Post-Traumatic Trigeminal Neuropathy: Neurobiology and Pathophysiology.

Painful traumatic trigeminal neuropathy (PTTN) is a chronic neuropathic pain that may develop following injury to the trigeminal nerve. Etiologies include cranio-orofacial trauma that may result from dental, surgical, or anesthetic procedures or physical trauma, such as a motor vehicle accident. Following nerve injury, there are various mechanisms, including peripheral and central, as well as phenotypic changes and genetic predispositions that may contribute to the development of neuropathic pain. In this article, we review current literature pertaining to the cellular processes that occur following traumatic damage to the trigeminal nerve, also called cranial nerve V, that results in chronic neuropathic pain. We examine the neurobiology and pathophysiology based mostly on pre-clinical animal models of neuropathic/trigeminal pain.

Pharmacological Topical Therapy for Intra-Oral Post Traumatic Trigeminal Neuropathic Pain: A Comprehensive Review.

Background: The efficacy of topical treatments in alleviating neuropathic pain is well-established. However, there is a paucity of research on topical interventions designed specifically for intra-oral application, where the tissue composition differs from that of exposed skin. Methods: This comprehensive review endeavors to assess the extant evidence regarding the efficacy of topical treatments in addressing neuropathic pain within the oral cavity. Utilizing combinations of search terms, we conducted a thorough search across standard electronic bibliographic databases-MEDLINE (via PubMed), Embase, Google Scholar, and Up to Date. The variables under scrutiny encompassed topical treatment, local intervention, chronic oral and orofacial pain, and neuropathic pain. All pertinent studies published in the English language between 1992 and 2022 were included in our analysis. Results: Fourteen relevant manuscripts were identified, primarily consisting of expert opinions and case reports. The comprehensive review suggests that topical treatments, especially when applied under a stent, could be effective in mitigating neuropathic pain in the oral area. However, it is crucial to conduct further studies to confirm these preliminary results. The limitations of the reviewed studies, mainly the reliance on expert opinions, small sample sizes, inconsistent study designs, and a lack of long-term follow-up data, highlight the need for more rigorous research. Conclusions: Although initial findings indicate topical treatments may be effective for oral neuropathic pain, the limitations of current studies call for more thorough research. Further comprehensive studies are essential to validate the efficacy of these treatments, standardize procedures, and determine long-term results. This will provide clearer guidance for treating chronic neuropathic pain in the oral cavity.

Time-Course Progression of Whole Transcriptome Expression Changes of Trigeminal Ganglia Compared to Dorsal Root Ganglia in Rats Exposed to Nerve Injury.

Mechanisms underlying neuropathic pain (NP) are complex with multiple genes, their interactions, environmental and epigenetic factors being implicated. Transcriptional changes in the trigeminal (TG) and dorsal root (DRG) ganglia have been implicated in the development and maintenance of NP. Despite efforts to unravel molecular mechanisms of NP, many remain unknown. Also, most of the studies focused on the spinal system. Although the spinal and trigeminal systems share some of the molecular mechanisms, differences exist. We used RNA-sequencing technology to identify differentially expressed genes (DEGs) in the TG and DRG at baseline and 3 time points following the infraorbital or sciatic nerve injuries, respectively. Pathway analysis and comparison analysis were performed to identify differentially expressed pathways. Additionally, upstream regulator effects were investigated in the two systems. DEG (differentially expressed genes) analyses identified 3,225 genes to be differentially expressed between TG and DRG in naïve animals, 1,828 genes 4 days post injury, 5,644 at day 8 and 9,777 DEGs at 21 days postinjury. A comparison of top enriched canonical pathways revealed that a number of signaling pathway was significantly inhibited in the TG and activated in the DRG at 21 days postinjury. Finally, CORT upstream regulator was predicted to be inhibited in the TG while expression levels of the CSF1 upstream regulator were significantly elevated in the DRG at 21 days postinjury. This study provides a basis for further in-depth studies investigating transcriptional changes, pathways, and upstream regulation in TG and DRG in rats exposed to peripheral nerve injuries. PERSPECTIVE: Although trigeminal and dorsal root ganglia are homologs of each other, they respond differently to nerve injury and therefore treatment. Activation/inhibition of number of biological pathways appear to be ganglion/system specific suggesting that different approaches might be required to successfully treat neuropathies induced by injuries in spinal and trigeminal systems.

