Rett syndrome (RTT) is a neurodevelopmental disorder that affects approximately 1 in every 10,000 live births, almost exclusively female [1], and is caused by the mutation of a gene in the X chromosome that encodes the binding protein methyl- CpG 2 (MeCP2). Alteration of the MECP2 protein leads to the activation or deactivation of some genes that affect brain development, causing a series of behavioral and neurological alterations [2—4]. The clinical picture is characterized by the progressive loss of manual skills, language, anomalies or absence of movement and by the appearance of stereotypies of the hands, alterations of breathing with hyperventilation when awake and frequent convulsions [5—10]. Various comorbidities are present in RTT in addition to epilepsy, the most frequent being gastrointestinal and orthopedic problems, as well as less frequent issues such as endocrinological and cardiac problems, but also liver damage, respiratory disorders, urological dysfunctions, and inflammatory diseases, which make it a very complex and multifaceted syndrome [11—14]. According to caregivers, many of these chronic health problems cause pain and impair the quality of life of patients with RTT [12, 15]. Many conditions are particularly painful, such as low bone density. In these individuals, the risk of fractures and microfractures is three to four times greater than in typical individuals [13, 16—18], particularly in the vertebrae and in the femur, thus causing considerable pain. Contractures of the ankle, knees, hip/trunk, elbows and wrist joints have also been reported [19—24]. Less common musculoskeletal problems are also present, such as juvenile idiopathic arthritis [19, 25], osteopenia/osteoporosis [19, 26—27], joint hypermobility [19, 28—31], muscle atrophy [19, 32], lordosis [33] and torticollis [34—35]. Skeletal deformations were also found, especially in patients with more severe mutations (e.g. Arg255X) or with large deletions [36—38], especially scoliosis, which, in addition to causing pain, is associated with both an unfavorable prognosis and worse life expectancy [36, 38] and often with severe respiratory tract infections [36]. Breathing difficulties are also among the most common comorbidities. Indeed, during apnea at rest and, less frequently, in hyperventilation, air may be ingested, leading to abdominal swelling, which, in some cases, can lead to gastric perforations and peritonitis [16—39]. Orally, one of the conditions that causes pain is bruxism, which can eventually lead to tooth wear, fractures, a series of muscle pains in the jaw, and temporomandibular disorders [16, 40—42]. Long-term sucking or biting of the fingers can also lead to mandibular alterations that lead to increased pain [16, 40]. Problems related to the digestive system, such as reflux and esophagitis, are also frequent, and the associated pains worsen or change when lying down [16, 43]. Constipation can also cause pain both in the abdominal area and during the passage of stool [16, 44]. Comorbidities of patients with Rett syndrome are varied and cause a lot of pain, but communicating this suffering is difficult for these patients due to their problems, such as apraxia that does not allow them to express pain in a timely manner [45], and their difficulties with language that also do not permit them to communicate. In literature, there have been attempts to identify the modalities of manifestation of pain in patients who have communication difficulties, such as in patients in the final phase of dementia, in advanced malignancy at end-of-life, in severely brain-damaged patients, with a disturbance of consciousness such as coma, a vegetative state or a state in which the subject is unconscious, and mechanically ventilated intensive care unit (ICU) patients [46—51]. In all these cases, even highly trained physicians, nurses and caregivers may make mistakes in evaluating the presence, location, severity, or impact of pain. Moreover, there are many factors that can influence the underestimation or overestimation of the precise nature of pain, its severity and its location, for example, the subjective nature of pain perception, given that an individual’s threshold experience of pain increases the difficulty of measuring and quantifying the intensity of pain [52].
To try to overcome the problems of subjective measures, various alternative methods for the clinical assessment of pain in non- communicating patients have been proposed such as Pain assessment in advanced dementia (PAINAD) [53], the Critical care pain observation tool (CPOT) [54], the Non-communicating Children's Pain Checklist-Revised (NCCPC-R) [55], visual analogue scale (VAS), verbal rating scale (VRS), and numerical rating scale (NRS) [56]. McGuire et al. (2016) [57] in a study which describes different methodologies, suggest that the physiologic and behavioral dimensions of pain are the most important. Indeed, they can be useful tools that use observable behaviors (such as facial tension or restlessness) to assess pain, and/or physiologic indicators such as vital signs, which are used as cues for more in-depth assessment. In patients with RTT, few studies have evaluated pain perception [15, 45, 58]. In the study by O’ Leary et al. [58], scales that take autonomic response into account, such as electrodermal activity (EDA) and heart rate (HR) were used, associated with the Face Legs Activity Cry Consolability (FLACC) behavioral scale [59], which evaluates post-operation pain in young children. Symons et al. (2013) [15] described pain sources and frequency using NCCPC-R, which assesses pain in non- communicating children. In the study by Barney et al. (2015) [58], a parent was asked to assess the pain of their daughters through NCCPC-R, the Brief Pain Inventory (BPI) [60] and the Dalhousie Pain Interview (DPI) [55], evaluating pain expression with the Pain Examination Procedure/Pain and Discomfort Scale (PADS/PEP) [61]. BPI is a scale that was originally created for patients with cancer pain, which is now also used with generic pain for other chronic pain conditions and with non-verbal subjects with disabilities [62—63]. The DPI is used to assess the type, frequency, duration and intensity of pain in children with severe intellectual disability. The PADS/PEP evaluates pain in adults with severe or profound intellectual disability and measures the expression of pain by enabling the evaluator to isolate a source/location of pain [58].
All these scales are generic and do not take the typical characteristics of RTT into account. Patients with Rett syndrome try to communicate their suffering through various behaviors, such as clapping, laughing, delayed pain response, grinding of teeth, sticking out the tongue, moving the body in a specific way, jumping, shaking, self-harming, but also grimacing, vocalizing, moaning, whimpering, screaming, and saying a specific sound or word [15, 16, 38, 58]. The behaviors displayed by subjects with RTT make pain measurement and assessment problematic, especially for healthcare professionals, doctors and nurses who must understand the nature of pain to prescribe and administer drugs.
Since there is no scale in literature that was created exclusively for patients with RTT, the aim of this study is to adapt existing scales to assess pain in patients with Rett syndrome. Many studies rely on voluntary pain induction [64—67], but in this study pain was not induced voluntarily in the girls with RTT and the patients were not hospitalized. Thus, the methodological difficulty was to wait for the spontaneous appearance of pain in RTT patients, not to induce it, and then ask the parents to video-record the event when it occurred.
More in detail, the first aim of the present study is to describe a pain situation by collecting information and by asking the parents the 5 W's and one H (Who? What? When? Where? Why? How?) questions, in addition to some other questions, such as the estimated intensity of pain, the part of the body with pain, what the parents did to decrease it and the duration of the pain after the intervention of the parents.
The second aim was to test and compare existing questionnaires on pain such as PAINAD [53], CPOT [54], and NCCPC-R [55] to assess which of them is best related to the pain behavior of patients with RTT.
The third aim was to identify the specific verbal and non-verbal behaviors that characterize pain in girls with Rett syndrome, discriminating them from non-pain behaviors. Through analysis of the video-recorded behavioral characteristics, both in the condition of pain and in the condition of baseline (well-being), we tried to identify the most frequent behaviors to be able to discriminate pain from baseline.
To analyze if there are more consistent behaviors in a single patient with respect to more patients, two studies were conducted in the present work: the first refers to a group study and the second to a single case study with repeated measurements of the pain event.