Mast cell activation syndrome and the vagus nerve

Ross Hauser, MD

There is a connection between neck pain and instability and mast cell activation syndrome.

Over the years we have seen many patients who among their long list of symptoms and ailments include Mast Cell Activation Syndrome. They also had neck pain. For many, their neck pain was seen as a manifestation of their illnesses, but rarely was it seen as the cause of their illnesses.

So many of these people took it upon themselves to explore upper cervical instability and cervical spine instability not as another symptom, but rather as the possible cause for their long list of ailments.  Which brings us to an important question, which came first? Autonomic nervous dysfunction or immune-mediated allergy?  At a minimum, we know they are interconnected. A lot of antigen-antibody immune complexes and a host of histamine releases are going to excite the autonomic nervous system throughout and likewise, autonomic nervous system dysfunction makes antigen-antibody reactions more likely. The patient has the symptoms, is it the neck causing them? Is it the allergies?

People will tell us that in their own research, they came upon the idea that cranial cervical instability may be the cause of their prolonged illness including diagnosis of Chronic Fatigue Syndrome, Myalgic Encephalomyelitis, POTS, and Mast Cell Activation Syndrome. What we observe in our own patients and what we see in people that we talk to who are interested in becoming patients is that among their many symptoms is neck pain. However, for some, their neck pain was seen as a manifestation of their illnesses, but rarely was it seen as the cause of their illnesses.

So many of these people have taken it upon themselves to explore upper cervical instability and cervical spine instability as not a symptom, but rather a cause. These people then make appointments with Cervicocranial specialists who examine them and take imagining studies. In some of these images, the patients learn that they have degenerative disc disease in their cervical spine and a loss of the cervical curve contributing to kyphosis.

When the vagal nerve sensory afferents are dysfunctional, the important body sensors for homeostasis are switched off. Cervicovagopathy or vagus nerve disorder brought on by cervical spine instability, has wide-ranging negative effects on mucosal barriers in the intestines and lungs, producing a large number of inflammatory mediators, including histamine. This has been demonstrated by a number of recent studies as we will examine below. First, let’s have an article outline.

Article outline:

  • Controversies, Symptoms, and Complaints of Mast Cell Activation Syndrome
  • POTS, hypermobile Ehlers-Danlos syndrome (hEDS), and MCAS
  • The difficulty in diagnosis Mast Cell Activation Syndrome –  Idiopathic mast cell activation syndrome
  • One of the body’s more important immune modulators and neurotransmitters, histamine, has wide-ranging effects.
  • Conventional care treatments for MCAS
  • Cervical spine instability, the vagus nerve, and histamine
  • The level of histamine correlates with the symptoms produced
  • With unknown origin – is it dysfunction in the nerves and immune cells’ ability to communicate that causes Mast Cell Activation Syndrome?
  • The next step is the parasympathetic nervous system – the domain of the vagus nerve
  • Vagus nerve – parasympathetic dysfunction
  • Bad vagus signals cause chronic gastrointestinal distress by way of gastric mast cells
  • Skin rashes, eczema, psoriasis mast cells, and their interaction with nerve cells.
  • Repairing the ligaments and curve for a long-term fix

Controversies, Symptoms, and Complaints of Mast Cell Activation Syndrome

Skin lesions of mast cell activation syndrome

In December 2022, researcher Cem Aki from the University of Michigan’s Department of Medicine wrote in the publication Hematology / the Education Program of the American Society of Hematology (1) “There is quite an extensive controversy surrounding the diagnosis of MCAS, and alternative diagnostic schemes with broader inclusion criteria may result in diagnosing nearly 17% of the general population with MCAS. (An April 2020 review paper in the journal Diagnosis is cited (2)). However, this can become problematic for patients whose symptoms may be caused by another entity that may simply be associated with reactive mast cell activation because focusing on mast cell activation may leave the underlying entity undiagnosed. Contributing to this controversy somewhat is the International Classification of Diseases ICD-10-CM classification of diagnostic codes that currently includes additional categories of mast cell activation, including “Mast cell activation, not otherwise specified,” which until recently did not have diagnostic guidance. (3)

This controversy is not new to patients who suffer from MCAS.

