Oral Appliance Research Articles

Evidence in Reaching Consensus in Usage of Mandibular Advancement Device for Pre- and Post-obstructive Sleep Apnea Treatment with Blood and Salivary Inflammatory Biomarkers Profiles

Evidence in Reaching Consensus in Usage of Mandibular Advancement Device for Pre- and Post-obstructive Sleep Apnea Treatment with Blood and Salivary Inflammatory Biomarkers Profiles

Changes in self-reported sleep and awake bruxism in relation to the management of temporomandibular disorders ("care as usual") in a specialty clinic population.

The treatment of temporomandibular disorders (TMD) often includes the management of sleep bruxism (SB) and awake bruxism (AB). However, few studies have investigated how SB and AB change after the initiation of the interventions aimed at reducing the activity of masticatory muscles in TMD patients. The aim of the present study was to investigate changes in self-reported SB and/or AB with regard to baseline at 6 weeks after receiving TMD treatment, i.e., counseling alone or counseling combined with any other treatment, and to investigate the association between the type of TMD treatment and changes in self-reported SB and/or AB. A total of 68 TMD patients were included in this prospective study, and they all received counseling. Thirty-three of the 68 patients received additional treatment, e.g., physical therapy, psychological therapy and/or an oral appliance, beside counseling. The self-reported SB and AB frequency values were obtained from the Oral Behavior Checklist (OBC) questionnaire at baseline (t0) and at week 6 after receiving treatment (t1). The frequency of SB and AB was assessed as SB, AB-grinding, AB-clenching, AB-bracing, and AB-combined (i.e., the maximum frequency of all AB types combined). The Wilcoxon signed-rank test was used to compare the SB and AB frequency at t0 and t1 in patients who received counseling alone and those who received counseling combined with other treatment. The χ2 test was used to investigate the association between the type of TMD treatment and changes in SB and/or AB. The frequency of self-reported SB and all types of AB did not change in patients who received counseling only. In contrast, there was a significant increase in the frequency of AB-bracing and AB-combined between t0 and t1 in patients who received counseling combined with other treatment. No changes in the frequency of self-reported SB and all types of AB were found in patients who received counseling only. However, patients who received counseling combined with other treatment showed a significant increase in the frequency of AB-bracing and AB-combined as compared to baseline.

Understanding the clinical management of co-occurring sleep-related bruxism and obstructive sleep apnea in adults: A narrative and critical review.

Sleep-related bruxism (SRB) is a motor oral behavior characterized by tooth grinding and jaw clenching activity, reported by 8%-12% of the adult general population and 3% of older individuals. The frequency of one of its biomarkers, rhythmic masticatory muscle activity (RMMA), remains elevated across ages. Obstructive sleep apnea (OSA) is associated with the brief and repetitive pause of breathing (apnea) and with transient reduction in oxygen (hypoxia). OSA is observed at all ages and in about 50% of older individuals with a male preponderance. SRB clinical assessment is based on self-reporting of tooth grinding sound, awareness of clenching, jaw pain or headache, and clinical observation of tooth damage. OSA clinical assessment is based on sleepiness and fatigue, snoring, sleep quality, and awareness of breathing cessation, plus clinical examination of anatomical factors (e.g., obesity, retrognathia, large tonsil, macroglossia), age, gender, and body mass. Although the literature does not support association or causality between these two conditions, the co-occurrence is reported in about 30%-50% of adults. To confirm a diagnosis of co-occurring SRB and OSA, home sleep testing (HST) may be indicated. A sleep test is performed using electromyography (EMG) of jaw muscle (masseter or temporalis) and cardio-respiratory variables (e.g., air flow, respiratory effort, oxygen level, heart rate). The management of co-occurring SRB and OSA for individuals with prosthodontic needs is challenging to prevent compromising the oro-pharyngeal space and breathing efficiency. OSA treatment in the presence of SRB includes continuous positive airway pressure (CPAP) use alone or with an occlusal splint or mandibular advancement device (MAD). In addition, the following may be considered: supine sleep correction device, myofuncional therapy, medications, and surgeries. All have limitations and risks. Individual variability suggests that phenotyping is mandatory to select the most efficient and personalized treatment.