Orofacial pain for clinicians: A review of constant and attack-like facial pain syndromes.

BACKGROUND: Primary headache syndromes such as migraine are among the most common neurological syndromes. Chronic facial pain syndromes of non-odontogenic cause are less well known to neurologists despite being highly disabling. Given the pain localization, these patients often consult dentists first who may conduct unnecessary dental interventions even if a dental cause is not identified. Once it becomes clear that dental modalities have no effect on the pain, patients may be referred to another dentist or orofacial pain specialist, and later to a neurologist. Unfortunately, neurologists are also often not familiar with chronic orofacial pain syndromes although they share the neural system, i.e., trigeminal nerve and central processing areas for headache disorders. CONCLUSION: In essence, three broad groups of orofacial pain patients are important for clinicians: (i) Attack-like orofacial pain conditions, which encompass neuralgias of the cranial nerves and less well-known facial variants of primary headache syndromes; (ii) persistent orofacial pain disorders, including neuropathic pain and persistent idiopathic facial/dentoalveolar pain; and (iii) other differential diagnostically relevant orofacial pain conditions encountered by clinicians such as painful temporomandibular disorders, bruxism, sinus pain, dental pain, and others which may interfere (trigger) and overlap with headache. It is rewarding to know and recognize the clinical picture of these facial pain syndromes, given that, just like for headache, an internationally accepted classification system has been published and many of these syndromes can be treated with medications generally used by neurologists for other pain syndromes.

Orofacial Migraine or Neurovascular Orofacial Pain from Pathogenesis to Treatment.

The purpose of the present study is to examine possible differences between orofacial migraine (OFM) and neurovascular orofacial pain (NVOP). Facial presentations of primary headache are comparable to primary headache disorders; but occurring in the V2 or V3 dermatomes of the trigeminal nerve. These were classified and recently published in the International Classification of Orofacial Pain, 1st edition (ICOP). A category in this classification is "orofacial pains resembling presentations of primary headaches," which encompasses OFM and NVOP. The differences between NVOP and OFM are subtle, and their response to therapy may be similar. While classified under two separate entities, they contain many features in common, suggesting a possible overlap between the two. Consequently, their separation into two entities warrants further investigations. We describe OFM and NVOP, and their pathophysiology is discussed. The similarities and segregating clinical signs and symptoms are analyzed, and the possibility of unifying the two entities is debated.

Effects of intra-nasal melanocortin-4 receptor antagonist on trigeminal neuropathic pain in male and female rats.

Treatment of chronic orofacial pain remains a major therapeutic challenge despite available medications. Melanocortins have been implicated in pathologic pain. Intrathecal administration of MC4R antagonists has been shown to alleviate neuropathic pain (NP) in male rats. However, intrathecal delivery is very invasive and requires surgeon's intervention. Intra-nasal rout offers a non-invasive drug delivery method that can be self-administered making it very attractive clinically. In this study, we investigated the effects of intra-nasally delivered MC4R antagonist (HS014) on trigeminal neuropathic pain (TNP) in male and female rats. We also measured the MC4R protein levels in the trigeminal ganglia (TG) and infraorbital nerve (ION) of rats. We used ION chronic constriction injury (ION-CCI) to induce TNP in rats. We used von Frey and pinprick assays to measure the development of hypersensitivity in the face following ION-CCI. At 22 days post-ION-CCI, we delivered HS014 intra-nasally to measure its effects on TNP in rats. We used enzyme linked immunosorbent assay to measure MC4R protein levels in the TG and ION. ION-CCI resulted in a significant increase of MC4R protein levels in the ipsilateral TG and ION of male and female rats. Intra-nasal delivered HS014 resulted in a significant reduction of ION-CCI induced hypersensitivity in male and female rats. These results demonstrate that intranasal delivery of MC4R antagonist alleviated TNP in male and female rats and suggest that such treatment could be beneficial therapeutically for individuals with chronic NP.