As I described above many patients reach out to us after an identification of suspicion that neck instability is involved. This is the type of email we receive:

“I have recently and finally been diagnosed with Atlantoaxial instability. . . I have been extremely disabled for several years. I have EDS, POTS, and MCAS and am hoping that getting treatment for the Atlantoaxial instability may improve many of my symptoms. “

Another reads:

“I am a college student. I have been diagnosed with: Hypermobile Ehlers-Danlos Syndrome, Gastroparesis, POTS, SIBO, Leaky Gut, Fibromyalgia, Chronic Fatigue Syndrome, in-progress diagnosis of MCAS, Mitral Valve Prolapse, Heart Murmur, Low Blood Pressure, Arrhythmia. I am in pain all over inside and out every day, am exhausted and can hardly sleep, am extremely stressed out all the time, can tolerate very few foods anymore or I vomit them up, am nauseous with stomach pain and bloating after eating, and have a diminished quality of life.” When someone has a myriad of symptoms like this, it is of course difficult to believe they all start spontaneously without a common thread linking them together. In a person like this, when all is a mystery, we follow the neurology, we look for short-circuiting messages between brain and body being caused by compression of the arteries, veins, and the nerves that travel through the cervical spine.

This person is unfortunately not unique. A February 2022 paper in the journal Cureus (4) summarizes the symptoms and complaints of Mast Cell Activation Syndrome:

The most frequent symptoms reported by patients with MCAS are gastrointestinal – crampy abdominal pain, diarrhea, nausea, vomiting; cardiovascular – hypotension, tachycardia, syncope (fainting); cutaneous – pruritus (itchy skin and rash), urticaria (hives), flushing, angioedema (deep welts); respiratory – wheezing, stridor (wheezing or “Darth Vader” sounds when breathing).

Patients with MCAS may have a variable clinical phenotype (diagnosis), affecting multiple organ systems but the key feature is recurrent episodes of severe symptoms (anaphylaxis), with concurrent involvement of a minimum of two organ systems and association with an acute increase of specific biologic mediator levels, considered biomarkers of mast cell activation, mainly the serum tryptase. (Tryptase is an enzyme along with histamine and other chemicals, released from mast cells when they are activated as part of a normal immune and allergic response).

This paper was cited by a May 2022 paper from the York University in Toronto and The Pennsylvania State University published in the medical journal Medical Sciences (5) which adds the long-term effects of Covid-19 to the list of maladies: “Specialists and researchers note that MCAS is likely grossly under-diagnosed; therefore, public health agencies and policymakers should urgently attend to community-based experiences of adverse COVID outcomes.”

POTS, hypermobile Ehlers-Danlos syndrome (hEDS), and MCAS

Many of the same symptoms are seen in MCAS, POTS, and Ehlers-Danlos Syndrome.

From Shaw BH, Stiles LE, Bourne K, Green EA, Shibao CA, Okamoto LE, Garland EM, Gamboa A, Diedrich A, Raj V, Sheldon RS. The face of postural tachycardia syndrome–insights from a large cross‐sectional online community‐based survey. Journal of Internal Medicine. 2019 Oct;286(4):438-48.

It should be noted that many of the MCAS symptoms reported above overlap with those of POTS. Cases have been reported of a clear connection between MCAS, POTS, and Ehlers-Danlos hypermobility type, and researchers are proposing a triad of MCAS, POTS, and Ehlers-Danlos Syndrome as a new disease cluster. This idea remains controversial.

One person wrote to us: “(I have) hEDS, POTS, Dysautonomia, MCAS, fibromyalgia, CFS, IBS, migraines, allergies/food intolerances, exercise intolerance, light/noise/smell/chemical sensitivity, balance/gait problems, neuropathy. . . constant neck pain and headaches.” The grouping of MCAS, POTS, and Ehlers-Danlos Syndrome into a cluster may have not been controversial to them.

In 2018 French doctors (6) reported on “the history of a 15-year old patient with a hypermobile Ehlers-Danlos syndrome (hEDS) (his mother, his two brothers, and his sister have the same phenotype as him). He suffers mainly from a severe mast cell activation syndrome (MCAS) with an overreaction of the skin to any kind of contact (water of the shower, clothes, bed sheets) but he has also fatigue, headaches, and rash.” In this paper, they introduced the term “MASED” to this MCAS, associated, linked, or entangled to hEDS.”

In June 2020, researchers at Florida Atlantic University (7) questioned this association outright. They wrote: “In recent years, an association between hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS), and postural orthostatic tachycardia syndrome (POTS) has garnered attention and patients are increasingly presenting with this triad. However, a real relationship between these entities is unclear due to a lack of scientific validity. . . The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.”

