Rethinking ADHD: Integrating Hypermobility, Orthostatic Intolerance, and Immune Dysregulation into a Dimensional Framework

Attention-Deficit/Hyperactivity Disorder (ADHD) is traditionally characterised by inattention, hyperactivity, and impulsivity. However, emerging evidence highlights a complex web of physical and mental health comorbidities associated with ADHD. Among these, the intersection with hypermobility spectrum disorders (HSD), orthostatic intolerance, and immune dysregulation has drawn increasing attention. This article explores these links, considering potential subtypes of ADHD and advocating for a more dimensional framework.

ADHD and Hypermobility: An Overlooked Connection.

Hypermobility, particularly in the form of hypermobile Ehlers-Danlos Syndrome (hEDS) or generalised joint hypermobility (GJH), is significantly associated with ADHD. Studies estimate that 50% of individuals with neurodevelopmental disorders, including ASD and ADHD, also have joint hypermobility (Csecs JLL et al., 2022). Conversely, individuals with Ehlers-Danlos Syndrome (EDS) are five to six times more likely to have ADHD (Csecs JLL et al.,2022).

Why the Link?

Neurobiological Overlap: Both ADHD and hypermobility involve variations in neurological functioning, which can manifest in different ways. Some researchers suggest that abnormalities in the nervous system may contribute to ADHD symptoms and joint laxity observed in hypermobility (Glans et al., 2021). Connective tissue abnormalities in hypermobility may affect autonomic nervous system functioning, contributing to ADHD-like symptoms such as poor focus and emotional dysregulation
ADHD and Immune Dysregulation: The Missing Link? The interplay between ADHD and immune function is an area of growing interest. Hyperactive immune responses, including autoimmune conditions, are more common in individuals with ADHD. For example, studies have found higher rates of coeliac disease, autoimmune thyroiditis, and allergic conditions in ADHD populations. Chronic low-grade inflammation has been proposed as a shared factor in ADHD and autoimmune diseases. Dysregulated cytokine production could impact brain development and function, particularly in regions like the prefrontal cortex (Saccaro et al. 2021). Elevated levels of specific cytokines have been observed in individuals with ADHD, suggesting an underlying inflammatory component (Verlaet, A.A.J. et al., 2014). Additionally, large cohort studies have indicated that children born to mothers with autoimmune diseases are more likely to develop ADHD, further implicating immune system involvement (Johanne T. Instanes. et al., 2017)
Autonomic Dysregulation: Orthostatic intolerance (OI), including Postural Orthostatic Tachycardia Syndrome (PoTS), is common in hypermobile individuals. Dysregulation of the autonomic nervous system — manifesting as dizziness, fatigue, or cognitive fog — may exacerbate ADHD symptoms and complicate diagnosis.
Gut-Brain Axis: The gut microbiome plays a role in both immune function and mental health. Dysbiosis in the gut microbiota may influence ADHD symptoms via immune and neuroinflammatory pathways (Checa-Ros A et al., 2021).
Hormonal and Sex-Based Factors: Women are at a higher risk of autoimmune conditions, which may contribute to the sex differences observed in ADHD presentations. This highlights the need to account for immune-related factors in ADHD diagnosis and treatment planning. Women with ADHD and hypermobility often report worsening symptoms during hormonal fluctuations (e.g., menstruation or menopause). This may indicate sex-specific subtypes of ADHD, where hypermobility-related issues are particularly prominent

Subtyping ADHD: A Dimensional Approach

The heterogeneity in ADHD presentations suggests the need for subtyping beyond the traditional categories of inattentive, hyperactive-impulsive, and combined types. Emerging evidence supports distinct subgroups based on physical and biological markers, such as:

Hypermobile ADHD:

Predominantly found in women.
High rates of orthostatic intolerance, fatigue, and chronic pain.
Autonomic and connective tissue dysregulation as core features.

2. Non-Hypermobile ADHD:

More commonly associated with classic ADHD symptoms without significant physical health issues.
May exhibit stronger genetic links to other neurodevelopmental conditions like autism

3. Immune-Dysregulated ADHD:

Characterised by co-occurring autoimmune or allergic conditions
May present with heightened emotional reactivity and inflammatory biomarkers
May cluster with hypermobile ADHD

A Hierarchical Framework

Broad Dimensions:

Core ADHD traits (inattention, hyperactivity, impulsivity)

Specific Domains:

Physical health (hypermobility, PoTS, immune markers).
Emotional regulation (rejection sensitivity, mood instability).

Trait Interactions:

Symptom clusters that account for comorbidities and their dynamic interactions.

Clinical Implications

Comprehensive Assessment:

Screen for hypermobility and orthostatic intolerance in ADHD patients, particularly women
Evaluate for autoimmune markers or chronic inflammatory conditions

2. Medication considerations:

Adjust stimulant dosages for patients with autonomic issues (e.g., PoTS)
Consider variable stimulant doses in PMS/PMDD
Consider non-stimulant options like guanfacine or clonidine as adjunctive treatments for hypermobility-related dysregulation, PMS/PMDD, orthostatic intolerance or body restlessness

3. Lifestyle Interventions:

Encourage fluid intake, salt supplementation, and compression garments for orthostatic intolerance.
Recommend physiotherapy for joint stability in hypermobility
Magnesium supplements can reduce side effects and improve sleep in ADHD treatment regimes
Iron supplements can help with body restlessness.
Vagal nerve strategies very helpful for orthostatic intolerance

4. Psychotherapy:

Address emotional dysregulation and anxiety exacerbated by physical health issues.
Educate patients about managing their hypermobility, orthostatic intolerance and gut problems
Vagus nerve exercises often help with stress

5. Research and Advocacy:

Advocate for studies exploring the intersection of ADHD, hypermobility, and immune dysfunction.
Develop guidelines that incorporate these comorbidities into ADHD diagnostic and treatment protocols.

Conclusion

ADHD is a multidimensional condition with significant physical and mental health comorbidities. The observed overlap among ADHD, joint hypermobility, and immune dysregulation suggests a complex interplay of genetic and biological factors. While these associations are compelling, current evidence remains preliminary.

Adopting a dimensional framework, enables us to can better capture the complexity of ADHD. Comprehensive studies are needed to elucidate the genetic, neurological, and immunological underpinnings connecting ADHD, hypermobility, and immune dysregulation. Such research could pave the way for integrated treatment approaches that address the cognitive, physical, and immunological aspects of these conditions.

Understanding these connections is crucial not only to enhance diagnostic accuracy. but also to develop holistic management strategies and more personalised and effective treatments to improve outcomes for diverse patient populations.

Sources

Tagged ADHD, Adult ADHD, Diagnosis, Mental Health, Diagnosis, Psychiatry, Depression, Anxiety, therapy, hypermobility, PoTS, women