrophages that recycle senescent erythrocytes, from duodenal enterocytes that absorb dietary iron and from hepatocytes involved in iron storage.
▪ Inflammation will increase plasma concentrations of hepcidin; suppression of erythropoiesis by direct effects of cytokines on the marrow Variable effects of inflammation on erythropoietin production, renal excretion of hepcidin.

What treatment approach can be pursued?
It is best to identify and treat the root cause of the underlying disease and the contributors to chronic inflammation; in some cases there may be an underlying infectious trigger as well (e.g. streptococcus, varicella etc.) and these should be treated accordingly as well.

The significance of this study and corresponding information.
Iron is of central importance to many vital processes because the metal is a catalytic component of crucial metabolic enzymes in the citric acid cycle, mitochondrial respiration, replication, myelin production and/or neurotransmitter synthesis (dopamine and serotonin). We know that in the pathophysiology of a disorder such as idiopathic restless legs syndrome, for example, disturbances of dopaminergic function and alterations of iron homeostasis are involved in its pathogenesis. We also know the impact in PANS and PANDAS of dysregulated dopamine in the basal ganglia. Children with iron deficiency conditions are prone to developmental delays, reduced school performance, and behavioral disorders.

An association has been found between low Hb and smaller brain volume, providing a potential mechanism to explain the greater risk of adults with dementia in individuals with anemia. The overall negative effect of low Hb on brain outcomes in these data supports the notion that chronic hypoxia accelerates cognitive decline and increases the risk of brain disease.3

Certainly these and other available studies shed more light on PANS and the role of inflammation in the course of this disease. But, as noted by the principal investigators, further research must be conducted to more fully explore the foundations of these neuropsychiatric disorders. Toward this goal, integrative medicine, which recognizes that all systems and processes are intricately connected, can play an important role in identifying expanded treatment protocols…and ultimately giving more patients and families alike the hope of improved health outcomes.

In health,
Dr. Suzanne Gazda

References:

*The PANDAS Network
http://pandasnetwork.org/medical-information/

1 Chan A, Karpel H, Spartz E, et al. Hypoferritinemia and iron deficiency in youth with pediatric acute-onset neuropsychiatric syndrome [published online ahead of print, 2020 Aug 3]. Pediatr Res. 2020;10.1038/s41390-020-1103-3. doi:10.1038/s41390-020-1103-3
https://pubmed.ncbi.nlm.nih.gov/32746449/

2 Nemeth, E., & Ganz, T. (2014). Anemia of inflammation. Hematology/oncology clinics of North America, 28(4), 671–vi. https://doi.org/10.1016/j.hoc.2014.04.005
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115203/

3 Jonassaint, C. R., Varma, V. R., Chuang, Y. F., Harris, G. C., Yasar, S., Polinder-Bos, H., & Carlson, M. C. (2014). Lower hemoglobin is associated with poorer cognitive performance and smaller brain volume in older adults. Journal of the American Geriatrics Society, 62(5), 972–973. https://doi.org/10.1111/jgs.12810
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292910/

Additional reading:

IntechOpen
https://www.intechopen.com/books/iron-deficiency-anemia/neurocognitive-dysfunctions-in-iron-deficiency-patients

The Atlantic
https://www.theatlantic.com/health/archive/2013/01/the-iron-in-our-blood-that-keeps-and-kills-us/266936/

First, what is the APOE gene?

Certain genes make you more likely to develop Alzheimer's, but there are many other genetic and environmental factors involved in disease initiation.
The APOE gene provides instructions for making a protein called apolipoprotein E(APOE). This protein combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream. Maintaining normal levels of cholesterol is essential for the prevention of disorders that affect the heart and blood vessels (cardiovascular diseases), including heart attack and stroke. APOE is thought to be responsible for the transportation of lipids within the brain, maintaining structural integrity of the microtubule within the neuron, and assisting with neural transmission. APOE is also intricately involved in the innate immune response in the body and the brain.  

There are three types of the APOE gene, called alleles: APOE2, E3 and E4. Everyone has two copies of the gene and the combination determines your APOE "genotype. The APOE4 allele, present in approximately 10-15% of people, increases the risk for late onset Alzheimer's and lowers the age of onset. Late-onset Alzheimer's disease, the subset of the disorder occurring in people age 65 and over, affects more than give million Americans, and is characterized by progressive memory loss and dementia. The early-onset form of AD (younger than 65 years old) is predominantly familial and most often linked to single mutations in the genes encoding APP, presenilin 1 (PSEN1) or presenilin 2 (PSEN2). Ninety percent of patients with dementia have an idiopathic form, which is considered an interplay between genes and the environment.

Note that having one copy of E4 (E3/E4) can increase your risk of disease occurrence by two to three times while two copies (E4/E4) can increase the risk by as many as 12 times.

How does the APO4 E gene increase the risk of cognitive decline?

The APOE4 gene locus has been discussed as a possible mediator of cognitive impairment as it is associated with the evolution of dementias like Alzheimer’s disease.  Outside the brain, APOE4 can increase the risk of atherosclerosis (hardening of the arteries) and stroke, which may explain why APOE4 is a risk factor for vascular causes of cognitive impairment and dementia. APOE is thought to be involved in repairing neuronal injury, synapse formation, and scavenging of toxins.

APOE in the brain is primarily expressed by astrocytes and microglia, cell types that are now widely appreciated to play key roles in the pathogenesis of AD. Data has emerged that shows APOE4 disrupts normal glial cell biology and impairs the metabolic activity of the human microglia. If microglia are compromised then widespread neuro-inflammation can spread like a wildfire out of control, toxic waste products like amyloid and tau cannot be cleared and the risk of cognitive decline is amplified.

Recent study findings
In this recently published study in Neurology®, Neuroimmunology & Neuroinflammation, the researchers sought to understand the impact of APOE polymorphisms on parameters of cognitive function in a large multicenter, prospectively collected German data set of untreated patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS). In this study, 552 newly diagnosed MS patients in Germany were followed.  25.2% of the patients were carriers of the APOE ε4 allele. Ten of these (1.8%) were homozygotes (e.g. they had two copies of the APOE4 gene.)

