Mechanobiology: The Mechanical Basis of Chronic Illnesses like ME/CFS, EDS, MCAS, and POTS

Chronic illnesses such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Ehlers-Danlos Syndrome (EDS), particularly the hypermobile type (hEDS), present a complex picture of overlapping symptoms and comorbidities. Recent research highlights the significant role of mechanobiology—the study of how mechanical changes in tissues influence biological processes—in these disorders. Understanding how connective tissue abnormalities contribute to symptoms like Intracranial Hypertension (IH), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS) opens new pathways for diagnosis and treatment.

Connective Tissue Pathology in EDS and ME/CFS

One of the defining features of Ehlers-Danlos Syndrome (EDS) is the abnormal structure of collagen, the main protein responsible for the strength and elasticity of connective tissues. Both the hypermobile type (hEDS) and the classical type (cEDS) of EDS exhibit defects in collagen that result in fragile, stretchable skin and unstable joints. These structural issues lead to a significant reduction in tissue stiffness, which plays a critical role in the development of comorbid conditions.

In patients with hEDS, the collagen fibrils, which provide structural support, are often larger and more irregularly shaped than normal. This abnormal collagen architecture leads to reduced stiffness in tissues such as skin, tendons, and ligaments​. The decreased tissue strength is a hallmark of EDS, explaining many of the physical symptoms, including hypermobility, frequent joint dislocations, and skin that stretches and tears more easily than it should.

The mechanical properties of connective tissues are altered in EDS, with softer and more extensible tissues making it difficult for the body to withstand everyday mechanical stress. This increased vulnerability underpins many of the symptoms seen in EDS patients and contributes to the development of associated conditions like ME/CFS​. In ME/CFS, abnormal tissue mechanics may also play a role, as the same types of connective tissue defects observed in EDS can lead to problems such as chronic fatigue, cognitive dysfunction, and widespread pain.

Intracranial Hypertension and Craniocervical Instability in ME/CFS and EDS

Intracranial Hypertension (IH) is one of the most common symptoms seen in patients with ME/CFS and hypermobility disorders like EDS. Studies show that signs of IH, such as increased pressure within the skull, are highly prevalent in these patients​. This pressure buildup can cause debilitating symptoms, including headaches, cognitive difficulties (commonly referred to as "brain fog"), and severe fatigue, all of which are frequently observed in both ME/CFS and hEDS.

Recent research using MRI imaging has revealed that many ME/CFS patients also have structural issues in the craniocervical region, such as cerebellar tonsillar ectopia, where parts of the brain press down into the spinal canal​. These craniocervical obstructions can cause mechanical compression of the brainstem and spinal cord, disrupting normal cerebrospinal fluid (CSF) flow and contributing to the symptoms of both ME/CFS and hEDS.

The mechanical instability seen in the neck and upper spine of these patients, often referred to as craniocervical instability (CCI), further exacerbates IH. This instability occurs when the connective tissues in the neck and spine are too weak to support the head properly, allowing excessive movement that puts pressure on the brainstem. As a result, patients experience symptoms like dizziness, orthostatic intolerance (difficulty standing for long periods), and cognitive dysfunction​.

The combination of weak connective tissue and increased intracranial pressure offers a mechanobiological explanation for many of the overlapping symptoms seen in ME/CFS and hEDS. By understanding the mechanical disruptions caused by these tissue abnormalities, researchers hope to develop more effective treatments aimed at stabilizing the craniocervical junction and relieving the pressure within the skull.

Mast Cell Activation Syndrome (MCAS) and Mechanosensitivity in EDS

Mast Cell Activation Syndrome (MCAS) is a common comorbidity in patients with hEDS. Mast cells, which are part of the immune system, are responsible for releasing chemicals like histamine in response to allergens. However, in patients with MCAS, these cells are overly sensitive and can be triggered by mechanical stimuli, leading to symptoms such as flushing, abdominal pain, and fatigue.

In hEDS, the reduced stiffness of connective tissue means that mechanical stress—such as pressure, vibration, or even normal movement—can trigger mast cells to release their contents (a process known as degranulation) much more easily than in healthy individuals​. This mechanosensitivity of mast cells is a key reason why patients with hEDS are so prone to allergic-like reactions without a clear environmental cause.

Mechanobiological research suggests that proteins like ADGRE2, which are found on the surface of mast cells, play a crucial role in detecting mechanical vibrations. When triggered by mechanical stress, these proteins can cause the mast cells to degranulate, releasing histamine and other substances that lead to the allergic reactions characteristic of MCAS​.

Vimentin, an intracellular protein that helps maintain cell stiffness, also plays a role in regulating mast cell activation. In patients with hEDS, the irregular collagen network may reduce the tension and stability within mast cells, making it easier for them to release their contents in response to even minor mechanical stimuli​. This explains why mechanical triggers, rather than traditional allergens, are often responsible for MCAS symptoms in hEDS patients.

