The Association Between Fibromyalgia, Hypermobility and Neurodivergence Extends to Families: Brief Report
OBJECTIVES
Fibromyalgia is associated with symptomatic hypermobility. People with these conditions have a higher prevalence of neurodivergent conditions. Many fibromyalgia patients with hypermobility also report similar symptoms within their family....
This self-reported small case-control study confirms the association of fibromyalgia, hypermobility and neurodivergence, and suggests that close relatives also exhibit this association.
Many patients presenting with fibromyalgia have features of neurodivergence
This combination is strongly associated with the presence of joint hypermobility
The relatives of these patients also report an increased prevalence of all three conditions
Fibromyalgia (FM) has an estimated lifetime prevalence in the west of 0.2-6.8% [1]. Clinical experience suggests patients are presenting to rheumatology specialists with the combination of FM and symptomatic hypermobile Ehlers-Danlos syndrome (hEDS) at a younger age than a decade ago. Case studies prompted interest in the potential overlap between fibromyalgia (FM) and attention deficit hyperactivity disorder (ADHD) over a decade ago [2] and high rates of prior ADHD were reported among women who later presented with features of FM [3]. The term ’neurodivergence’ incorporates conditions such as ADHD, autism and Tourette’s syndrome and further observations confirmed that a quarter of people with neurodivergence had FM [4], commensurate with a report that the prevalence of ADHD was raised in Dutch women with FM [5]. This association was soon confirmed by van Rensburg who demonstrated that 45% of FM patients also had ADHD [6]. Both conditions are associated with lower circulating levels of dopamine, with evidence of an overlap in the gene coding for dopamine receptor function, which is thought to explain some of the personality traits associated with each condition [7].
A Spanish study highlighted the overlap between autism, hEDS and FM and suggested that neurodivergent conditions in general were associated with both chronic pain and hEDS [8]. A high prevalence of joint hypermobility was recorded among women with ADHD [9], and hEDS itself was linked to the presence of several of the personality traits described among both people with chronic musculoskeletal pain and those with ADHD [9]. Eccles et al demonstrated that brain structure was different among people with hEDS and suggested that this explained many of the psychiatric features which mirrored those observed in neurodivergent conditions [10].
Psychological distress in early life was suggested as a predisposing factor for chronic pain, especially if adverse childhood experiences (ACE) included lack of parental support or validation which were also associated with personality traits seen in neurodivergence [11]. Considering mechanisms by which these diagnoses may occur, Khalil suggested that ADHD may trigger FM via central sensitisation, consequent upon ACEs [12], and that this might explain the pain and motor distress [13] seen in FM. Stimulants given for ADHD have been described as both reducing pain and improving cognitive dysfunction, the latter being a hallmark of FM (‘fibrofog’) [14]. A French study emphasised the extensive co-occurrence associated with ADHD and the overlap with both widespread musculoskeletal pain and personality disorders. They also noted that fatigue was a major aspect of ADHD, and that associated sleep disturbance was common [15]. They suggested that the prevalence and severity of co-occurring conditions increased with age, and this was supported by Asztely who demonstrated that 77% of neurodivergent women developed chronic musculoskeletal pain in later life [16]. Although most literature on the overlap between FM and neurodivergence has come from Europe, there is evidence that the relationship between these conditions also applies to populations in the Far East [17].
More recently, hypermobility was observed in over half of a neurodivergent group with an odds ratio of 4.5 compared to a comparison group. The extent of hypermobility mediated the relationship between neurodivergence and both dysautonomia and musculoskeletal pain [18]. Casanova et al. reviewed the evidence linking neurobehavioral and pain syndromes with dysautonomia and dysregulation of the immune system. They reported significant genetic overlap between each of neurodivergence, hEDS and FM, suggesting that hypermobility and pain may even be considered as aspects of autism [19].
Clinical experience has revealed that many patients presenting with FM and hEDS also report symptoms of chronic pain and mental health issues among their family members. Although the links between these conditions are now recognised among patient populations, we are unaware of any previous studies of the frequency with which they occur within families of those affected. An increased prevalence within close relatives might be expected given the genetic overlap between these disorders. Our objective was to investigate the incidence of diagnosed FM, hEDS and neurodivergence within first-and second-degree relatives of index cases with both FM and hEDS to assess whether this is greater than that observed within a comparison group of index cases attending the same clinical service but with a different musculoskeletal diagnosis.