Along with parameters of a higher disease burden, APOE ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and RRMS.  Other factors that were associated with worse cognition were higher expanded disability status scale (EDSS) scores and higher lesion volume on MRI. Previous studies in smaller cohorts of patients with MS with mean disease durations of 8.328 and 13 years reported an association of APOE ε4 with dysfunction in some cognitive domains including verbal fluency and memory.1

The role of microglia as both “angels” and “assassins.”

As the resident immune cells in the central nervous system, microglia are also involved in: synaptic organization; trophic neuronal support during development; phagocytosis of apoptotic cells in the developing brain; myelin turnover; control of neuronal excitability; and phagocytic debris removal as well as brain protection and repair. Microglia seem to drive synapse loss in neurodegenerative diseases through out-of-control and misguided synaptic pruning. Acting as the brain’s clean-up crew, microglia maintain a vigilant watch for injury or infection, clearing away pathogens, malformed proteins, and dead cells. However, it is possible that activated microglia can set off chronic neuroinflammation and subsequent neurodegeneration due to the release of pro-inflammatory cytokines, chemokines, and other inflammatory impacts along with reactive oxygen species (ROS) and reactive nitrogen species (RNS).

Just this month, researchers at Yale University, School of Medicine, Grutzendler Lab for the first time captured images of the process of brain cell death at the level of a single neuron, showing how specialized brain cells coordinate the removal of neuronal corpses and dendrites from the central nervous system.2 This is both a remarkable accomplishment and fascinating to see exactly how this process takes place.

For more information regarding microglia, you may also want to read “The Angel and the Assassin: The Tiny Brain Cell That Changed the Course of Medicine” by Donna Jackson Nakazawa. She details how once-healthy microglia can in a toxic environment actually destroy the brain and become its untimely “assassin.” As discussed in our numerous blogs and scientific articles, we know anything that affects the behavior of the microglia may set the stage for the development of one of many neurodegenerative and neuropsychiatric diseases. So clearly, microglia can be either our best friend or worst enemy.

All factors leading to decline of brain function need to be considered in MS and other neurodegenerative diseases. It could be that the APOE 4 genotype may be a biomarker in MS and may also influence other neurological conditions such as those that occur with traumatic brain injury and Parkinson's disease. And undoubtedly more studies are needed to fully understand the role of genetic influences. But, it’s equally critical to remember that genes are just one part of the equation and that lifestyle and environmental factors also contribute to disease initiation. We cannot change our genes, but we definitely can change many things about how we live to give ourselves the best chance at a healthier life.

In hope and healing,
Dr. Suzanne Gazda

References:

1 Is APOE ε4 associated with cognitive performance in early MS?
Sinah Engel, Christiane Graetz, Anke Salmen, Muthuraman Muthuraman, Gerrit Toenges, Björn Ambrosius, Antonios Bayas, Achim Berthele, Christoph Heesen, Luisa Klotz, Tania Kümpfel, Ralf A. Linker, Sven G. Meuth, Friedemann Paul, Martin Stangel, Björn Tackenberg, Florian Then Bergh, Hayrettin Tumani, Frank Weber, Brigitte Wildemann, Uwe K. Zettl, Gisela Antony, Stefan Bittner, Sergiu Groppa, Bernhard Hemmer, Heinz Wiendl, Ralf Gold, Frauke Zipp, Christina M. Lill, Felix Luessi, for the German Competence Network of Multiple Sclerosis
Neurol Neuroimmunol Neuroinflamm Jul 2020, 7 (4) e728; DOI: 10.1212/NXI.0000000000000728
https://nn.neurology.org/content/7/4/e728.abstract?etoc

2 Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo
BY EYIYEMISI C. DAMISAH, ROBERT A. HILL, ANUPAMA RAI, FUYI CHEN, CARLA V. ROTHLIN, SOURAV GHOSH, JAIME GRUTZENDLER
SCIENCE ADVANCES26 JUN 2020 : EABA3239
https://advances.sciencemag.org/content/6/26/eaba3239

Additional references and reading:

Christopher Carlin, BSc, Lilian Murray, PhD, David Graham, PhD, FRCPath, David Doyle, MD, James Nicoll, MD, FRCPath, Involvement of Apolipoprotein E in Multiple Sclerosis: Absence of Remyelination Associated with Possession of the APOE ε2 Allele, Journal of Neuropathology & Experimental Neurology, Volume 59, Issue 5, May 2000, Pages 361–367, https://doi.org/10.1093/jnen/59.5.361
https://academic.oup.com/jnen/article/59/5/361/2609860

Liu G, Hannon T. Reasons for the prevalence of childhood obesity - Genetic predisposition and environmental influences. ENDOCRINOLOGIST. 2005;15:49-55.
https://journals.lww.com/theendocrinologist/Abstract/2005/01000/Reasons_for_the_Prevalence_of_Childhood_Obesity_.11.aspx

Michaelson DM. APOE ε4: the most prevalent yet understudied risk factor for Alzheimer's disease. Alzheimers Dement. 2014;10(6):861-868. doi:10.1016/j.jalz.2014.06.015

Nathoo, N., Chetty, R., van Dellen, J. R., & Barnett, G. H. (2003). Genetic vulnerability following traumatic brain injury: the role of apolipoprotein E. Molecular pathology : MP, 56(3), 132–136. https://doi.org/10.1136/mp.56.3.132
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1187307/

Safieh, M., Korczyn, A.D. & Michaelson, D.M. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med 17, 64 (2019). https://doi.org/10.1186/s12916-019-1299-4
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1299-4