To advance this understanding, the researchers conducted an extensive review of the published medical literature. Their observations are recorded here: “MCAS is a poorly defined clinical entity, and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS but might be for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear. An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. . . current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. . . ”

In December 2021 Dr. Lawrence B. Afrin wrote in the American Journal of Medical Genetics. Part C, Seminars in medical genetics (8) “Although hEDS is seen in only a minority of MCAS cases, limited studies have identified an association between hEDS and MCAS, fueling speculation that certain variants of MCAS may drive hEDS. No laboratory studies probing cellular or molecular linkages between hEDS and MCAS have been conducted yet, and research efforts to identify the genetic roots of hEDS should also consider those of MCAS.”

Above I described the possibility that cervical spine instability may provide neurological answers to neck structural issues in this triad of problems. What the researchers here suggest is that genetic, molecular, or cellular explanations, or more simply, a specific neurodegenerative or autoimmune disease are at the root of the problems. We tend to agree.

The difficulty in diagnosis Mast Cell Activation Syndrome –  Idiopathic mast cell activation syndrome

A January 2022 case study presented by Dutch physicians wrote (9): “Idiopathic (sudden development from an unknown cause) mast cell activation syndrome (MCAS) is one of the causes for recurrent complaints. The diagnosis is sometimes delayed but also often made incorrectly.

Case: (A) patient presented with recurrent attacks of itching, redness of the skin, diarrhea, and near collapse. During an attack, his serum tryptase level rose significantly. We could not identify an underlying trigger. A diagnosis of idiopathic mast cell activation syndrome was made. He was successfully treated with a combination of H1 (blocking the production of histamine) and H2 blockade (stopping the production of stomach acids). Conclusion: MCAS is characterized by recurrent complaints. To make the diagnosis a significant rise in mast cell mediators (serum tryptase) is required. Given the diversity of symptoms, many patients with somatically unexplained symptoms are wrongfully believed to be suffering from MCAS.

Somatically unexplained symptoms

Somatically unexplained symptoms are sometimes generally classified into two groups – “we don’t know” or “It’s all in their head – psychiatric problems are suspected.” Yet people tell us of multiple skin biopsies, extensive dermatologists, immunologists, allergist visits, and extensive steroids. Some tell us that their vagus nerve has been damaged by infection or other means and MCAS, insomnia, anxiety, sensitivity to cold, ear fullness, and digestive problems. Some will have more extensive testing and tell us about their diagnosis of POTS, Dysautonomia, and hypermobile Ehlers-Danlos Syndrome.

Inflammatory bowel disease and irritable bowel syndrome

Above we saw that people suffer from inflammatory bowel disease and MCAS. A May 2021 study in the journal Frontiers in Pharmacology (10) wrote:

“Inflammatory bowel disease, irritable bowel syndrome, and severe central nervous system injury (of which the vagus nerve plays a dominant role) can lead to intestinal mucosal barrier damage, which can cause endotoxin/enterobacteria translocation (movement, or better thought of as escaping to other parts of the body) to induce infection and is closely related to the progression of metabolic diseases, cardiovascular and cerebrovascular diseases, tumors and other diseases.”

The researchers add that repairing the intestinal barrier represents a potential therapeutic target for many diseases. Repair means addressing the dysfunction of enteral afferent nerves, efferent nerves, and the intrinsic enteric nervous system that play key roles in regulating intestinal physiological homeostasis and coping with acute stress. Furthermore, innervation actively regulates immunity and induces inherent and adaptive immune responses through complex processes, such as secreting neurotransmitters or hormones and regulating their corresponding receptors.

The parasympathetic vagal nerve has been put forward as an integral part of an immune regulation network

A 2013 paper in the journal International Scholarly Research Network Gastroenterology from Dr. Wouter J de Jonge describes the role of the vagus nerve in the immune system. (11)

“The gut immune system shares many mediators and receptors with the autonomic nervous system. Good examples thereof are the parasympathetic (vagal) and sympathetic neurotransmitters. . . Earlier and more recent studies in neuroscience and immunology have indicated the anatomical and cellular basis for bidirectional interactions between the nervous and immune systems.

Sympathetic immune modulation (Simply the workings of the immune system in the “fight or flight response) is well described . . . (more recently) the parasympathetic vagal nerve has been put forward as an integral part of an immune regulation network via its release of Ach, a system coined “the cholinergic anti-inflammatory reflex.” (This is part of the nervous system that helps control and regulate inflammation)

A prototypical example is an inflammatory reflex, comprised of an afferent arm that senses inflammation and an efferent arm: the cholinergic anti-inflammatory pathway, that inhibits innate immune responses.”

The last sentence represents the yin and yang concept of the central nervous system’s turning on and turning off inflammation.