Response profile in a rat model of exercise-induced hypoalgesia is associated with duloxetine, pregabalin and diclofenac effect on constriction-induced neuropathy.

BACKGROUND: Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise. OBJECTIVES: A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain. METHODS: EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications. RESULTS: Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH. CONCLUSIONS: The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment. SIGNIFICANCE: Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile.

Pathophysiology of Post-Traumatic Trigeminal Neuropathic Pain.

Trigeminal nerve injury is one of the causes of chronic orofacial pain. Patients suffering from this condition have a significantly reduced quality of life. The currently available management modalities are associated with limited success. This article reviews some of the common causes and clinical features associated with post-traumatic trigeminal neuropathic pain (PTNP). A cascade of events in the peripheral and central nervous system function is involved in the pathophysiology of pain following nerve injuries. Central and peripheral processes occur in tandem and may often be co-dependent. Due to the complexity of central mechanisms, only peripheral events contributing to the pathophysiology have been reviewed in this article. Future investigations will hopefully help gain insight into trigeminal-specific events in the pathophysiology of the development and maintenance of neuropathic pain secondary to nerve injury and enable the development of new therapeutic modalities.

Sensory Changes Related to Dental Implant Placement: A Scoping Review.

AIMS: To perform a scoping review of the literature to elucidate the occurrence of nerve damage related to dental implant placement and the factors causing the sensory changes. METHODS: An extensive electronic search was conducted using the Cochrane Library, Medline via Ovid, PubMed, Wiley Online, Science Direct, CINAHL, and the Google Scholar databases from the year 1950 to 2020. RESULTS: The search resulted in 1,067 articles, out of which 76 were selected for this review. The articles were categorized as literature review articles, retrospective studies, prospective studies, and case series/case reports. Altogether, 2,526 subjects were assessed retrospectively, with 5.27% transient and 1.39% persistent sensory changes, and a cohort of 2,750 subjects were followed prospectively, with 6.22% transient and 1.31% persistent sensory changes. A total of 336 subjects were enrolled in various case reports and case series, with 5.95% transient sensory changes and 84.52% persistent neurosensory changes. The articles included were not of high quality and have variations in their study designs and reporting procedures, with limited sensory change data to include in this study. CONCLUSION: After surgical placement of dental implants in 5,612 patients, the incidence of transient sensory changes was 5.63%, and the incidence of persistent sensory changes was 6.33%. Factors affecting the incidence were: mandibular location of the implant, with the inferior alveolar nerve as the most commonly affected nerve. The common symptoms reported were paresthesia and dysesthesia. Age and gender were among other factors, for which data were not available in all the articles.

A Review of Current Perspectives on Facial Presentations of Primary Headaches.

Orofacial pain (OFP) has recently been classified and subdivided into a number of groups, similar to headache disorders in the International Classification of Headache Disorders (ICHD). A novel group of OFP has been established whose major feature is that they resemble primary headache disorders occurring in the V2 or V3 dermatomes. These follow the clinical criteria and associated symptoms of the eponymous headache syndromes. Following the recent International Classification of Orofacial Pain (ICOP), three types are differentiated: Headache which spread into the face (type 1), facial pain which replaced headache but maintained the same characteristics and associated symptoms of the former headache (type 2), and de-novo orofacial pain that resembles primary headache types without any involvement of the ophthalmic trigeminal branch (type 3). The epidemiology is unclear: type 1 and 2 are not exactly common, they certainly exist in a notable proportion of headache patients, whereas type 3 may be rather rare. Since effective treatment options are available, it is important for clinicians to recognize such syndromes early to avoid misdiagnosis and unnecessary treatment, which most of these patients still experience. This review gives an up-to-date summary of diagnosis, pathophysiology and treatment of attack-like non-dental facial pain disorders.

