Mast Cells: A Possible Link Between Migraine, POTS, and Ehlers-Danlos Syndrome

Migraine is rarely a simple, isolated condition. Many people living with chronic or treatment-resistant migraine experience a wide range of additional symptoms—such as dizziness, fatigue, flushing, gastrointestinal issues, and joint pain—that extend far beyond the head. Increasingly, researchers and clinicians are exploring whether these symptoms may be connected through overlapping medical conditions, including mast cell activation syndrome (MCAS), postural orthostatic tachycardia syndrome (POTS), and Ehlers-Danlos syndrome (EDS).

In this Migraine World Summit session, neurologist Dr. Jennifer Robblee of the Barrow Neurological Institute discusses how these conditions may intersect with migraine and what current science suggests about their possible relationship.

While research is still emerging, understanding these connections may help explain why some people experience particularly complex or difficult-to-treat migraine patterns.

Understanding Mast Cells and Their Role in the Body

Mast cells are part of the body’s immune and allergic response system. They are found throughout tissues, particularly near blood vessels and nerve endings.

When mast cells are activated, they release a variety of chemical substances—including histamine and inflammatory molecules—that help coordinate immune responses. This process is known as mast cell degranulation.

During migraine attacks, a complex series of biological events occurs in the tissues surrounding the brain. These events include changes in blood vessels, activation of pain-sensing nerves (nociceptors), and the release of inflammatory chemicals. Mast cells appear to play a role in this process by releasing substances that can influence pain pathways and vascular changes.

Although mast cells are not considered the primary cause of migraine, they appear to be one component of the broader biological cascade involved in migraine attacks.

What Is Mast Cell Activation Syndrome?

Mast cell activation syndrome (MCAS) is a condition in which mast cells release excessive amounts of chemical mediators, leading to recurring symptoms across multiple body systems.

In 2022, expert consensus criteria were proposed to help guide the diagnosis of MCAS. The criteria include three major components:

1. Symptoms affecting multiple organ systems

People with MCAS typically experience recurrent episodes that involve at least two different body systems. Symptoms may include:

Skin symptoms

• Flushing

• Hives (urticaria)

• Swelling such as angioedema

Gastrointestinal symptoms

• Abdominal pain

• Bloating

• Nausea or vomiting

• Diarrhea

Respiratory symptoms

• Wheezing

• Chest tightness

• Nasal congestion or itchy eyes

Cardiovascular symptoms

• Low blood pressure

• Rapid heart rate

• Chest discomfort

Neurological symptoms

• Brain fog

• Headache

Systemic symptoms

• Fatigue

• Severe allergic reactions such as anaphylaxis

  
  

2. Improvement with mast cell–targeted treatments

Another key part of diagnosis is improvement in symptoms when patients receive treatments that affect mast cell activity. These may include:

• Antihistamines

• Leukotriene inhibitors

• Mast cell stabilizers

• Prostaglandin blockers

• Biologic medications such as omalizumab

  
  

3. Laboratory evidence of mast cell activation

Blood or urine testing may show elevated levels of mast cell mediators during symptomatic episodes. One of the most commonly measured markers is serum tryptase, though other substances may also be evaluated.

Why Mast Cell Disorders Can Be Difficult to Diagnose

Diagnosing MCAS can be challenging for several reasons.

Many of the symptoms associated with mast cell activation—such as nausea, vomiting, fatigue, nasal congestion, and headache—are also common symptoms of migraine itself. This overlap can make it difficult to determine whether mast cell activation is contributing to migraine symptoms or simply occurring alongside them.

In addition, there are multiple types of mast cell disorders, including:

• Primary mast cell disease (such as mastocytosis)

• Secondary mast cell activation linked to allergies or immune disorders

• Genetic forms related to elevated tryptase levels

• Combined types involving multiple mechanisms

• Idiopathic MCAS, where no clear underlying cause can be identified

Because of these variations and the complexity of testing, many cases may go undiagnosed, while others may be misdiagnosed.

The “Autonomic Trifecta”: MCAS, POTS, and Ehlers-Danlos Syndrome

Many clinicians have observed that mast cell activation syndrome often appears alongside two other conditions:

• Postural orthostatic tachycardia syndrome (POTS)

• Ehlers-Danlos syndrome (EDS)

Together, these conditions are sometimes informally referred to as the “autonomic trifecta.” 

Postural Orthostatic Tachycardia Syndrome (POTS)

POTS is a disorder of the autonomic nervous system, the part of the nervous system responsible for regulating involuntary bodily functions.