One of the body’s more important immune modulators and neurotransmitters, histamine has wide-ranging effects.

Histamines are chemicals produced by the immune system to get rid of allergens, toxins, or substances that cause an immune response or allergic reaction. Itching a rash is a histamine response, sneezing is a histamine response. However, when your body overreacts to this stimulus, an antihistamine is typically called for to calm down the immune response symptoms. When increased levels of histamines become unmanageable histamine-induced illnesses can be caused, which include histamine intolerance, mast cell activation syndrome (MCAS), and even IgE-mediated serious allergic diseases. During activation, the mast cells release histamine. Hence the name mast cell activation syndrome (MCAS).

  • Blood clots: Blood clots or Deep vein thrombosis. Research has demonstrated that immune cells and inflammatory processes are involved in Deep vein thrombosis.
  • Elevated Heart Rate
  • Joint swelling and inflammation
  • Adrenaline release
  • Gastric acid secretion
  • Blood vessel dilation
  • Increased capillary permeability (causes of swelling and edema)
  • Increased mucus secretion and bronchoconstriction.

Above I wrote that cervicovagopthy or vagus nerve disorder brought on by cervical spine instability, has wide-ranging negative effects on mucosal barriers in the intestines and lungs, producing a large number of inflammatory mediators, including histamine.  Increased levels of histamines cause histamine-induced illnesses, which include histamine intolerance, mast cell activation syndrome (MCAS), and even IgE-mediated serious allergic diseases. During activation, the mast cells release histamine.

Increased levels of histamines cause histamine-induced illnesses, which include histamine intolerance, mast cell activation syndrome (MCAS), and even IgE-mediated serious allergic diseases. During activation, the mast cells release histamine.

Conventional care treatments

In November 2022, doctors at Washington University School of Medicine and the University Hospital Bonn Germany published their findings (12) on the use of hydroxyurea in mast cell activation syndrome. The researchers here looked to determine the effectiveness and possible side effects of hydroxyurea in patients who had not responded to other conventional care treatments. Hydroxyurea is an antineoplastic drug. These are medications used to treat cancer and are considered chemotherapy treatments.

Patients studied:

  • Twenty-six patients were diagnosed with MCAS and prescribed hydroxyurea. Patients included 22 females, average age of 42.4 years.
  • Patients had complaints of bone pain, abdominal pain, diarrhea, bloating, and nausea.
  • Dysautonomia was present in 60%.
  • An average of 10.6  medications were used prior to adding hydroxyurea to various concomitant medications. The average dose of HU was 634 mg.

Follow up:

  • In 20 patients who continued therapy for more than 2 months, there was a statistically significant reduction in bone pain, abdominal pain, diarrhea, bloating, and nausea.
  • Fourteen patients noted prolonged success with therapy.
  • Six patients stopped hydroxyurea within 6 weeks because of side effects.

Cervical spine instability, the vagus nerve, and histamine

Cervical spine instability caused by damaged cervical ligaments’ inability to hold the “wandering” vertebrae in place can be the structural etiological basis or co-morbidity in all these illnesses through its effects on the vagus nerves. While histamine intolerance may need an adjustment of histamine-containing foods in the diet, MCAS, and IgE-mediated allergic diseases necessitate more aggressive treatments.

When the vagal nerve sensory afferents are dysfunctional, (the vagus nerve is off) the important body sensors for homeostasis (system balance) are off. Cases of cervical instability with vagal nerve irritation may increase mast cell histamine content; the coincident dysfunction of the vagal tone’s effect on the cholinergic anti-inflammatory pathway (the immune system’s response to stimuli or injury) can disrupt parasympathetic-mast cell functional units (those cells that regulate mast cells – immune cells from “runaway” inflammation, believed to exist in skin, lung, and intestine, leading to potential ease of mast cell activation through neurogenic inflammation (cell signaling – messages to the immune cells to calm down or get excited). Simply, negative effects on mucosal barriers in the intestines and the lungs, produce a large number of inflammatory mediators including histamine.

The GI tract harbors the largest population of mast cells in the body and is thus the main reservoir of the body’s histamine. The mast cells’ job is to maintain intestinal permeability and make sure that no microorganisms or antigens enter the body. (A dysfunction of this system can lead to Leaky Gut Syndrome and inflammation of the intestines.) The neurological control over mast cells and their various digestive functions is via the vagal influences on the enteric nervous system.

