Fatigue and hEDS
Fatigue is one of the most common and disabling symptoms reported by people with hypermobile Ehlers-Danlos syndrome (hEDS). It is not simply feeling “tired.” Many individuals experience deep physical exhaustion, reduced stamina, slowed thinking, difficulty recovering after activity, and limited ability to sustain daily tasks. Fatigue often interacts with pain, autonomic symptoms, sleep disruption, and multiple organ systems, making it complex and difficult to treat.
Large studies suggest that approximately 75–85% of people with hEDS experience clinically significant fatigue, compared with roughly 10–20% of healthy controls, depending on the measurement tool used. Fatigue severity in hEDS is often comparable to fibromyalgia and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS), and substantially higher than in the general population.
Empirical Evidence of Fatigue Severity and Persistence
Most research on fatigue in hEDS comes from cross-sectional studies (single time-point assessments) rather than long-term tracking across the lifespan. These studies consistently show that fatigue levels in hEDS are significantly higher than in healthy controls using standardized fatigue scales.
In one well-characterized cohort, the average fatigue score on the Checklist Individual Strength (CIS) was approximately 98 out of a possible 140, compared with approximately 46 in healthy controls, representing more than a two-fold difference in fatigue burden. Clinically, this level of fatigue is comparable to that seen in fibromyalgia and ME/CFS.
Long-term data specifically measuring fatigue progression are limited. Small follow-up studies examining muscle strength and endurance suggest that physical capacity deficits in hEDS tend to persist over time rather than fully normalize. While these studies do not directly track fatigue symptoms, muscle weakness and endurance limitations strongly influence fatigue experience.
In children and adolescents with hEDS, fatigue is already prominent and strongly associated with pain, anxiety, depression, and reduced quality of life. Broader pediatric chronic pain research shows that fatigue in youth with chronic pain is more likely to persist or worsen over time than to fully resolve, suggesting early vulnerability to long-term fatigue trajectories.
Overall, available evidence indicates that fatigue in hEDS is highly prevalent, persistent, and often resistant to complete resolution, although individual trajectories vary.
Why Fatigue Occurs in hEDS: Key Biological and Functional Drivers
Fatigue in hEDS arises from multiple interacting systems rather than a single cause.
Connective Tissue and Circulation
Abnormal connective tissue affects not only joints and ligaments, but also blood vessels. Increased vessel flexibility can impair the ability to push blood efficiently back to the heart when standing or moving. This contributes to orthostatic intolerance and postural orthostatic tachycardia syndrome (POTS), which commonly cause lightheadedness, rapid heart rate, reduced blood flow to the brain, and increased energy demand during basic activities.
Autonomic Nervous System Dysregulation
The autonomic nervous system regulates heart rate, blood pressure, digestion, temperature control, and energy balance. Many people with hEDS have dysautonomia, meaning these automatic systems do not regulate efficiently. The body must work harder to maintain basic stability, which increases physical strain and contributes directly to fatigue. In hEDS, autonomic dysfunction is often driven by impaired vascular tone and sometimes small-fiber neuropathy (damage to the tiny nerve fibers that regulate blood vessel constriction, sweating, and pain signaling), which reduces the body’s ability to rapidly stabilize circulation during posture changes.
Chronic Pain and Muscle Inefficiency
Joint instability, muscle guarding, nerve pain, and early degenerative changes increase muscular workload. Muscles often fatigue more quickly and recover more slowly. Repeated micro-instability and altered movement patterns increase neuromuscular inefficiency (muscles requiring more energy than normal to perform the same task due to poor joint stability and altered motor control), accelerating fatigue during everyday activities. Pain also disrupts sleep and reduces activity tolerance, further worsening stamina and conditioning over time.
Deconditioning and Reduced Activity
When movement becomes painful or destabilizing, people naturally reduce activity. This leads to loss of muscle strength and cardiovascular conditioning, which increases fatigue even during minor exertion. This cycle can reinforce itself without targeted rehabilitation.
Sleep Disruption and Cognitive Load
Sleep problems are common in hEDS due to pain, autonomic instability, gastrointestinal symptoms, and anxiety. Poor sleep reduces physical recovery, worsens concentration, and amplifies pain sensitivity, all of which increase fatigue.
Immune and Metabolic Factors (Emerging Evidence)
Emerging research suggests that low-grade inflammation and immune dysregulation may contribute to persistent fatigue in some individuals with hEDS, similar to mechanisms described in chronic fatigue conditions. Inflammatory signaling can shift how cells generate energy, moving from efficient oxidative phosphorylation (the normal process by which mitochondria produce high-yield cellular energy using oxygen) toward less efficient aerobic glycolysis (a faster but lower-energy pathway that produces less usable energy per unit of fuel). This metabolic shift may reduce overall cellular energy availability, increase reactive oxygen species (oxidative byproducts that can stress cells and tissues), and impair insulin sensitivity (how effectively cells use glucose for energy). Together, these changes may contribute to persistent physical exhaustion, slower recovery after activity, and reduced stamina.