Shi J, Tu JL, Gale SD, et al. APOE epsilon4 is associated with exacerbation of cognitive decline in patients with multiple sclerosis. Cogn Behav Neurol 2011;24:128–133.
Bachiller, S., Jiménez-Ferrer, I., Paulus, A., Yang, Y., Swanberg, M., Deierborg, T., & Boza-Serrano, A. (2018). Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response. Frontiers in cellular neuroscience, 12, 488. https://doi.org/10.3389/fncel.2018.00488
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305407/

NA ZHAO, OLIVIA N. ATTREBI, YINGXUE REN, WENHUI QIAO, BERKIYE SONUSTUN, YUKA A. MARTENS, AXEL D. MENESES, FUYAO LI, FRANCIS SHUE, JIAYING ZHENG, ALEXANDRA J. VAN INGELGOM, MARY D. DAVIS, AISHE KURTI, JOSHUA A. KNIGHT, CYNTHIA LINARES, YIXING CHEN, MARION DELENCLOS, CHIA-CHEN LIU, JOHN D. FRYER, YAN W. ASMANN, PAMELA J. MCLEAN, DENNIS W. DICKSON, OWEN A. ROSS, GUOJUN BU. SCIENCE TRANSLATIONAL MEDICINE05 FEB 2020
APOE4 exacerbates α-synuclein pathology in a synucleinopathy mouse model, and APOE4 genotype associates with increased α-synuclein pathology in humans.
https://stm.sciencemag.org/content/12/529/eaay1809.abstract

Liu G, Hannon T. Reasons for the prevalence of childhood obesity - Genetic predisposition and environmental influences. ENDOCRINOLOGIST. 2005;15:49-55.
https://journals.lww.com/theendocrinologist/Abstract/2005/01000/Reasons_for_the_Prevalence_of_Childhood_Obesity_.11.aspx

In this particular referenced study using laboratory mice that also drew upon the results of previous research, scientists examined the biological links between chronic social defeat (CSD) and affective disorders including the impact on areas of the brain associated with aging, depression, anxiety and other neurological conditions.

Research findings indicated that “CSD stress produces anxiety-like and depressive-like behavioral declines in susceptible mice; recovery after CSD cessation was marked by recruitment of leukocytes perhaps participating in vascular repair. The data suggest that co-morbidity of affective disorders and vascular diseases may be attributed in part to a common link in altered endothelial cell function.”

This points to several significant study highlights:

1.  Chronic social defeat caused behavioral deficits and blood-brain barrier breaks.
2.  Breaks showed tiny bleeds, fibrinogen deposition, and angiogenesis markers.
3.  Brain endothelial cells were isolated for analysis at gene transcriptional level.
4.  Stressed endothelial cells engaged vascular injury, growth, and repair programs.
5.  These repair programs are also seen in hypertension, cardiovascular disease, and aging.

Additionally, the study results identified the relationship between fibrinogen deposition in brain vasculature and declines in mood that suggest this fibrinogen entry provides an inflammatory signal that could transmit effects of CSD across the BBB. Fibrinogen in other disease states causes neuroinflammation, apparent as microglial activation; you can read more about the involvement of microglia in our blog, “What Causes our Body to Attack the Mind.”

We know too from the Global Burden of Disease Study (2017 data) that “major depressive disorder and related psychopathologies are a leading cause of disability in the world.” This longtime study has since 1990 provided comprehensive worldwide observational epidemiological data including mortality and morbidity from major diseases, injuries and risk factors to health at global, national and regional levels. By examining trends and making comparisons across populations, as well as looking at historical data, researchers are afforded the most in-depth understanding of the changing health challenges facing people across the world today.

It is imperative that we focus on employing science in identifying the root causes of multiple conditions, both chronic and acute, to fully understand the path to appropriate interventions –we must understand the cause of any condition and not just treat the symptoms. Integrative medicine affords us with this opportunity as well as the perspective to consider the best means and the methods to continue to offer the most hope for more patients.

In health,
Dr. Suzanne Gazda

Additional references:

Global Burden of Disease Study
https://www.thelancet.com/gbd

Golden, S., Covington, H., Berton, O. et al. “A standardized protocol for repeated social defeat stress in mice.” Nature Protocols 6, 1183–1191 (2011). https://doi.org/10.1038/nprot.2011.361
https://www.nature.com/articles/nprot.2011.361

This medication is also commonly prescribed off label for chronic fatigue, ADHD, mood boosting and cognitive enhancement.

One of the most common complaints in all patients with autoimmune disease is chronic fatigue. Modafinil is a psychostimulant drug that was approved in 1998 by the Food and Drug Administration (FDA) for the treatment of narcolepsy, excessive daytime sleepiness and obstructive sleep apnea. This medication is also commonly prescribed off label for chronic fatigue, ADHD, mood boosting and cognitive enhancement.

A recently published article, “Modulating the immune response with the wake-promoting drug modafinil: a potential therapeutic approach for inflammatory disorders” reports on the findings in a 2019 study at the University of Sweden that looked at possible immunomodulatory effects of this medication. The authors stated, “We conclude that there is unequivocal evidence of an anti-inflammatory effect of modafinil in experimental animal models of brain inflammation and neurodegenerative disorders, including systemic inflammation and methamphetamine-induced neuroinflammation, Parkinson’s disease, brain ischemia, and multiple sclerosis."

How it works: back to dopamine and other neuro-chemical messengers.

I previously have written about the importance of dopamine receptors in PANS and PANDAS conditions. Dopamine is an essential neurotransmitter for many brain actions and helps regulate mood, movement, cognition and behavior - and now we can see that dopamine is clearly tied to the health of the immune system.  

Dopamine actions: The dopamine D1 and D2 receptors have been considered to be essential in mediating the wakefulness promoted by modafinil. There is a significant affinity of modafinil to the dopamine transporter (DAT). If one blocks the DAT receptor then there will be more dopamine available. The dopamine transporter (DAT) controls the spatial and temporal dynamics of dopamine (DA) neurotransmission by driving reuptake of extracellular transmitter into presynaptic neurons.  