Diagnosis and Management of Obstructive Sleep Apnea: Updates and Review

Obstructive sleep apnea (OSA) is a heterogenous disease process that cannot be adequately categorized by AHI alone. There is a significant prevalence of OSA in the general population with ongoing efforts to evaluate the risk factors contributing to OSA and its associated clinical implications. Only by improving our understanding of OSA can we advance our methods in the diagnosis and treatment of OSA. For this article, the authors reviewed keywords of obstructive sleep apnea diagnosis and therapy in the databases of Embase, Medline, and Medline ePub over the past 3 years, excluding any articles that only addressed sleep apnea in children under age 17 years. This review article is divided into three main sections. First, we will investigate the use of novel screening tools, biomarkers, anthropometric measurements, and novel wearable technologies that show promise in improving the diagnosis of OSA. There is mention of comorbid conditions seen in OSA patients since certain disease combinations can significantly worsen health and should raise our awareness to diagnose and manage those concomitant disorders. The second section will look at the current and developing treatment options for OSA. These include positive airway therapy (PAP), mandibular advancement device (MAD), exciting new findings in certain medications, orofacial myofunctional therapy (OMT), hypoglossal nerve stimulation therapy (HGNS), and other surgical options. We will conclude with a section reviewing the current Clinical Practice Guidelines for Diagnostic Testing in Adults with Obstructive Sleep Apnea from 2017, which strongly advises polysomnography (PSG) or home sleep apnea testing (HSAT), along with comprehensive sleep evaluation for uncomplicated patients with a clinical presentation of OSA.

Awareness of deleterious oral habits and knowledge of habit breaking appliance among parents in Alkharj - A cross sectional study

Background Actions that are repetitive and being practiced automatically are called habits. Oral habits can be classified as normal or deleterious. Oral health education starts from footprints of awareness. Growing children require appropriate guidance for healthy growth and maintenance of their teeth, which makes the parent an active participant in the prevention and treatment of malocclusion and thus is majorly affected by their knowledge and attitude regarding various deleterious oral habits and habit breaking appliances. Aim To assess and compare awareness of deleterious oral habits and knowledge of habit breaking appliance, among parents at Alkharj Saudi Arabia. Methodology Study assessed awareness of deleterious oral habits and knowledge of habit breaking appliances among parents in Alkharj, Saudi Arabia. Results Conclusion Majority of the parents were aware of different deleterious oral habits but not aware of the dimensions of interventions like types of appliances, duration of use, etc. without knowing mentioned facts, in future which leads to development of malocclusion which probably requires orthodontic, surgical or prosthetic intervention correcting the outcomes of oral deleterious habits.

Drug induced sleep endoscopy and simultaneous polysomnography to predict the effectiveness of mandibular advancement device in obstructive sleep apnea treatment.

To evaluate whether mandibular advancement device therapy is recommended in patients affected by obstructive sleep apnea. In order to predict oral appliances therapy response, drug induced sleep endoscopy with cardio-respiratory polygraphy and mandibular advancement device simulator was carried out. Patients in which upper airway obstruction was resolved on all levels and AHI was normalized (< 5/h), were referred for oral appliance therapy. At 5 months follow up, a cardio-respiratory polygraphy with MAD was performed. 36 patients who have evidence of resolution of UA collapse and AHI below 5 events per hour, were referred for MAD therapy. At follow up, the mean AHI decreased from 29.1 ± 13.1 to 3.3/h ± 1.9 (p < 0.001). All the patients were responders. Combining the evaluation of drug induced sleep endoscopy and cardio-respiratory polygraphy data simultaneously during mandibular protrusion, has the potential to be a useful tool for prediction of MAD therapy response.

Management of Obstructive Sleep Apnea in the Infant: A Systematic Review and Meta-analysis.