Elevated histamine levels in the body occur when there is an increase in intestinal permeability (regardless of the cause), including that from synthetic foods (industrial food additives, chemicals in food, genetically modified foods), Ehlers-Danlos syndrome (EDS), and cervical spine instability induced cervicovagopathy.

In fact, tight junction dysfunction is common in multiple autoimmune diseases and the central part tight junctions play in autoimmune diseases’ pathogenesis has been extensively described.

  • Tight junctions are intercellular adhesion complexes (these are facilitators or mediators that allow cells to talk to each other) in epithelial and endothelia (the outer covering of organs and inner surfaces) that control intestinal permeability.

It is hypothesized that commonly used industrial food additives abrogate human epithelial barrier function, thus increasing intestinal permeability through the opened tight junction, resulting in the entry of foreign immunogenic antigens and activation of the autoimmune cascade. The effect of synthetic foods, including industrial food additives, chemicals in foods, and genetically modified food has been shown to increase intestinal tight junction permeability.

Histamine intolerance results from excessive histamine and a decreased ability to absorb or neutralize it.  Elevated levels of histamine give symptoms that mimic allergic reactions, and these include diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritis, flushing, and skin lesions. A true allergy is tied to IgE-mediated histamine release, which is to be differentiated from histamine intolerance. The latter is associated with some forms of urticaria, eczema, asthma, food sensitivity, migraines, and chronic GI and neurological ailments, including inflammatory and irritable bowel syndromes.

Histamine is synthesized by mast cells, basophils, platelets, histaminergic neurons, and enterochromaffin cells, where it is stored intracellularly and released upon stimulation. It can be found basically everywhere in the body, including the spinal cord and brain. Histamine causes smooth muscle cell contraction, vasodilation, increased vascular permeability and mucus secretion, tachycardia, alterations of blood pressure, and arrhythmias, while it stimulates gastric secretion and nociceptive nerve fibers. Histamine increases secretions such as hydrochloric acid in the stomach and is vital to protecting the lungs and gastrointestinal tract from infections. When histamine levels are high, increased secretions in the lungs, therefore, cause coughing, phlegm production, sneezing, and diarrhea occur in the digestive tract in an attempt by the body to rid itself of an infectious agent or toxin.

The level of histamine correlates with the symptoms produced.

What we see in this table is the measured histamine effects according to plasma histamine concentration. (13)

Histamine (ng/ml Nanograms per milliliter) of:

  • 1 – 2 Increased gastric acid secretion and heart rate
  • 3 – 5 Tachycardia, headache, flush, urticaria, pruritus
  • 6 – 8 Increased arterial pressure
  • 7 – 12 Bronchospasm
  • over 100 Cardiac arrest

The reservoir of histamine in the body originates in the gut and comes from the breakdown of food that is ingested or the microbiota-generated histamine. Histamine intolerance is akin to lactose intolerance in that the body is missing a key enzyme to digest a food substance. In histamine intolerance, it is DAO in the digestive tract, a deficiency of which leads to elevated histamine levels in the body. DAO is synthesized by the intestinal villi (enterocytes) and is constantly released from the intestinal mucosa into the gut, as well as the blood circulation, during eating and digestion.

The diagnosis of histamine intolerance can be made by noting elevated levels of histamine in the blood and low levels of DAO activity.  The most common symptoms of histamine intolerance are digestive and include bloating, postprandial fullness, diarrhea, and abdominal pain. When placed on a histamine-reduced diet, an improvement in symptoms occurs. DAO activity and a lowering of histamine levels support a successful diagnosis.

This is summed up in an April 2021 paper in the journal Nutrients on Histamine Intolerance. (14)

“Histamine intolerance is assumed to be due to a deficiency of the gastrointestinal enzyme diamine oxidase (DAO) and, therefore, the food component histamine not being degraded and/or absorbed properly within the GI tract. Involvement of the GI mucosa in various disorders and diseases, several with unknown origin, and the effects of some medications seem to reduce gastrointestinal DAO activity. Histamine intolerance causes variable, functional, nonspecific, non-allergic GI and extra-intestinal complaints. Usually, evaluation for Histamine intolerance is not included in differential diagnoses of patients with unexplained, functional GI complaints or (other) disorders and diseases. The clinical diagnosis of Histamine intolerance is challenging, and the thorough (patient account, history, and diary) of all Histamine intolerance-linked complaints, using a standardized questionnaire, is the mainstay of Histamine intolerance diagnosis.”

With unknown origin – is it dysfunction in the nerves and immune cells’ ability to communicate that causes Mast Cell Activation Syndrome?