Norepinephrine actions: Modafinil also affects the central norepinephrine (NE) system by binding to the norepinephrine transporter (NET) and by blocking the reuptake of NE. This serves to help prevent sleep activation in the ventrolateral preoptic nucleus (VLPO), which is a group of sleep-active neurons that has been identified in the hypothalamus of rats and is thought to inhibit the major ascending monoaminergic arousal systems during sleep.

GABAergic actions: Modafinil tends to reduce the Gamma-aminobutyric acid-ergic (GABAergic) transmission, which results in increased brain levels of glutamate and serotonin. GABA's role in the brain is reducing neuronal excitability throughout the nervous system and it is well established that activation of the GABA(A) receptors favors sleep.

Growing evidence that modafinil does so much more than improve patient fatigue.

Additional results that bear continued efforts to investigate modifinil and its diverse application in neurological instances include:

Cognitive Enhancement.
Studies show that modafinil is beneficial in improving working and recognition memory, attention and other cognitive functions. It has also proven effective in improving cognition in adolescents with ADHD and adults with schizophrenia (Battleday and Brem, 2015 ); Minzenberg and Carter, 2008 ). This might be relevant to the ability of modafinil to increase hippocampal neurogenesis, an effect reported following acute treatment in both laboratory mice and rats. (Brandt et al., 2014 ); Sahu et al., 2013 ).

Reduction in Neuroinflammation.
Modafinil has been shown to impact specific aspects of the brain immune response, such as monocyte recruitment and activation (Zager et al., 2018 ), T cell differentiation, cytokine production (Brandão et al., 2019 ) and glial activation (Raineri et al., 2012 ).
The data from in vivo and in vitro models of neuroinflammation consistently show that modafinil is an effective blocker of microglial activation and consequently of in situ production of pro-inflammatory cytokines and other inflammatory mediators. This makes modafinil a promising therapeutic approach to neurodegenerative disorders in which neuroinflammation plays a significant role.

Potential for use in neurodegenerative disease.
Relative to use in Parkinson’s disease, Fuxe and colleagues were the first to show that modafinil treatment prevents the loss of dopaminergic neurons in the substantia nigra (SN) and also has neuroprotective effect on GABAergic neurons in the substatia nigra, with a small increase in the number of non-neuronal cells, likely glial cells.

Modafinil is commonly prescribed for multiple sclerosis patients and, as shown for the first time by this groundbreaking study, it’s clear that the therapeutic properties are closely linked to an anti-inflammatory effect.

The mechanism in mice models revealed:
1.  Reduction in the frequency of T helper (Th)-1 cells (which drive autoimmunity against myelin).
2.  A drastic decrease in interferon (IFN)-γ.
3.  Reduced severity of EAE (experimental autoimmune encephalitis) symptoms.

These results provide further indication that modafinil may do much more than just improve fatigue in patients with neurological/ autoimmune problems.

Immunomodulation with modafinil.

The immunomodulating effects of this drug have been studied extensively and although modafinil has been shown to be pro-inflammatory in peripheral immune cells of naive mice by stimulating IFN-mediated immunity, it has been demonstrated to be anti-inflammatory in animal models of inflammatory diseases. There are now proposed mechanisms that show modafinil may shear up the blood-brain-barrier (BBB) through directly or indirectly influencing the function of the BBB or circumventricular organs, such as the choroid plexus, most likely by affecting its permeability to immune cells and inflammatory mediators.

Dopamine and the reward system also has been shown recently to be a new pathway between the brain and immunity. Researchers have shown that increased dopamine, the brain’s pleasure and ‘feel good’ chemical messenger, is linked to improved immune function. This suggests that activities that physiologically stimulate the reward system, such as engaging in sex, social interactions and even physical activity, might have beneficial effects via this newly proposed mechanism when fighting an infection or cancer.

Since we know that modafinil increases dopamine levels in the brain, it appears to be a therapeutic option for use beyond addressing fatigue symptoms alone and may offer another immunomodulatory resource for physicians to consider in designing patient protocols.

(1) The excessive extracellular dopamine negatively influences the infiltration and activation of immune cells and resident microglia, probably by acting on the dopaminergic receptors of these cells.
 (2) Direct action of modafinil on DAT expressed by immune cells and glia, which is a mechanism independent of brain dopamine levels

Delving into new mechanisms to explain psychoneuroimmunology is leading us down an entirely new level of understanding. After 30 years of study, I continue to remain awestruck at the complexity of the miraculous brain and the opportunities to offer patients more treatment opportunities that can enhance their quality of life.  

In health,
Dr. Suzanne Gazda

 https://www.researchgate.net/deref/http%3A%2F%2Fdx.doi.org%2F10.1016%2Fj.euroneuro.2015.07.028

 https://www.ncbi.nlm.nih.gov/pubmed/17712350

 https://www.ncbi.nlm.nih.gov/pubmed/25158676/

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195593/

 https://www.sciencedirect.com/science/article/abs/pii/S0889159119314953#b0240

 https://www.frontiersin.org/articles/10.3389/fimmu.2019.00452/full

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464292/

 https://www.sciencedirect.com/science/article/abs/pii/S0889159119314953#b0240

Coronavirus (CoV) is an enveloped virus with a large positive-sense, single-stranded RNA genome belonging to the Coronaviridae family; examples of CoV are SARS, MERS and now COVID-19.

It’s important to note that increased evidence shows that coronaviruses are not always confined to the respiratory tract.  In fact, it may also invade the central nervous system and subsequently induce neurological diseases. The infection with SARS‐CoV has been reported in the brains of both human patients and laboratory animals where the brainstem was heavily infected, indicating the virus invades the nervous system. If the medulla (or brainstem) becomes involved, this could be another explanation for the respiratory decline that has been observed in the past and as well as the present iterations of the virus.