To evaluate the improvement in respiratory parameters of infants with obstructive sleep apnea (OSA) treated with medical or surgical intervention. A comprehensive review was completed using the PubMed, Web of Science, Embase, and Cochrane libraries including articles published from 1975 to 2024. Interventions studied included adenotonsillectomy, mandibular distraction osteogenesis (MDO), tongue/lip adhesion, partial glossectomy, floor-of-mouth release, supraglottoplasty, oral appliances, tracheostomy, and positioning. Continuous positive airway pressure (CPAP) served as a control. Outcomes studied included pre- and postintervention obstructive apnea-hypopnea index. Studies included randomized controlled trials and case-control trials. A total of 2161 records were identified, and 59 studies were included in the analysis. Data was extracted following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and pooled using a random-effects model. The primary study outcome established prior to data collection was a change in the apnea-hypopnea index. A meta-analysis of MDO performed in infants for OSA demonstrated an overall pooled mean difference (pre-apnea-hypopnea index minus post-apnea hypopnea index) of 30.1 (95% confidence interval: 22.9, 37.4; 10 studies, 373 patients). No other data was pooled for analysis due to study heterogeneity. All CPAP studies showed apnea resolution. Tailored therapies including supraglottoplasty and tongue-lip adhesion reduced but did not resolve apneic events. Current investigations of the evaluation and treatment of infant OSA are limited by heterogeneity in reporting and study. Mandibular distraction and CPAP are promising.

Practices and Perception of Paediatric Obstructive Sleep Apnea Among Orthodontists and Paediatric Dentists in Brazil: A Mixed-Methods Study.

To explore orthodontists' (OTs) and paediatric dentists' (PDs) practices and perceptions regarding the screening and management of paediatric obstructive sleep apnea (OSA). This explanatory sequential mixed methods design included OTs and PDs with active clinical practice in Brazil and encompassed a quantitative phase followed by a qualitative phase. In the quantitative phase, a survey assessing OSA screening and management practices was administered to OTs and PDs practicing in Brazil. Information-rich OTs and PDs were interviewed in the qualitative phase. Descriptive statistics and the chi-square test were used to analyse the survey data, while inductive content analysis was applied to the interview data. The results from both phases were integrated and reported narratively. Three hundred eighty-one OTs and PDs completed the survey, and ten of them were interviewed. Nearly half of OTs and PDs administered sleep questionnaires and demonstrated some knowledge about paediatric OSA signs and symptoms. PDs and OTs primarily offered rapid maxillary expansion and functional mandibular advancement for managing selected children with OSA, with OTs being more frequently involved in this task than PDs. OTs and PDs identified several barriers and expressed the need for support regarding access to reliable screening tools and interprofessional care. Brazilian OTs and PDs were aware of the main signs and symptoms of paediatric OSA and were somewhat involved in offering oral appliance management options. To further define the role of these professionals, increasing support for dental professionals in OSA management and updating existing clinical guidelines is warranted.

Cone beam computed tomography changes upon oral appliance therapy for adult patients with obstructive sleep apnea: A non-randomized clinical trial.

Obstructive sleep apnea (OSA) is caused by narrowing or obstruction of the airway lumen at single or multiple levels of the airway, starting from the nasal cavity up to the larynx. Oral appliance therapy for the management of OSA is prescribed as an alternative treatment option for patients with mild to moderate OSA who fail to adhere to Continuous Positive Airway Pressure (CPAP) therapy. Treatment with oral appliances addresses the craniofacial deficiencies that cause OSA by providing means to mandibular advancement and palatal expansion, thus opening the airways and potentially preventing airway collapse during sleep. Imaging the upper airway is employed to investigate the narrowing or the obstruction in the airway. Three-dimensional imaging modalities such as cone beam computed tomography (CBCT) allow for detecting obstructions before commencing treatment and for evaluating changes in the upper airway dimensions after treatment. To evaluate the effect of the biomimetic oral appliance therapy (BOAT) device on the airway measurements taken from a CBCT before and after treatment in correlation with the changes in the AHI. A non-randomized clinical trial. About 17 patients with mild-moderate OSA (9 males, 8 females; age, mean [SD]: 45.76 [10.31]) underwent BOAT therapy. Subjects had 2 months of follow-up visits, including examinations for progress and adjustment of the appliances. The mean apnea-hypopnea index (AHI) with no appliance in the mouth before BOAT and after treatment was recorded. The midpalate screw mechanism of the appliance was advanced once per week. The subjects were asked to wear the appliance for 10 to 12 h/d and night. Pre and Post CBCT were taken. Paired T-test was used to analyze the results. The treatment duration was 15.4 ± 6.3 months. Before treatment, at the diagnosis stage, the mean AHI of the sample (n = 17) was 24.0. After treatment, the mean AHI fell by 5% to 22.8% (P = .019), indicating enhanced upper airway functions. Airway measurements from the CBCT were not statistically significant despite improvement in the polysomnographic parameters. CBCT is a valuable tool for airway assessment and the determination of upper airway anatomic risk factors for OSA.