In the past decades, researchers have come to the opinion that immune cells and nerve cells talk to each other. An April 2019 study in the journal Neuroscience (15) offers a brief explanation

“Inflammation in the nervous system, termed “neuroinflammation,” has become increasingly recognized as being associated with neurodegenerative diseases. Early attention focused primarily on morphological changes in astrocytes (the glial cells (cells of the central nervous system) in the brain that are closely associated with neuronal synapses) and microglia glial cells that clean up dead brain cells; however, brain and central nervous system resident mast cells are now receiving attention as a result of being “first responders” to injury.

Mast cells also exert profound effects on their microenvironment and neighboring cells including behavior and/or activation of astrocytes, microglia, and neurons, which, in turn, are implicated in neuroinflammation, neurogenesis, and neurodegeneration. Mast cells also affect disruption/permeability of the blood-brain barrier enabling toxin and immune cell entry exacerbating an inflammatory microenvironment.”

What is being suggested is that the Mast cells are causing runaway neurological inflammation by exerting a disruptive influence (bad messages) on the central nervous system and brain and this is leading to neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease for example.

The next step is the parasympathetic nervous system – the domain of the vagus nerve

A 2015 paper in the Journal of Methods in Molecular Biology (16) gives us this connection between the parasympathetic nervous system and regulating immune responses.

“Often considered as the archetype of neuroimmune communication, much of our understanding of the bidirectional relationship between the nervous and immune systems has come from the study of mast cell-nerve interaction. Mast cells play a role in resistance to infection and are extensively involved in inflammation and subsequent tissue repair. Thus, the relationship between mast cells and neurons enables the involvement of peripheral and central nervous systems in the regulation of host defense mechanisms and inflammation. Recently, with the identification of the cholinergic anti-inflammatory pathway, there has been increased interest in the role of the parasympathetic nervous system in regulating immune responses.”

Vagus nerve – parasympathetic dysfunction

The cause of vagal or parasympathetic dysfunction has many symptoms including a depressed or overactive immune system and systemic inflammation. A cause of these symptoms that is often overlooked is a structural injury to the cervical spine.

Bad vagus signals cause chronic gastrointestinal distress by way of gastric mast cell

A March 2021 study in the Journal of Clinical Investigation (17) insight wrote: “Functional dyspepsia is associated with chronic gastrointestinal distress and with anxiety and depression.” What the researchers in this paper wanted to demonstrate was that aberrant gastric signals, transmitted by the vagus nerve, may alter key brain regions modulating affective and pain behavior. In animal research, these investigators found Functional dyspepsia is characterized by gastric hypersensitivity, depression-like behavior, and anxiety-like behavior and found that vagal activity – in response to gastric distention – was increased in the animals with Functional dyspepsia.

It was observed that Functional dyspepsia was associated with gastric mast cell (overactivation) increased expression of corticotrophin-releasing factor (peptide hormone that affects the stress response) and decreased brain-derived neurotrophic factor genes (peptides or proteins that support neuron growth) in the central amygdala (the area of the brain where emotional behavior resides). Subdiaphragmatic vagotomy (the removal of the vagus nerves in laboratory rats) reversed these changes and restored effective behavior to that of controls. In conclusion, vagal activity, partially driven by gastric mast cells, induces long-lasting changes in corticotrophin-releasing factor signaling in the amygdala that may be responsible for enhanced pain and enhanced anxiety- and depression-like behaviors.

Restoring vagus nerve function

In the above study what was being suggested was that the vagus nerve was sending bad signals into the digestive system causing dysfunction. The proof of this was that if you removed the vagus nerve portion that leads to the GI tract, you could stop functional dyspepsia in laboratory animals. Removing the vagus nerve is obviously not ideal in humans. However, removing the vagus nerve dysfunction is.

In a September 2019 paper in the journal Allergy (18), researchers noted the importance of the vagus nerve “as an important modulator of the intestinal immune system.” In this paper, the researchers wanted to know to what extent the vagus nerve impacts the inflammatory response to food allergy is still unclear.  To do this, the researchers removed the vagus nerve or used vagus nerve stimulation to increase its function, and then the mice were given a challenge that they were sensitive to. Then they looked for signs of food sensitivity in the mice including elevated mast cells.

What they found was vagus nerve stimulation resulted in a significant reduction of the different inflammatory parameters assessed. They said their results underscore the anti-inflammatory properties of the vagus nerve and the potential of neuro-immune interactions in the intestine.

In other words, if the vagus nerve is working correctly, anti-inflammatory and mast cell activation could be suppressed.