Common contributors to fatigue in hEDS include
Impaired circulation and autonomic regulation
Chronic pain and neuromuscular inefficiency
Deconditioning cycles
Sleep disruption
Immune and metabolic inefficiency
Why Fatigue Often Feels Progressive Over Time
Many individuals with hEDS report that fatigue becomes more limiting as they age. Several overlapping mechanisms help explain this pattern.
Accumulation of musculoskeletal strain from years of joint instability, micro-injuries, and compensatory movement patterns increases energy demands and pain burden.
Progressive deconditioning occurs when repeated symptom flares limit physical activity, gradually reducing cardiovascular and muscular capacity.
Expansion of comorbid conditions such as dysautonomia, gastrointestinal dysmotility, mast cell activation symptoms, sleep disorders, and neuropathic pain increases overall physiological load.
Reduced physiologic reserve with aging lowers the body’s ability to compensate for stressors, recover from exertion, and maintain stability.
Chronic nervous system sensitization (sometimes referred to as central sensitization, where the brain and spinal cord amplify threat and energy demand signals) increases baseline energy expenditure and symptom sensitivity.
Cumulative psychosocial stress related to medical burden, functional limitations, and social disruption contributes to cognitive and emotional fatigue.
In addition to clinical studies, large patient communities consistently report that many individuals with hEDS experience increasing fatigue and shrinking functional capacity with age, sometimes to a disabling degree. These reports likely reflect a concentration of individuals with higher symptom burden, multiple comorbidities, and greater care needs.
While these communities may not represent the full spectrum of hEDS severity in the general population, the consistency of these patient-reported patterns suggests that progressive fatigue may be more common than currently captured in formal research, particularly among individuals with complex multisystem involvement.
Not all individuals experience progressive worsening. Some stabilize or improve with early intervention, appropriate rehabilitation, and proactive comorbidity management. However, the underlying biology of hEDS creates ongoing vulnerability to cumulative fatigue burden.
How Fatigue in hEDS Compares to Other Conditions
Fatigue severity in hEDS is significantly higher than in healthy populations and often exceeds that seen in many other chronic medical conditions. Rates of severe fatigue approach those seen in fibromyalgia and ME/CFS.
Unlike inflammatory autoimmune diseases, where fatigue often fluctuates with disease activity and inflammation, fatigue in hEDS is more strongly linked to mechanical instability, autonomic dysfunction, neuromuscular inefficiency, and multisystem stress. Improvement is less predictable and often slower.
People with overlapping conditions such as POTS, mast cell activation symptoms, chronic pain syndromes, or ME/CFS typically experience greater fatigue severity and reduced quality of life.
Age-Related Considerations and Comorbidity Impact
Children and Adolescents
Fatigue in youth with hEDS is strongly associated with pain, anxiety, depression, school limitations, and reduced physical participation. Early patterns of activity avoidance and sleep disruption can shape long-term conditioning and symptom trajectories.
Adults
In adults, fatigue correlates closely with autonomic symptoms, pain severity, physical activity levels, and social participation. Many adults report difficulty sustaining work, caregiving, and community engagement due to energy limitations.
Older Adults
Direct data in older hEDS populations are limited. However, normal aging processes combined with long-standing autonomic dysfunction, musculoskeletal strain, and multisystem involvement likely increase fatigue vulnerability.
Major Comorbid Drivers
Comorbidities that commonly intensify fatigue include:
Dysautonomia (POTS and orthostatic intolerance)
Chronic pain syndromes
Mast cell activation symptoms
Gastrointestinal dysmotility and malabsorption
Sleep disorders
Mood and anxiety disorders
These conditions interact and amplify fatigue when not adequately managed.
Management Strategies, Measurement, and Research Gaps
Effective Interventions
Fatigue management is most effective when multidisciplinary and individualized. Helpful approaches may include
Physical therapy and graded conditioning
Activity pacing
Management of autonomic symptoms
Multimodal pain treatment
Sleep optimization
Psychological support
Self-management strategies
Digital health programs and telemedicine models show promise but require further validation in hEDS populations.
Measurement Limitations
There are currently no fatigue measurement tools specifically validated for hEDS. Most research relies on general fatigue scales, which may not fully capture the multidimensional nature of fatigue in connective tissue disorders or detect meaningful change over time.
Research Gaps
There is a lack of long-term, age-stratified studies tracking fatigue trajectories in hEDS. Better measurement tools and longitudinal cohorts are needed to clarify natural history and treatment response.
Summary
Fatigue in hypermobile Ehlers-Danlos syndrome is common, often severe, and driven by interconnected musculoskeletal, autonomic, neurologic, metabolic, and psychosocial factors. Many individuals experience persistent or gradually worsening fatigue over time due to cumulative biomechanical strain, deconditioning, expanding comorbidities, and reduced physiologic reserve. Patient communities and specialty clinics consistently report that a substantial subgroup of individuals with hEDS develop progressively worsening fatigue that can become significantly disabling, particularly when multiple comorbidities are present, even though long-term population-based data remain limited. Multidisciplinary management can significantly improve function and quality of life, but not all individuals achieve full resolution of fatigue even with appropriate treatment. Early intervention, individualized care, and continued research are essential to improving long-term outcomes.