Effects on Sleep Bruxism Activity of Three Different Oral Appliances: One Year Longitudinal Cohort Study.

Different oral appliances (OAs) have been proposed to control sleep bruxism (SB) detrimental effects on the stomatognathic system. The aim of the study was to evaluate the effect of different OAs on SB activity and masticatory muscle activity (sMMA) measured by EMG. This longitudinal cohort study was conducted on 51 patients (21 M, 30 F, mean age 26,5 ± 3,5) suffering from SB diagnosed with a validated portable EMG-ECG holter and wearing different OAs: occlusal splints, functional appliance with metallic bites and clear aligners followed after 1 week, 1 month, 3 months, 6 months and 12 months from delivery. A control group of 16 non-treated SB patients (6 M, 10 F mean age 27,1 ± 1,4) was used as a reference. A multiple regression analysis was performed to estimate the differences between groups. The level of significance was set as P value <0,05. Occlusal splint reduced sleep bruxism index after 1 week, 3, 6 and 12 months from delivery while functional appliance only after 12 months. Occlusal splints reduced general phasic contractions only in the first week and sleep bruxism-related phasic contractions at 1 week, 3 and 6 months after delivery with no significant reductions after 12 months. Patients wearing clear aligners showed a reduction in general tonic contractions after 6 and 12 months. Resin and metal bites can reduce sleep bruxism index, while resin bites can reduce sleep bruxism-related phasic contractions. Clear aligners do not influence sleep bruxism index but can reduce tonic contractions.

Oral appliances in the management of neuropathic pain

Oral appliances in the management of neuropathic pain

Evaluation of oral appliance therapy for sleep apnoea patients

Evaluation of oral appliance therapy for sleep apnoea patients

Precision medicine approaches in obstructive sleep apnoea: The role of dentist-sleep physician partnerships.

Obstructive Sleep Apnoea (OSA) is a common heterogenous sleep disorder that is associated with a wide range of comorbidities and consequences, including the development of neurocognitive and cardiometabolic disorders. The heterogeneity of OSA necessitates a precision medicine approach to accurately diagnose this condition and to effectively manage patients. One of the primary models of precision medicine is described by the P4 approach of predicting those who are susceptible to disease, preventing the occurrence of disease, personalizing treatment, and encouraging patients to participate in their individual healthcare journey. Recent advances in oral appliance therapy and OSA monitoring techniques have fostered an exciting opportunity for enhanced collaboration between dentists and sleep physicians to optimize OSA precision medicine care. This review aims to discuss the sources of heterogeneity among OSA patients, provide an overview of the growing applications of oral appliance therapy and tailored monitoring programs for OSA that are shifting treatment to a more personalized and participatory model of care, and outline the pivotal role of dentists in managing patients with OSA.

Elastic Bands Improve Oral Appliance Treatment Effect on Obstructive Sleep Apnoea: A Randomised Crossover Trial.

Oral appliances (OAs) that limit mouth opening during sleep, such as monobloc appliances, have shown superior treatment effects in subgroups of patients with obstructive sleep apnoea. The application of elastic bands on bibloc appliances may resemble these benefits. The primary objective was to investigate if application of elastic bands to bibloc appliances improves treatment success (> 50% reduction of respiratory event index (REI)), in addition to other subjective variables. Furthermore, we aimed to identify variables predicting the need for elastic bands in OA treatment. Included patients (n = 69) were randomly assigned to OA treatment with or without elastic bands. After 3 weeks, treatment effect was investigated with home respiratory polygraphy and questionnaires. Thereafter, patients changed treatment modality, with identical follow-up regime. Statistical analyses were performed using Student's t-test and Pearson's chi-squared test to investigate differences between the two treatment modalities, and logistic regression analysis was conducted to investigate variables tentatively associated with treatment success. Based on REI, the success rate with OA treatment was in favour of elastic bands (53.9% vs. 34.6%, p = 0.002). Male sex and larger maximum mouth opening were identified as predictors for increased treatment success with elastic bands. The main benefit with elastic bands seemed to be greater reduction of REI when supine. However, patients seem to prefer OA without elastic bands. Elastic bands improved OA treatment effect by reducing the REI in supine position. Patient groups that seemed to benefit from elastic bands in OA treatment were men with large maximum mouth openings.