Other studies have indicated that coronaviruses are also associated with central nervous system (CNS) diseases such as acute disseminated encephalomyelitis and multiple sclerosis. A 2016 investigation looked at two groups (183 and 236 hospitalized children), with acute encephalitis-like syndrome and respiratory tract infection, respectively; the pediatric patients were screened for anti-CoV IgM antibodies and findings showed the expression profiles of multiple cytokines were determined in CoV-positive patients with a high incidence of CoV infection in hospitalized children particularly with CNS illness.  

But what about THIS Coronavirus?  

Recently, a study posted in medRxiv - The Preprint Server for Health Sciences, (see references at end of article) has reported neurological manifestations in COVID-19 in the current outbreak that involved 214 patients, of which 78 (36.4%) patients had neurologic manifestations, which affirms the rationale of the neurotropic potential in the COVID-19 virus.

In a review article first published February 27, Yan-Chao Li of Jilin University in China and colleagues argue that if SARS-CoV-2 infects nerve cells, particularly neurons in the medulla oblongata, which is part of the brain stem that serves as the control center for the heart and the lungs, the damage could contribute to “acute respiratory failure of patients with COVID-19.”  

One of the papers, a review published March 13, 2020, mentioned that SARS-CoV-2, like other coronaviruses such as SARS-CoV and MERS-CoV, could target the central nervous system, possibly infecting neurons in the nasal passage and disrupting the senses of smell and taste or the other plausible explanation in inflammation driven by the viral pathophysiology.  

Total loss of smell, called anosmia, can be caused by many viruses, including various strains of both coronaviruses and rhinoviruses, both of which can cause the common cold. Hyposmia, the partial loss of smell as well as anosmia may be accompanied by dysgeusia, the loss of taste. Either of these sensory losses have been reported in patients with COVID 19 and in some patients can be present in the asymptomatic phase of the illness and may be the first sign of COVID 19. Other neurological symptoms that have been noted with COVID 19 include headache, nausea, and vomiting exclusive of other gastrointestinal signs.  

There is at this writing one case report of a patient with this disease that presented with an acute encephalopathy. It appears that any neurological symptom should be considered as a consequence. 

In Bejing, there have been other reported cases of patients presenting with alteration of consciousness. Testing of the cerebrospinal fluid confirmed novel coronavirus as well as a diagnosis of encephalitis, an inflammation of the brain.

The brain under siege: what are the mechanisms?

SARS-CoV-2 enters human cells using a receptor called ACE2.   Researchers have reported that ACE2 regulates cardiovascular function, and according to a search of protein databases, many human cell types express ACE2, including lung, heart, kidney, intestine, and brain tissue.  The brain has been reported to express ACE2 receptors that have been detected over glial cells and neurons, which makes them a potential target of COVID-19.
ACE receptors line in blood vessel lining and thru this mechanism might breach the blood brain barrier and allow viral access to the brain   

The blood-brain barrier, or BBB, is a single-layered lattice of cells joined together by tight junctions that keep most substances from crossing this barrier into the brain. It was once thought to be impenetrable, but now we know that there is an “ebb and flow” of toxins, pathogens, inflammatory cells and other harmful elements that are in fact crossing into and traversing the central nervous system over the course of our lives. Many factors affect the integrity of the BBB including diet, sleep, environmental influences, infections, EMFs, leaky gut syndrome and more. All of that means our brains are essentially under siege far more regularly than we may have ever realized, particularly given the toxic world in which we live.

transgenic mice expressing human ACE2 through neurons in the nose. The virus then rapidly spread to connecting nerve cells. The extensive nerve damage was the major cause of death, the team reported, even though low levels of the virus were detected in the animals’ lungs. Anosmia occurred, with the olfactory neuronal pathways identified as the source of neuro-inflammation.     

In research conducted in PANS and PANDAS/autoimmune encephalitis, this neuronal highway to the brain has been studied in detail. Once an infectious pathogen or inflammatory cells (TH1 lymphocytes) is allowed entry via this route, the olfactory cortex becomes damaged and results in loss of sense of smell and sometimes taste. Neighboring structures like the frontal and temporal lobes, basal ganglia and limbic system also become affected, manifesting in a wide variety of symptoms from headache, depression and anxiety to OCD, memory impairment and movement abnormalities. Anosmia is not uncommon in neurodegenerative diseases such as Alzheimer’s and multiple sclerosis (MS). Recent studies have also established anosmia as a prodromal biomarker for Alzheimer’s disease and the presence of olfactory deficits in a subset of MS patients correlating with symptom severity.

Perhaps we should rephrase Hippocrates’ statement from “all disease begins in the gut” to all disease begins in the gut AND the nose.

Viruses with neurotropic potential: do they lead to neurodegenerative disease?

One of the earliest links between influenza viruses and neural dysfunction was a correlation between the 1918 Spanish flu, caused by a subtype called H1N1, and an epidemic of Parkinson’s a few decades later. This was termed post-encephalitic Parkinson’s (also known as sleeping sickness or von Economo encephalitis). In the 1940s and early 1950s, diagnoses of the neurodegenerative disease abruptly appeared to increase, from 1 to 2 percent of the U.S. population to 2.5 to 3 percent  before declining to its original level. But the increase during those years represented 50 percent more people who subsequently developed Parkinson’s disease.  

Viruses can induce brain dysfunction by either direct cytolytic effects or bystander inflammatory reactions. To date, there is evidence of systemic viral infections that occur with every neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, autism spectrum disorders, autoimmune encephalitis and PANS and PANDAS. It is has been found that neuroinflammation plays a critical role in priming vulnerable neuronal populations for subsequent degeneration.  


What does the future hold?

No one really knows at this moment what the post-recovery outcomes will be after this pandemic subsides.
Will there be a rise in neurodegenerative disease?  
Will we see rates of neuropsychiatric disease including depression increase? There already exist numerous studies that clearly show depression rates soaring after infections.
Only time will tell what or if there will be neurological sequalae to COVID-19.
No doubt, the additional physical and environmental stressors imposed on a global scale will bear close examination for years to come.

