Prospective Study to Determine the Prevalence of Signs of Central Sensitization in Adults With ASD Without Intellectual Developmental Disorders

Groupe Hospitalier Mutualiste de Grenoble100 enrolled

Overview

Autism is a neurodevelopmental disorder (NDD) characterized by two key features: persistent deficits in communication and social interaction, and restricted, repetitive patterns of behavior, interests, and activities. Ninety-five percent of children aged 3 to 6 with autism spectrum disorder (ASD) have sensory peculiarities. In adulthood, this figure remains at 90%. This atypical sensory processing has been part of the DSM diagnostic criteria since 2013. Each sense can be affected by hypo- or hypersensitivity. In the continuum of this particular sensory processing, pain, which is defined as an unpleasant sensory and emotional experience, can be very present but also difficult to detect and manage. It is now established that there are other characteristics that impact pain in ASD: information processing time may be longer, referred to as "latency time," but there are also difficulties in representing the body schema and difficulties in identifying and/or interpreting perceptions. Expression may be atypical, and there may be an apparent lack of reaction to pain due to a lack of flexibility. All of these characteristics themselves vary over time (with age, the menstrual cycle, lack of sleep, fatigue, etc.), to the point that even pain specialists in pain clinics may not recognize them. It is therefore essential to carry out appropriate, individualized assessments. The scientific literature refers to the high frequency of painful events in ASD. For example, the prevalence of gastrointestinal disorders with their associated abdominal pain is significantly higher. Recent research has revealed that 82.4% of children and adolescents with ASD have at least one gastrointestinal symptom. Researchers have found that children with ASD are almost eight times more likely to have one or more chronic gastrointestinal symptoms than typically developing children. There are also more common comorbidities that facilitate or maintain chronic pain: Ehler Danlos syndrome and hypermobility spectrum disorders, IBD, ADHD, post-traumatic stress disorder, depression, migraines and tension headaches, anxiety disorders, epilepsy, small fiber pathologies, nutritional deficiencies, musculoskeletal disorders, etc. Mutations in certain genes involved in ASD (such as SCN9A, SHANK3, and CNTNAP2) lead to impaired neuronal function, producing different responses to pain, as demonstrated in both mouse and human models. The links between ASD and chronic pain are therefore complex. Sometimes it is the unusual characteristics of the pain that could lead to a diagnosis of ASD. The concept of central sensitization (CS), which underlies the type of pain known as "nociplastic," helps explain the state of pain hypersensitivity and pathologies such as fibromyalgia and irritable bowel syndrome. In 2022, Grant et al. found that 21% of adults with ASD surveyed in the cohort reported having a diagnosis of central sensitization syndrome (CSS), but 60% scored at or above the cut-off. This suggests that CS symptoms such as pain and fatigue are very common in people with autism, and perhaps more prevalent than in the general population. For example, three-quarters of women diagnosed with ASD and/or ADHD in childhood report chronic pain in adulthood. The issue is the disability associated with this chronic pain and the impairment of quality of life.

Autism is a neurodevelopmental disorder (NDD) characterized by two key features: persistent deficits in communication and social interaction, and restricted, repetitive behaviors, interests, and activities. 95% of children aged 3 to 6 with autism spectrum disorder (ASD) have sensory peculiarities. In adulthood, this figure is estimated to be 90%.. This atypical sensory perception has been included in the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM) since 2013, and recommendations advocate for sensory assessment (HAS, 2010) as part of treatment. Each sense can be affected by hypo- or hypersensitivity. Pain is now defined by international consensus as an unpleasant sensory and emotional experience, which may or may not be associated with injury. In the continuum of this particular sensory experience, pain can be very present but also difficult to detect and manage. It is now established that there are other characteristics that impact pain in ASD: information processing time may be longer, referred to as "latency time," but there are also difficulties in representing body image and difficulties in identifying and/or interpreting perceptions. The expression of pain may be atypical, with an apparent lack of reaction to pain due to a lack of flexibility. All of these characteristics themselves vary over time, with age, the menstrual cycle, lack of sleep, fatigue, etc., to the point that even pain specialists in pain clinics may not recognize it. It is therefore essential to carry out appropriate and individualized assessments. The scientific literature refers to the high frequency of painful events in ASD. For example, the prevalence of gastrointestinal disorders with associated abdominal pain is significantly higher. Recent research has revealed that 82.4% of children and adolescents with ASD have at least one gastrointestinal symptom. Researchers have found that children with ASD are almost eight times more likely to have one or more chronic gastrointestinal symptoms than typically developing children. In addition, there are more common comorbidities that facilitate or maintain chronic pain : Ehler Danlos syndrome and hypermobility spectrum disorders, IBD, ADHD, post-traumatic stress disorder, depression, migraines and tension headaches, anxiety disorders, epilepsy, small fiber pathologies, nutritional deficiencies, and musculoskeletal disorders. Mutations in certain genes involved in ASD (such as SCN9A, SHANK3, and CNTNAP2) lead to impaired neuronal function, producing different responses to pain, as demonstrated in both mouse and human models. The links between ASD and chronic pain are therefore complex. In some cases, it is the unusual characteristics of the pain that can lead to a diagnosis of ASD. Pain can be nociceptive (due to lesions that stimulate peripheral receptors) or neuropathic (related to a lesion or pathology of the nervous system). A third mechanism of pain is now being discussed, linked to the plasticity of the nervous system, known as nociplastic pain. The concept of central sensitization (CS) underlying this type of pain helps explain the state of painful hypersensitivity and conditions such as fibromyalgia and irritable bowel syndrome. There are close links between these conditions and ASD. Grant et al. in 2022 found that 21% of adults with ASD surveyed in the cohort reported having a diagnosis related to central sensitization syndrome (CSS), but 60% scored 40 or higher, the cut-off point for the Central Sensitization Index, which rates symptoms of CS. These signs of CS are therefore thought to be common and may explain why the prevalence of chronic pain (lasting more than three months) is high in ASD. This suggests that CS symptoms such as pain and fatigue are very common in people with autism and may be more prevalent than in the general population. In comparison, the prevalence of chronic pain in France is estimated at 31.7%. According to Grant et al., autistic women are more likely to report a diagnosis of CFS and exhibit more symptoms of CF than men. Sensory sensitivity, anxiety, age, and gender were significant predictors of CF symptoms, with sensory sensitivity and anxiety modulating the relationship between autistic traits and CF symptoms. Three-quarters of women diagnosed with ASD and/or ADHD in childhood report chronic pain in adulthood. The issue is the disability associated with this chronic pain and the impairment of quality of life. There is no specific tool for assessing nociplastic pain. The Central Sensitization Inventory (CSI) is a self-report questionnaire validated in 2014 by Neblett et al. that attempts to measure central sensitization. The cut-off point was set at 40. In the study by Grant et al., which surveyed adults with ASD without TDI using this tool, the group with SSC had an average score of 55.3 (versus 52.4 in Neblett's cohort), but the group without diagnosed SSC had a score of 40.6 (versus 30.9 in Neblett's cohort). This suggests that pain and fatigue are very common in people on the autism spectrum. They could explain why the prevalence of chronic pain (i.e., lasting more than 3 months) is high in ASD and why the nociplastic nature of this pain must be taken into account. On the other hand, there is a FIRST self-administered questionnaire for fibromyalgia that allows for simple screening for this condition, which is at the top of the list of CSDs. Finally, as Grant et al. Investigator investigate the relationship between autistic traits and central sensitization syndromes by studying the correlation with the 10-item Autism Spectrum Quotient (AQ) and the relationship between sensory perception and central sensitization syndromes by studying the correlation with the Sensory Perception Quotient (SPQ) and SSC. Chronic pain is common in ASD, and its nociplastic nature is poorly understood. In this context, the objective of this study is to determine the prevalence of signs of central sensitization in adults with ASD (without intellectual developmental disorder).