This study confirmed a high prevalence of neurodivergence among patients presenting to a hospital clinical with features of FM and hEDS. Furthermore, close relatives of these patients’ self-reported increased levels of neurodivergence, FM and hypermobility among themselves. Those relatives who reported a diagnosis of neurodivergence also reported higher percentages of diagnosed FM and hypermobility.
The incidence of diagnosed neurodivergent conditions within first-and second-degree relatives of index cases with both FM and hypermobility was significantly greater than that observed within a comparison group of relatives. We included OA patients and their families as appropriate comparator controls as many immune disorders are increased in prevalence among neurodivergent people. In addition, the incidence of both FM and hypermobility were also increased among close relatives of those with these conditions, with the rates highest among neurodivergent relatives. This supports previous findings of overlap between these disorders and strongly suggests that neurodivergent people are at much greater risk of developing FM [3][4][5][6].
Neurodivergent conditions are present from birth and therefore predate the onset of both HSD and FM. However, symptoms arising from these conditions are very varied and may not be recognised as being due to neurodivergence until adult life. This is more often the case for females than males, and within trans and non-binary people, which may increase their psychological distress and promote anxiety. Overlapping psychological features are described among females with FM and ADHD females [9][10]. Chronic pain may be consequent upon central sensitisation, which can develop in more than three-quarters of women with ADHD over time [16] and this study suggests that similar trends are found among their close relatives.
The presence of hypermobility may mediate the relationship between neurodivergence and chronic pain in FM [18]. Psychological distress in early life is suggested as a predisposing factor for chronic pain, especially if adverse childhood experiences (ACEs) included lack of parental support or validation which may produce personality traits resembling those seen in neurodivergence [11][22]. As the present study demonstrated, females are disproportionately overrepresented within these pain populations, in contrast to the distribution of neurodivergent conditions in the community where diagnosis in males is more common, perhaps due to underdiagnosis in younger females. Many females obtain their diagnosis of neurodivergence during their teenage years or in early adulthood, while males are often diagnosed at an earlier age. Further research should focus on screening for neurodivergent conditions among patients referred to services for the management of chronic pain so that appropriate support and intervention can be offered. The association between FM and neurodivergent conditions is under-appreciated by many clinicians working in these areas and the promotion of greater awareness and understanding of the overlap between these conditions would benefit patients and clinicians alike. This study is very relevant to today's society where many young people are struggling with their identity. Pain in all its manifestations can be associated with this process, and it is important for health-care professionals to recognise this. Understanding how best to respond to young people's emotional and social issues is fundamental to providing an efficient and cost-effective health system.
Power calculations prior to the study were performed and the results used to guide the study design. Despite small numbers, the results were highly significant, supporting the validity of this approach. However, we acknowledge that this is a small study with significant limitations which include the fact that all data relied on self-reporting and that reported diagnoses were not independently verified. The lack of an objective determination of each diagnosis limits the results' internal and external validity. This could have led to an overestimate of the prevalence of neurodivergence, FM or hypermobility because of greater awareness of these conditions within affected families. By contrast, it is also possible that the reported prevalence estimates may be an underestimate, as not all relatives would have undergone diagnostic assessment for their symptoms, which may not have yet evolved in younger family members.
An overlap of genes coding for neurodivergence and for symptomatic hEDS has been reported [19]. This may explain some of relationship between the three conditions although further research is needed to confirm the extent of this association [23]. However, it is becoming evident that the relationship between FM and neurodivergent traits is not confined to patient populations. Recent work has shown a strong correlation between FM and autistic traits in a large, self-selected adult community population [24], mediated by a combination of hypermobility and food intolerance [25]. Clearly, more work is needed to assess the risk factors for chronic musculoskeletal pain among neurodivergent people both in diagnosed populations and in the community if we are to learn how to intervene early and effectively. It is essential that the voices of neurodivergent people are listened to and that their input to this p