In hope and healing,
Dr. Suzanne Gazda

Additional references:
R. Ciurleo et al., Olfactory dysfunction as a prognostic marker for disability progression
in multiple sclerosis: An olfactory event related potential study. PLoS One 13, e0196006
(2018).

M. M. E. Silva, P. B. S. Mercer, M. C. Z. Witt, R. R. Pessoa, Olfactory dysfunction in
Alzheimer’s disease systematic review and meta-analysis. Dementia & Neuropsychologia. 12,
123–132 (2018).

https://pubs.acs.org/doi/10.1021/acschemneuro.0c00122

Mao, L., Wang, M., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Li, Y., Jin, H., and Hu, B. Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study. medRxiv.org, 2020.02.22.20026500 DOI: 10.1101/2020.02.22.20026500 (accessed on 2020-02-28).

Li YC1, Bai WZ2, Hashikawa. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.

https://www.ncbi.nlm.nih.gov/pubmed/32104915

Gale, S.D., Berrett, A.N., Erickson, L.D. et al. Association between virus exposure and depression in US adults. Psychiatry Res. 2018;261:73-79.

Mason, B.W., Lyons, R.A. Acute psychological effects of suspected bioterrorism. Journal of Epidemiology and Community Health. 2003;57:353-354

Lau KK, Yu WC, Chu CM, Lau ST, Sheng B, Yuen KY: Possible central nervous system infection by SARS coronavirus. Emergent Infectious Diseases. 2004;10:342-344.

Arbour N, Day R, Newcombe J, Talbot PJ: Neuroinvasion by human respiratory coronaviruses. Journal of Virology. 2000;74:8913-8921.

https://www.ncbi.nlm.nih.gov/pubmed/25230220

Deleidi, M., Isacson, O. Science Translational Medicine. Viral and Inflammatory Triggers of Neurodegenerative Diseases. 2012 Feb. 15; 4(121): 121ps3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982831/

These 17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious
autoimmune encephalitis.
Maryann P. Platta,b, Kevin A. Boldingc, Charlotte R. Wayneb,d, Sarah Chaudhryb, Tyler Cutforthb, Kevin M. Franksc, and Dritan Agalliub,   www.pnas.org/cgi/doi/10.1073/pnas.1911097117  
https://www.pnas.org/content/suppl/2020/03/10/1911097117.DCSupplemental

This recent study showed that patients with multiple sclerosis (MS) have reduced IgG levels, while prior studies also showed a link to other types of autoimmune diseases and similar low IgG levels. We need to ask why this matters and why does this occur? And just as important, what can we do with this new information to positively impact our treatment approaches? 

Low IgG levels indicate serious immune dysregulation, which could increase a patient’s risk of getting an infection, cancer or autoimmune disease. IgG are immune cells; when your body feels it is under attack, it makes special proteins called immunoglobulins or antibodies. These antibodies are made by B cells and plasma cells and are released throughout the body to help kill bacteria, viruses and other germs.

This particular 2019 study, published in Therapeutic Advances of Neurological Diseases, demonstrated that a substantial proportion of patients with MS had serum IgG concentrations below the lower limit of normal (LLN). Researchers noted that these levels were influenced by the MS disease course and certain immunotherapies (rituximab, intravenous corticosteroids, natalizumab, and fingolimod).

So we must ask if whether we are setting up our patients for future serious side effects with some of the disease-modifying therapies that cause further immunosuppression. For example, might we be worsening the immune dysregulation that may have caused the problem in the first place? Certainly, while MS therapies can be beneficial, there is no doubt that some of these treatment options can lead to serious consequences or even death.   

We know too that all patients with MS have a dysregulated immune system, which is considered to be multifactorial, involving a ‘perfect storm’ of genetic susceptibility, epigenetic and post-genomic events and environmental factors.

No one just “walks in the door and gets MS” and if we identify the various potential environmental triggers and carefully address these, perhaps we can remarkably improve a patient's autoimmune disease. The “cross talk” between the innate and adaptive immune system is an ongoing process that may be opening the door for MS as well as continued disease progression. Antigen-presenting cells in the periphery are the spark that begins the cascading levels of immune dysregulation thru the concept of molecular mimicry causing what is essentially “bystander activation.” Given all these potential inciters of disease, I believe that unless we address the root causes of MS, it will continue to be very difficult to effectively treat this neurodegenerative disease.       

IVIG can indeed be a very beneficial treatment for MS and other autoimmune diseases because of its multiple mechanisms of boosting the immune function. We know that animal models have also shown the potential for IVIG to remyelinate, or help regrow the protective sheath, of our body’s neurons.  

Now with this study's findings, it is no wonder we are seeing the benefits following IVIG treatment in our MS patients. I look forward to more information being made available that points to similar results and can better guide our approaches and options for our patients’ wellbeing.

References:

Zoehner G, Miclea A, Salmen A, et al. Reduced serum immunoglobulin G concentrations in multiple sclerosis: prevalence and association with disease-modifying therapy and disease course. Published September 27, 2019, accessed October 28, 2019.
https://journals.sagepub.com/doi/full/10.1177/1756286419878340?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed.

A basic overview of multiple sclerosis immunopathology, European Journal of Neurology 2015, 22 (Suppl. 2): 3–13

Cusick MF, Libbey JE, Fujinami RS. Molecular Mimicry as a Mechanism of Autoimmune Disease. Clinical reviews in allergy & immunology. 2012;42(1):102-111.

Chastain, E. M. L. and Miller, S. D. (2012), Molecular mimicry as an inducing trigger for CNS autoimmune demyelinating disease. Immunological Reviews, 245: 227–238.

The Enigmatic Role of Viruses in Multiple Sclerosis: Molecular Mimicry or Disturbed Immune Surveillance? Gegenant A ,et al . Trends in Immunology
Published: May 23, 2017DOI: https://doi.org/10.1016/j.it.2017.04.006
 
Immunoglobulins stimulate cultured Schwann cell maturation and promote their potential to induce axonal outgrowth . Nevena Tzekova, André Heinen, et al.   Journal Of Inflammation May 2015 https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-015-0331-

In a recent journal published in Brain, Behavior and Immunity* we can truly see how mold is bad news for the brain. In this study they dripped Stachybotrys fungi into the nose of rats   (can’t imagine having this job!) and found within a short period of time hippocampal immune activation, decreased memory and striking anxiety and as well reduced levels of dopamine .   