Management of paediatric sialorrhea

Purpose of review To summarize current understanding of and recent literature on the management of sialorrhea in children. Recent findings Sialorrhea is a symptom of oropharyngeal dysphagia and reduced clearance. Sialorrhea can be anterior, with forward overflow of saliva, causing skin rash, social embarrassment and spillage on communication devices; or posterior, where there is pharyngeal pooling of saliva, which may cause aspiration. Assessment of sialorrhea involves a clinical evaluation, focusing on the individual's age, development, underlying medical condition and whether the sialorrhea is anterior, posterior or both. Craniomaxillofacial structure, posture, airway patency, neuromotor control, level of social awareness, motivation and caregiver concerns are assessed. To manage sialorrhea, integration of multiple strategies is usually needed. There is good evidence for behavioral intervention, oral appliances, anticholinergic medications, botulinum toxin injection and surgery. The role of various options of surgery in providing a longer lasting effect is supported. Adjunctive airway and craniomaxillofacial surgery may be indicated. Summary Sialorrhea is a modifiable condition with multifactorial causes requiring multimodal therapy by an inter-disciplinary team. There is increasing evidence on the role of saliva surgery in improving the quality of life for the person with sialorrhea and their caregivers.

Dentoskeletal changes of long-term oral appliance treatment in patients with obstructive sleep apnea: A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to evaluate the dental and skeletal effects of the long-term oral appliance (OA) treatment in patients with obstructive sleep apnea (OSA) and provide insights for clinicians in treatment planning and decision-making for OSA patients undergoing OA treatment. A comprehensive literature search was conducted in major databases up to April 2024. Studies were included if they assessed long-term OA treatment (≥6 months) in adults with OSA using any type of mandibular advancement device (MADs) or tongue retaining device (TRD). Dental and skeletal changes, measured by dental cast and cephalometric analysis, were the primary outcomes. A total of 42 studies were included in the systematic review, with 23 included in the meta-analysis. Long-term OA treatment was associated with a significant decrease in overbite (0.87mm, 95% CI: 0.69-1.05) and overjet (0.86mm, 95% CI: 0.69-1.03). Subgroup analyses showed the decrease of overbite and overjet progressively changed over the years intervals. There was a significant retroclination of the upper incisors (U1-SN, 2.58°, 95% CI: 1.07-4.08) and proclination of the lower incisors (L1-MP, -2.67° (95% CI: -3.78-1.56). Skeletal changes were not significant. Overbite and overjet gradually decreased in the long-term OA treatment, which might predominantly result from the retroclination of the upper incisors and the proclination of the lower incisors. The skeletal patterns in the anteroposterior and vertical direction might remain relatively stable over time. There was a tendency for the clockwise rotation of the mandible.

Effect of exercise versus mandibular advancement device in moderate obstructive sleep apnea patients with mandibular retrognathia: A randomized clinical trial

ABSTRACT Objective The aim of this study was to investigate the effects of exercise and mandibular advancement device (MAD) on severity of Obstructive sleep apnea syndrome (OSAS) with mandibular retrognathia. Methods Patients were randomly allocated into either exercise group or MAD group. All patients underwent blood tests, polysomnography studies and questionnaires studies at enrollment and at the 12-week’s follow-up. Results Our study showed MAD was superior to exercise in improving polysomnographic outcomes and Snore Scale (SS) score. No significant difference was observed between the two treatments in terms of Epworth Sleepiness Scale (ESS) score. Moreover, in the exercise group, improvements were also observed in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Conclusion MAD was more effective than exercise in improving sleep efficiency. Exercise can improve daytime sleepiness and lipid metabolism, independent of the effects on BMI. Trial registration ChiCTR2000034188

Polysomnographic phenotypes: predictors of treatment response in Obstructive Sleep Apnea with Mandibular Advancement devices

Polysomnographic phenotypes: predictors of treatment response in Obstructive Sleep Apnea with Mandibular Advancement devices

Biofilm formation of Streptococcus mutans, Streptococcus sanguinis, Staphylococcus epidermidis, Staphylococcus aureus, Lactobacillus casei, and Candida Albicans on 5 thermoform and 3D printed orthodontic clear aligner and retainer materials at 3 time points: an in vitro study