Outcomes

Primary Outcomes

Determine the prevalence of signs of central sensitization in adults on the autism spectrum without intellectual developmental disorders.

Percentage of patients with a CSI score ≥ 40 Total Score CSI :\[0-100\] A CSI score \> 40 points defines clinically significant central sensitization. The score is divided into intervals: 0 to 29 = subclinical CS, 30 to 39 = mild CS, 40 to 49 = moderate CS, 50 to 59 = severe CS, 60 to 100 = extreme CS.

Time frame: At inclusion

Secondary Outcomes

Determine the average level of central sensitivity in adults on the autism spectrum, with at least one diagnosis of SSC

Average CSI score (part A) in this subgroup Total Score CSI (part A): \[0-100\] The score is divided into intervals: 0-29 = subclinical central sensitisation, 30-39 = mild central sensitisation, 40-49 = moderate central sensitisation, 50-59 = severe central sensitisation, 60-100 = extreme central sensitisation.

Time frame: At inclusion

Determine the average level of central sensitivity in adults on the autism spectrum without a diagnosis of SSC

Average CSI score (part A) in this subgroup Total Score CSI (part A) :\[0-100\] The score is divided into intervals: 0-29 = subclinical central sensitisation, 30-39 = mild central sensitisation, 40-49 = moderate central sensitisation, 50-59 = severe central sensitisation, 60-100 = extreme central sensitisation.

Time frame: At inclusion

Determine the prevalence of SSC diagnoses

Percentage of patients with at least one SC diagnosis (part B of the CSI) Total Score SCI (part B) : \[0-10\].This section provides additional clinical information, but does not count toward the numerical score.

Time frame: At inclusion

Determine the average anxiety level

Average HAD-A Anxiety Score Total Score HAD-A : \[0-21\] Score \[0 - 7\]: no anxiety and/or depressive disorders. Score \[8- 10\]: questionable symptoms. Score \[11 - 21: confirmed anxiety and/or depressive disorders of varying severity.

Time frame: At inclusion

Determine the average level of depression

Average HAD-D Depression Score Total Score HAD-D : \[0-21\] Score \[0 - 7\]: no anxiety and/or depressive disorders. Score \[8- 10\]: questionable symptoms. Score \[11 - 21: confirmed anxiety and/or depressive disorders of varying severity.

Time frame: At inclusion

Determine the prevalence of subjects who test positive on the fibromyalgia self-assessment questionnaire

Percentage of patients with a score greater than 5 on the FIRST self-assessment questionnaire Total Score FIRST :\[0-6\] A score of 5 out of 6 items can detect fibromyalgia with a sensitivity of 90.5% and a specificity of 85.7%.

Time frame: At inclusion

Determine the prevalence of acute pain in the last 12 weeks

Percentage of subjects with pain score \>3 for several days in the last 12 weeks Total score EN Pain : \[0-10\] (0 very bad to 10 very good)

Time frame: over the last 12 weeks prior to inclusion

Determine the average level of chronic pain

Average EN pain over the last 24 hours and over the last 7 days Total score EN Pain : \[0-10\] (0 very bad to 10 very good)

Time frame: T1 : over the last 24 hours prior to inclusion T2 : over the last 7 days prior to inclusion

Determine the prevalence of chronic pain

Percentage of subjects with pain score \>3, every day or almost every day for at least 3 months Total score EN Pain : \[0-10\] (0 very bad to 10 very good)

Time frame: over the last 3 months prior to inclusion