Skin rashes, eczema, psoriasis mast cells, and their interaction with nerve cells.

A September 2019 study in the Frontiers in Cellular Neuroscience (19) looked at the “intimate interaction between mast cells and sensory nerves.”

“The intimate interaction between mast cells and sensory nerves can be illustrated by the wheal and surrounding flare in an urticarial (welt) reaction in human skin. This reaction is typically associated with an intense itch at the reaction site. Upon activation, cutaneous mast cells release powerful mediators, such as histamine, tryptase, cytokines, and growth factors that can directly stimulate corresponding receptors on itch-mediating sensory nerves.  . . Even though mast cells are well recognized for their role in allergic skin wheeling and urticaria, increasing evidence supports the reciprocal function between mast cells and sensory nerves in neurogenic inflammation in chronic skin diseases, such as psoriasis and atopic dermatitis, which are often characterized by distressing itch, and exacerbated by psychological stress. Increased morphological contacts between mast cells and sensory nerves in the lesional skin in psoriasis and atopic dermatitis as well as experimental models in mice and rats support the essential role of mast cell-sensory nerve communication in consequent pruritus. “

Again we see that “mast cell-sensory nerve communication” is essential for regulating the immune response to skin disorders. Throughout this article, I focused on Mast Cell Activation Syndrome and its inflammatory response as culprits in the symptomology some people suffer from. As with many medical disorders, trying to find the source of the patient’s health challenges can be daunting, specifically in cases with a long list of symptoms and conditions related to a dysfunctional immune system and possible vagal involvement. Mast Cell Activation Syndrome response caused by cervical instability may be one possible explanation.

Mast Cell Activation Syndrome and Ehlers-Danlos Syndrome

Over the years we have seen many patients who among their long list of symptoms and ailments include Mast Cell Activation Syndrome. They also had neck pain. For many, their neck pain was seen as a manifestation of their illnesses, but rarely was it seen as the cause of their illnesses.

An April 2022 paper in the journal Immunologic Research (21) from the NYIT College of Osteopathic Medicine and the Icahn School of Medicine at Mount Sinai in New York says: “Evidence is still needed to determine the pathophysiology of hEDS; however, the association among these conditions and their prevalence in hEDS/hypermobile spectrum disorder may be explained through consideration of persistent chronic inflammation contributing to a disruption of the connective tissue. Aberrant mast cell activation has been shown to play a role in the disruption of connective tissue integrity, which affects multiple organ systems resulting in mast cell activation disorders (MCAD). The overlap of findings associated with MCAD and the immune-mediated and rheumatologic conditions in patients with hEDS/HSD may provide an explanation for the relationship among these conditions and the presence of chronic inflammatory processes in these patients.”

MCAS affects the skin, gastrointestinal, cardiovascular, respiratory, and neurological systems producing severe episodic symptoms including angioedema, flushing, nausea, vomiting, diarrhea, abdominal cramping, hypotensive syncope, tachycardia, wheezing, conjunctival injection, pruritus, nasal stuffiness which is typically controlled by medications that block the histamine or stabilize mast cells. Of interest is that MCAS is common in patients with EDS who have upper cervical instability but not in non-EDS patients with upper cervical instability, indicating that there is another component to the disease besides the instability. 

MCAS is primarily found in young hypermobile females, including those with EDS and POTS., Dysautonomia is 3-10 times more common in EDS, POTS, and allergic-type disorders than in the general population., Mast cells are in the connective tissues, near blood vessels, and in enteric mucosa, where they store and release histamine and other immune-modulating substances in response to antigens and other pathological stimuli associated with tissue injury, inflammation, and autoimmunity. Mast cells are critical for proper microbial defense, epithelial integrity, immune regulation, and proper neurological activity of vagal innervated organs and tissues.

EDS patients are at risk for MCAS through many mechanisms including loose connective tissue in the GI tract and blood, taking medications that raise histamine levels, and upper cervical instability-induced vagus dysfunction. While treatments directed at structural neck issues are helpful for histamine-induced symptoms, they must be combined with dietary changes to reduce synthetic and histamine-containing foods, as well as eliminate drugs that raise histamine levels. These include antibiotics, diuretics, H2 receptor antagonists, antidepressants, analgesics, muscle relaxants, and antihypertensive medications

While most conditions discussed in this article relate to low vagal tone, vagal nerve stimulation directly increases not only histamine but serotonin release into the plasma. It also increases respiratory mast cell secretion and exaggerated constriction of bronchioles to antigen. Histamine levels in the brainstem have a stimulatory effect on the dorsal vagal motor nucleus increasing vagal tone to the abdominal organ and lung mucosa to secrete and the smooth muscles to contract. 