Postural Orthostatic Tachycardia Syndrome (POTS) and Autonomic Dysfunction in hEDS

Postural Orthostatic Tachycardia Syndrome (POTS) is another condition commonly seen in patients with hEDS. POTS is a form of autonomic dysfunction in which patients experience an abnormal increase in heart rate when moving from a lying down to a standing position. This can cause symptoms such as dizziness, fainting, and rapid heartbeat, which are particularly debilitating for hEDS patients.

The mechanical instability of the cervical spine and craniocervical junction seen in hEDS can contribute to the development of POTS​. When the connective tissues in the neck are too weak to support the head properly, it can cause abnormal pressure on the autonomic nervous system, disrupting the regulation of heart rate and blood pressure. This results in the characteristic symptoms of POTS.

In addition to the mechanical factors, the weakened structure of connective tissues in hEDS can impair blood flow and pressure regulation, further exacerbating the autonomic dysfunction seen in these patients​. This combination of mechanical instability and disrupted blood flow is a key contributor to the high prevalence of POTS in hEDS patients.

Potential Treatment Implications

Understanding the mechanical factors behind ME/CFS, hEDS, and their associated comorbidities opens the door to new treatment approaches. For conditions like craniocervical instability and intracranial hypertension, surgical interventions such as spinal fusion may be necessary to stabilize the spine and relieve pressure on the brainstem​. However, not all patients require surgery, and many can benefit from non-surgical treatments aimed at reducing mechanical stress on the body.

Physical therapy (PT) plays a significant role in managing both musculoskeletal and neurological symptoms in hEDS and ME/CFS. PT can improve joint stability, muscle strength, and body mechanics, which helps to minimize the mechanical triggers for conditions like POTS, MCAS, and upper cervical instability (UCI). By addressing these underlying mechanical instabilities, physical therapy can reduce the severity of symptoms and improve the quality of life for patients​​.

Physical Therapy for Upper Cervical Instability (UCI)

Physical therapy is especially important for patients with upper cervical instability (UCI), a common issue in those with hEDS. Patients with musculoskeletal UCI typically respond well to interventions like posture correction, body mechanics education, and motor control exercises, which help to stabilize the cervical spine and reduce symptoms such as neck pain, headaches, and dizziness.

However, neurological UCI can present additional challenges. Patients with high irritability or sensitivity may not tolerate much neck movement or manual therapy, requiring a cautious approach. In these cases, therapists are advised to begin with gentle interventions, such as basic body alignment, breathing exercises, and pain management techniques like diaphragmatic breathing and posture education. As the patient’s irritability decreases, the therapist can progress to more active interventions​.

According to Russek (2023), it is important for therapists to tailor their interventions based on the patient's specific symptoms and level of irritability. For example, some patients with highly irritable UCI may only tolerate minimal neck motion, and manual therapy should be avoided until the patient is ready for more direct interventions. Russek emphasizes starting with gentle seated posture correction before progressing to exercises that involve more neck and upper body movement​.

Physical Therapy for POTS and Autonomic Dysfunction

For patients with POTS, where autonomic dysfunction is a key issue, physical therapy should focus on recumbent aerobic exercises, such as using a recumbent bike or pedal exerciser. These exercises avoid exacerbating orthostatic symptoms, which can be triggered by standing activities. Aerobic conditioning, combined with gentle strengthening exercises, can help improve autonomic regulation and reduce POTS-related symptoms​.

Overall, the key to managing these complex patients lies in a multidisciplinary approach that combines physical therapy, medical care, and, where necessary, surgical interventions. While surgery may be required for conditions like craniocervical instability, many patients will benefit from conservative treatments aimed at improving stability, posture, and neuromuscular control​.

Medications for MCAS and Symptom Management

In addition to physical therapy, medications aimed at stabilizing mast cells and reducing histamine release can help manage the symptoms of MCAS. Antihistamines, mast cell stabilizers, and other medications provide relief from allergic-like reactions. However, addressing the mechanical factors that trigger mast cell activation is also crucial for long-term symptom management. Stabilizing the body's mechanics, particularly in areas prone to instability, helps reduce the frequency and severity of MCAS flares​.

By combining physical therapy to address mechanical instability and medical treatments to manage the comorbidities like POTS and MCAS, patients with hEDS and ME/CFS can achieve better symptom control and improved quality of life.

Conclusion

Mechanobiology offers valuable insights into the complex relationship between ME/CFS, EDS, and their associated comorbidities like IH, POTS, and MCAS. By understanding how mechanical instability and connective tissue abnormalities contribute to these conditions, researchers and clinicians can develop more effective diagnostic tools and treatments. While further research is needed, these findings suggest that addressing the mechanical aspects of these disorders could significantly improve the lives of those affected.
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Citations

• Bragée, B., et al. "Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome." Frontiers in Neurology, 2020, https://doi.org/10.3389/fneur.2020.00828
• Royer, S.P., & Han, S.J. "Mechanobiology in the Comorbidities of Ehlers Danlos Syndrome." Frontiers in Cell and Developmental Biology, 2022, https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.874840/full
• Wood, Jeff. "The Mechanical Basis of ME/CFS." The Mechanical Basis of ME/CFS, https://www.mechanicalbasis.org/. Accessed 9 Oct. 2024.

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