IntroductionOrthodontic clear aligners and retainers have numerous advantages that is making them ever increasingly popular. However, they might, similar to any other oral appliance, contribute to biofilm formation and finally dental caries or white spot lesions or gingival inflammations. The literature on biofilm formation on orthodontic clear appliances is very scarce and limited to a few microorganisms and materials. Therefore, this experimental study evaluated the biofilm formation on 5 thermoformed and 3D printed CAD/CAM orthodontic retainers in 3 intervals.MethodsIn this in vitro study, 345 specimens (270 test discs and 45 negative controls) were created from fabricated retainers. Retainers included a 3D printed CAD/CAM material (Detax) and four thermoformed retainers [Erkodent (polyethylene terephthalate glycol [PETG]); EasyVac (polyethylene); DB (polyester based on terephthalic acid); and Clear Tech]. They were all 1 mm thick, and all completely fabricated, i.e., heated or printed. The discs were placed in 96-well plates. Microorganisms were cultured on 270 discs for 24 h (90 discs), 72 h (90 other discs), and 5 days or 120 h (90 other discs). Biofilm formation of the strains and negative controls was measured using the microtiter plate assay by ELISA reading. The microbes’ ability to produce biofilm was categorized based on the comparison of average optical density (OD) of tests versus a cut-off point OD (ODc) calculated as the average of the OD of corresponding negative controls plus 3× its standard deviation: non-biofilm former [OD ≤ ODc], weak biofilm former [ODc < OD ≤ (2 × ODc)], moderate biofilm former [(2 × ODc) < OD ≤ (4 × ODc)], and strong biofilm former [(4 × ODc) < OD]. These were also converted to ranked scores between zero (no biofilm) and 3. The difference between ODs with control ODs were calculated. These were analyzed using 3-way ANOVA, 2-way ANOVA, and Tukey tests (α = 0.05, α = 0.008).ResultsThe 3-way ANOVA showed that the overall difference among the ΔODs of 5 retainers (all microorganisms and all intervals combined, n = 270) was not significant (F = 1.860, P = 0.119). Nevertheless, the difference among 3 intervals (F = 31.607, P = 0.0000) and the difference among the 6 microorganisms (F = 24.044, P = 0.0000) were significant. According to the Tukey test, the differences between the 1st interval with either of the other two intervals was significant (both P values = 0.000). There were significant differences between Candida albicans with all other organisms (all 5 P values = 0.0000). All other pairwise comparisons were insignificant (all 10 P values ≥ 0.1). After taking the averages of the 3 intervals, the order of the biofilm generation for different materials were as follows: Detax (average score: 1.56), Easyvac (1.67), Erkodent (1.78), Clear Tech (1.83), BD (2.28).ConclusionsAs far as these 6 microorganisms are of concern, there might not be a significant overall difference among the clear retainer materials tested in this study. A significant overall increase was observed between the first and third days, which later did not significantly increase more until day 5. The Candida albicans biofilm was more intense than the tested 5 bacteria, which themselves showed rather similar growth patterns to each other.

Diagnosis and management of bruxism. A literature review

Bruxism, characterized by involuntary grinding or clenching of teeth, is a widespread condition with multifaceted implications for oral health, physical well-being, and quality of life. This comprehensive review aims to provide an in-depth study of bruxism, encompassing its definition, classification, etiology, pathophysiology, clinical manifestations, and consequences. Bruxism is classified based on its timing (sleep bruxism or awake bruxism). The etiology of bruxism is multifactorial, involving physiological factors such as central nervous system (CNS) pathways, sleep disorders, and occlusal factors, as well as psychological factors like stress, anxiety, personality traits and environmental factors including medications, substances, and stressors. Clinically, bruxism can result in various dental consequences, including tooth wear, fractures and damage to restorations, as well as temporomandibular disorders (TMDs) such as myofascial pain. These manifestations can negatively impact individual's oral health, physical well-being, and overall quality of life. Management strategies include behavioral and lifestyle changes, oral appliances, dental treatments for tooth damage, and, in certain instances, pharmacological interventions. While the current understanding of bruxism has advanced, further research is needed to fully elucidate its etiology, pathophysiology, and effective management strategies.