Neuropsychiatric disorders

An October 2023 paper in the Journal of Personalized Medicine (20) suggested that: “In patients with neuropsychiatric disorders refractory (not responding) to standard therapy who have systemic symptoms, underlying MCAS should be considered in the differential diagnosis.” The researchers led by Leonard B Weinstock, MD, a noted researcher in MCAS and SIBO writes: “MCAS  syndrome is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others. Although MCAS is common, it is rarely recognized, and thus, patients can suffer for decades.”

The goal of the paper was to present the cases of eight patients with significant neuropsychiatric disorders who were not responding to standard medical treatments as shown [by a positive response to focused MCAS treatments. In addition to MCAS:

  • Five patients had depression.
  • Five had generalized anxiety disorder.
  • Four had panic disorder.

Other psychiatric disorders included attention-deficit hyperactivity disorder, obsessive-compulsive disorder, phobias, and bipolar disorder. All eight patients were subsequently diagnosed with mast cell activation syndrome; six had comorbid autonomic disorders, the most common being postural orthostatic tachycardia syndrome; and four had hypermobile Ehlers-Danlos syndrome.

Treatments that these patients responded well included

“Step 1 therapy is a combination mast-cell-directed oral therapy using various over-the-counter histamine 1 receptor antagonists (variety of brands, twice daily), histamine 2 receptor antagonist (famotidine 20 mg twice daily), quercetin (1000 mg twice a day), sustained release vitamin C (1000 mg daily), and vitamin D (2000–5000 mg daily depending on vitamin D level).”

What are we seeing in this image?

A Digital Motion X-ray or DMX is a tool we use to help understand a patient’s neck instability and how we may be able to help the patients with our treatments. In the illustration below a patient who suffered from upper cervical instability demonstrated hypermobility of the C1-C2.

A Digital Motion X-Ray or DMX is a tool we use to help understand a patient' neck instability and how we may be able to help the patients with our treatments. In the illustration below a patient who suffered from upper cervical instability demonstrated hypermobility of the C1-C2. This hypermobility can result in common symptoms of neck pain, headaches, dizziness, vertigo, tinnitus, concentration difficulties, anxiety and other symptoms common in TMJ/TMD patients.

Repairing the ligaments and curve for a long-term fix

The goal of our treatment is to repair and strengthen the cervical ligaments and get your head back in alignment with the shoulders in a normal posture.

What are we seeing in this image?

In this illustration, we see the before and after of neck curve corrections. Ligament laxity or looseness or damage, whether the cause is from trauma or genetic as in cases of Ehlers-Danlos syndrome, ultimately causes a kyphotic force on the cervical spine, stretching the posterior ligament complex of the neck. As can be seen in the x-rays of this image, patients with a whiplash injury, Joint Hypermobility Syndrome, and Ehlers-Danlos syndrome can have their cervical curve restored with Prolotherapy Injections and the use of head and chest weights.

In this illustration we see the before an after of neck curve corrections. Ligament laxity or looseness or damage, whether the cause is from trauma, genetic as in cases of Ehlers-Danlos syndrome, ultimately causes a kyphotic force on the cervical spine, stretching the posterior ligament complex of the neck. As can be seen in the x-rays of this image, patients with a whiplash injury, Joint Hypermobility Syndrome, and Ehlers-Danlos syndrome can have their cervical curve restored with Prolotherapy Injections and the use of head and chest weights, documented below.

In this video, a demonstration of treatment is given

Prolotherapy is referred to as a regenerative injection technique (RIT) because it is based on the premise that the regenerative healing process can rebuild and repair damaged soft tissue structures. It is a simple injection treatment that addresses very complex issues.

This video jumps to 1:05 where the actual treatment begins.

This patient is having C1-C2 areas treated. Ross Hauser, MD, is giving the injections.

Summary and contact us. Can we help you? How do I know if I’m a good candidate?

Cervical instability is explained throughout this website: I would like to direct you to these articles to continue your research:

We hope you found this article informative. Just like you, we want to make sure you are a good fit for our clinic prior to accepting your case. While our mission is to help as many people with chronic pain as we can, sadly, we cannot accept all cases. We have a multi-step process so our team can really get to know you and your case to ensure that it sounds like you are a good fit for the unique testing and treatments that we offer here.

Please visit the Hauser Neck Center Patient Candidate Form

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This article was updated February 4, 2023

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