The condition is typically defined by a heart rate increase of at least 30 beats per minute within 10 minutes of standing. Symptoms may include:

• Rapid heartbeat

• Lightheadedness or dizziness when upright

• Fatigue

• Brain fog

• Exercise intolerance

POTS can significantly affect daily functioning and is increasingly recognized in patients with chronic migraine.

Ehlers-Danlos Syndrome (EDS)

Ehlers-Danlos syndrome is a group of genetic connective tissue disorders characterized by abnormalities in collagen.

One of the most common forms associated with migraine is hypermobile Ehlers-Danlos syndrome, which is diagnosed based on clinical criteria rather than a specific genetic test.

Symptoms may include:

• Joint hypermobility

• Joint instability

• Chronic pain

• Soft or stretchy skin

• Increased risk of ligament injuries

In some individuals, connective tissue instability may also affect structures in the neck or spine, potentially contributing to headache disorders.

How These Conditions May Interact with Migraine

Although the exact mechanisms are still being studied, researchers suspect that these conditions may interact through immune and autonomic nervous system pathways.

For example:

• Mast cell activation can increase inflammatory signaling.

• Autonomic dysfunction in POTS can alter blood flow and heart rate regulation.

• Connective tissue abnormalities in EDS may influence structural stability in the neck and spine.

When these processes occur together, they may contribute to a complex symptom pattern that includes migraine attacks.

Clinicians often observe that when one condition flares, the others may worsen as well, making management particularly challenging.

Challenges in Treatment and Care

One of the major challenges in managing these overlapping conditions is that no single specialty fully “owns” them.

Patients may need care from multiple specialists, including:

• Neurologists or headache specialists

• Cardiologists or autonomic specialists

• Allergists or immunologists

• Gastroenterologists

• Pain specialists

• Physical therapists familiar with hypermobility disorders

Because these conditions cross multiple medical disciplines, coordination of care can be difficult.

In addition, scientific evidence guiding treatment strategies remains limited. Much of the current approach is based on clinical experience and observational reports rather than large clinical trials.

Treatment Approaches That May Be Considered

While no universal treatment strategy exists, management often focuses on addressing each condition individually.

For mast cell activation syndrome, treatments may include:

• Antihistamines targeting H1 and H2 receptors

• Mast cell stabilizing medications such as cromolyn or ketotifen

• Leukotriene inhibitors

• Biologic therapies in selected cases

Some patients also explore dietary approaches, such as low-histamine diets, although strong scientific evidence for these strategies is still limited.

For POTS, management may involve:

• Hydration and increased salt intake

• Medications to regulate heart rate or blood pressure

• Lifestyle adjustments and exercise programs

For Ehlers-Danlos syndrome, physical therapy designed for hypermobility is often a central part of treatment.

Why Accurate Diagnosis Matters

Because the symptoms of these conditions overlap with migraine, obtaining an accurate diagnosis is essential.

Some patients may receive labels such as MCAS, POTS, or EDS without undergoing the appropriate diagnostic testing. This can make treatment more difficult if the underlying condition is not clearly identified.

Proper evaluation may involve:

• Tilt-table testing for POTS

• Blood or urine testing for mast cell mediators

• Clinical evaluation of joint hypermobility using scoring systems such as the Beighton score

Working with specialists familiar with these conditions can help ensure that diagnoses are based on established criteria.

A Field Still in Its Early Stages

Despite growing awareness, research into the connections between migraine, mast cell disorders, and autonomic dysfunction remains limited.

Scientific databases currently contain very few studies directly examining migraine and mast cell activation syndrome, highlighting the need for further investigation.

Important unanswered questions include:

• How common these overlapping conditions are among people with migraine

• Whether treating mast cell activation improves migraine outcomes

• How autonomic dysfunction contributes to migraine severity

• Which patients may benefit most from targeted therapies

Registries and research studies are beginning to explore these questions, and participation in such initiatives may help accelerate progress.

What This Means for People Living with Migraine

For individuals experiencing migraine alongside symptoms such as unexplained dizziness, severe fatigue, allergic-type reactions, or joint instability, these overlapping conditions may represent an important part of the puzzle.

While current knowledge is still evolving, increasing awareness among clinicians and patients may help lead to earlier recognition and better coordinated care.

Most importantly, ongoing research continues to uncover new insights into the complex biological networks that influence migraine—offering hope that future treatments will address not just the headache itself, but the broader systems that may contribute to it.