Study findings included:
1.  People are typically exposed to complex mixtures of molds, bacteria, and dust that activate stronger, synergistic immune responses than predicted by adding the effects of the individual stimuli.
2.  Mold exposure in homes is underestimated.
3.  Most mold exposure is not from spores, but to nanoparticles that are often hundreds, up to as much as a million times, more numerous and penetrate much deeper into the lungs than whole spores and inhaled mold and mycotoxins that essentially “hijack” the olfactory highway into the brain. Of note, it appears the brain is highly vulnerable to mold invasion due to its high fat content and the lipophilic nature of mold. Many mycotoxins can easily cross the blood brain barrier and disrupt not only microglial cells, but also astrocyte that provide the scaffolding and oligodendrocytes, which are important for myelin production.
4.   Since exposure to mold often persists for months or even years, it might be expected to cause prolonged innate immune activation of the type already demonstrated to be neurotoxic in a variety of diseases and even if mold exposure is ceased,   neuro-immune mechanisms persists for a long time.
5.   Mold exposure, both toxic and nontoxic, must be considered another factor like pesticide exposure or smoking that can add to an individual’s burden of inflammation with possible serious consequences for health and behavior.

Bottom line: Mold is a real concern and can negatively impact the wellbeing of our brains! As more studies provide links between neurological conditions and mold exposure, we can only hope that the resulting disorders exhibited by our patients is taken more seriously as a very real medical issue.

Source: Harding, C.F., Pytte, C.L., Page, K.G., Ryberg, K.J., Normand, E., Remigio, G.J., DeStefano, R.A., Morris, D.B., Voronina, J., Lopez, A., Stalbow, L.A., Williams, E.P., Abreu, o., Mold inhalation causes innate immune activation, neural, cognitive and emotional dysfunction, Brain, Behavior, and Immunity (2019), doi: https://doi.org/10.1016/j.bbi.2019.11.006

New data, “old” drug, new hope.

Since scientists first reported that minocycline showed neuroprotective effects in animal models of ischemic injury and that it easily crosses the blood brain-barrier, minocycline has sparked new interest for potential applicability in neurological treatments. Take, for example, this recent article  in Brain Behavior and Immunity, “Minocycline prevents the depressive-like behavior through inhibiting the release of HMGB1 from microglia and neurons.” Researchers looked at both minocycline and high mobility group protein box 1 (HMGBI), which is a sophisticated “danger signal” with pleiotropic functions that has been proved to function as a pro-inflammatory cytokine. In the central nervous system (CNS), HMGB1 can stimulate microglia, the immune cell in our CNS, to release inflammatory factors that cause chronic neurodegeneration. It was clearly chronic stress that released HMGBI into these nervous system cells.

Think about that – unremitting stress, especially in these times, is really something we have to control if at all possible to give our brains and our immune systems a fighting chance against disease. And if you look at even more of the current data,* it appears that inhibiting the HMGB1/RAGE/TLR4 signaling axis could be a novel therapeutic strategy against several HMGB1 mediated conditions like TBI, neuroinflammation, epilepsy, neurodegenerative diseases and cognitive dysfunction, and, given this latest study, could also improve depressive states.

Isn’t the challenge then to identify the means that patients may be able to tolerate a high enough dose where it is actually therapeutic? Perhaps we should consider whether it is possible to create a liposomal version of this drug - this mode of delivery offers a targeted method to get medicines or supplements into the bloodstream without being destroyed by the digestive enzymes or stomach acid and may help alleviate those side effects typically found with higher dose minocycline.

Definitely something to think about and news to keep in mind!

*Additional reading:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738663/  HMGB1 involved in stress-induced depression and its neuroinflammatory priming role: a systematic review.

https://pubs.acs.org/doi/10.1021/acschemneuro.9b00640  Potential Neuroprotective Effect of the HMGB1 Inhibitor Glycyrrhizin in Neurological Disorders.

https://www.frontiersin.org/articles/10.3389/fnins.2018.00628/full HMGB1: A Common Biomarker and Potential Target for TBI, Neuroinflammation, Epilepsy, and Cognitive Dysfunction.
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First, I have to say that I truly applaud the researchers behind this very pragmatic study looking at an older drug for treating Alzheimer’s disease (AD). And I'll venture to say too that the cost of this trial was a fraction of what “Big Pharma” has spent on their AD trials that have failed. So often, without a lucrative financial reward behind the trial design, it is extremely difficult to get studies done that employ inexpensive therapies such as minocycline.

Minocycline has been studied in multiple neurodegenerative conditions including CVA, MS, Huntington's, ALS, PKD, TBI, and others. In animal models it has been shown to easily cross the blood brain barrier (BBB), be neuroprotective, reduce microglial cell activation, improve mitochondrial function, regulate cell death and reduce amyloid and tau protein. Some believe it works early in the course of disease and or perhaps its positive effects simply wane over time. Others worry about its efficacy due to antimicrobial resistance and gut dysfunction from chronic antibiotic use.

The study and its results.
The Minocycline in Alzheimer Disease Efficacy (MADE) trial was a double-blind randomized trial, which investigated the administration of 200 mg or 400 mg of minocycline hydrochloride over 24 months in patients with mild AD (avg. MMSE was 26.4); 544 patients were followed for the full two years from 2014 to 2016. The MMSE and the Bristol Activities of Daily Living Scale (BADLS) were used as outcome measures.

Some of the key takeaways:
1.   Only 29% of the high dose group were able to complete the trial due to SE's and the other groups tolerability weren't much better either (placebo 64% vs 200 mg group 62%).
2.     Eligibility criteria were practical requiring 2011 McKhann criteria for possible or probable Alzheimer’s disease, without an upper age limit, MMSE score greater than 23, and, most importantly, that a participant have capacity to provide informed consent. Eligibility was assessed without reliance on extensive neuropsychological testing, volumetric or molecular imaging, or cerebrospinal fluid assays for biomarkers.
2.    The slight decrease in the MMSE score over 24 months in the combined minocycline group was similar to that in the placebo group (4.1 vs 4.3 points) and that worsening of BADLS scores over 24 months was also similar in all groups.
3.    Minocycline did not delay the progress of cognitive or functional impairment in people with mild AD during a 2-year period. This study also found that 400 mg of minocycline is poorly tolerated in this population.   

But did it REALLY not work??   

Would we see benefit if this treatment was used along with the Bredesen protocol or in conjunction with other outcome measures? Perhaps it should be combined with other things that could enhance mitochondrial function (e.g. CoQ10). Would it work if used in early or preventative strategies (such as a CIS MS trial (clinically isolated syndrome )?  Minocycline did seem to help reduce risk of MS progression, but only within the first six months and another trial showed benefit when used along with Copaxone. https://www.nejm.org/doi/full/10.1056/NEJMoa1608889

Other research shows that “animal studies, from which much of the evidence for minocycline as an anti-inflammatory and anti-AD agent come, generally used higher doses of minocycline (typically equivalent to 3-7 g per day in humans. Maybe we shouldn’t be so quick to dismiss the findings in this particular study if it’s possible further review and combination therapies could in fact be useful in helping our patients suffering from milder Alzheimer’s disease.

For more information and the full study paper see:
https://jamanetwork.com/journals/jamaneurology/fullarticle/801762

I recently was asked to consult on a case of a set designer with multiple years on Broadway who developed Multiple System Atrophy (MSA) in his early 50s. Within five years, he was no longer able to live independently.  
MSA is such a horrid disease. Characterized by younger onset, atypical Polycystic Kidney Disease (PKD), bad gait, ataxia, dysarthria, cerebellar strokes and autonomic failure, the slow and awful progression of MSA - like many others - indicates strong genetic linkage disequilibrium.

But the mysterious mis-folded proteins and weird inclusion granules (OGI's or oligodendroglial inclusion bodies)  and widespread neuronal cell death and destruction  seen post mortem in MSA have led many to start really looking at MSA epigenetics.

In a stellar article, world-renowned movement disorder specialist Dr. Joseph Jancovic  says that the cause of PKD and MSA are environmental toxins including pesticides and solvents.

And this 2014 article in Experimental Neurobiology notes, "There has been emerging evidence that neurodegenerative diseases are linked to exposure to chronic neurotoxic substances and other risk environmental factors resulting in a higher risk of disease development."
Causative environmental factors, to name a few, include:

• Plastic monomers
• Smoking 
• Organic solvents (a recent study last year linked a high risk of MS in those in the cleaning industry, and there are frequent case reports of MSA in folks that paint for a living) 
• Pesticides (many of my PKD patients are farmers from South Texas or former pesticide exterminators) 
• Drinking well water
• Mycotoxins and Lyme disease
• Meat eaters (too much red meat is inflammatory, and eating anything other than grass-fed meat is problematic) 
• Excessive alcohol consumption
• Maternal nutrition and transgenerational toxicity 
• Heavy metals 
• Dust and fumes 

All this said, it is never one bad apple in the basket of disease-provoking mechanisms. That “Perfect Storm” of etiological mechanisms ultimately cause neurodegenerative disease.

To counter this, it’s critical that patients make a comprehensive list of their toxin exposure beginning early in life. No doubt we all need to be concerned about the ill effects of environmental toxins in our air, water, soil, homes, food etc.  

At Gazda Integrative Neurology, we will develop a comprehensive wellness plan that includes healthy organic non-GMO food, a regular detox protocol, good quality sleep, exercise to lower stress and more. As a coordinated plan of care, this can all go a long way in preventing and sometimes even reversing disease.

In the new study “Multiple Sclerosis: Possibility of a Gut Environment-Induced Disease,” research once again outlines the importance of the status of the gut (microbiome) in health and wellness both for those who want to take a preventative approach, and also for those who are already on the road to disease.
 
The study focused on several key findings:

1. The number of officially registered Multiple Sclerosis (MS) patients in Japan increased almost twenty-fold between 1980 and 2014. Up until recent years, cases of MS in Asia were quite rare. It’s likely no coincidence that these developments have occurred with the introduction of the Western diet - we now see instances of MS rising in all parts of the world.
 
2. Gut microbiota significantly influences human gut homeostasis - as well as the central nervous system - via various mediators including lymphocytes in the intestines. Remember: we have 70 percent of our autoimmune function in our gut.
 
3. Numerous studies have shown distinct differences in fecal samples as they relate to the controlled alteration of the microbiome. In animal models, simply transplanting MS fecal material into a non-MS mouse will induce this disease. Recent studies from Germany and North America showed that when microbiome from an MS patient was administered to germ-free mice and EAE (an animal model of brain inflammation) was induced, the mice developed more severe symptoms and pathology compared to that when microbiome from a healthy subject was given. Collectively, these animal studies indicate that changes in gut microbiota play a causative role in the inflammation of the central nervous system, as well as both disease onset and progression.
 
It is absolutely critical to recognize that MS is a heterogenous disease (all are different), so we cannot expect one treatment approach to work for everyone. The alteration of the gut microbiota is a key factor in both the genesis of autoimmune disease and the advancement of disease, with immune cells linking the gut and the brain with constant “crosstalk.”
 
I continue to firmly believe that no treatment for MS is going to be very helpful unless we “heal the gut” starting with food as medicine, lifestyle changes, exercise, reducing toxic load and other approaches, including pharmaceutical use in some cases.
 
Staying healthy is more complicated than ever, but under the guidance of functional medicine, we can achieve it together. Call today to schedule your appointment!