Chemogenetic inhibition of trigeminal ganglion neurons attenuates behavioural and neural pain responses in a model of trigeminal neuropathic pain.

BACKGROUND: Nerve injury can lead to ectopic activation of injured nociceptorsand central sensitization characterized by allodynia and hyperalgesia. Reduction in the activity of primary afferent neurons has been shown to be sufficient in alleviating peripherally generated pain. The cell bodies of such trigeminal nociceptors are located in the trigeminal ganglia (TG) with central processes that terminate in the brainstem trigeminal nucleus caudalis (TNC). The TG is therefore a strategic locus where afferent input can be manipulated. We hypothesized that chemogenetic inhibition of TG would suppress TNC neuronal activity and attenuate pain behaviour in a rat model of painful traumatic trigeminal neuropathy (PTTN). METHODS: Trigeminal neuropathic pain was induced in adult male Sprague-Dawley rats (n = 24) via chronic constriction injury to the infraorbital nerve (ION-CCI). Naïve and sham rats were used as controls (n = 20/group). Rats within each group received TG-directed microinjections of AAV virus containing either the inhibitory hM4Di-DREADD construct or EGFP. RESULTS: In the ION-CCI group, systemic administration of the DREADD agonist clozapine N-oxide (CNO) reversed the hypersensitivity phenotype in animals expressing hM4Di but not EGFP. CNO-mediated activation of hM4Di DREADD in ION-CCI animals was also associated with reduced Fos expression in the TNC elicited by repeated mechanical stimulation of the dermatome ipsilateral to the injury. There was no effect of CNO on pain behaviour or TNC Fos expression in eGFP animals. CONCLUSION: Our results indicate that DREADDs may offer an effective therapeutic approach for treatment of trigeminal neuropathic pain. SIGNIFICANCE: Trigeminal neuropathic pain is highly resistant to therapy and we are in dire need of novel approaches. This study provides further evidence for the successful application of DREADDs as an effective tool for modulating central nervous system function. CNO mediated activation of hM4Di-DREADDs in the trigeminal ganglion (TG) attenuates nerve injury induced neuropathic pain by acting on hyperactive TG cells. It also establishes the TG as an effective target to manage pain in the face and head. Accessing the TG in clinical populations is a relatively simple and safe procedure, making this approach highly significant. Moreover, the methodology described here has applications in trigeminal neuropathic pain from traumatic other etiologies and in spinal neuropathic pain. Chronic pain syndromes are characterized by a progressive failure of brain centers to adequately inhibit pain and as these are identified, we may be able to target them for therapy. Therefore, our findings might have wide application in chronic pain syndromes.

The changing face of trigeminal neuralgia-A narrative review.

OBJECTIVE: This narrative review aims to update the reader on the new classification of trigeminal neuralgia (TN), clinical signs, pathophysiologic evidence, and their implications on management. This review is based on the authors' collective experience and knowledge of the literature in addition to a literature search. BACKGROUND: In recent years, the phenotype of TN has been intensively studied leading to discrete groups of patients. These include patients with TN with additional continuous pain, and patients with and without neurovascular compression of the trigeminal dorsal root entry zone. A number of associated clinical signs such as tearing and sensory changes need further research. METHODS: The literature on TN was searched in PubMed with the aims of providing evidence for the recently published third edition of the International Classification of Headache Disorders (ICHD) and update the clinical phenotype and management of the TN subcategories. RESULTS: The ICHD's new classification for TN is based on reliable clinical data, imaging, and neurophysiologic studies. The TN classification reflects current knowledge and has improved the possibility for clinicians to choose adequate management options. However, there is a lack of effective, safe drugs for the management of TN and sparse, robust data on neurosurgical options. CONCLUSION: Research into all aspects of TN-diagnosis, pharmacotherapy, surgery, long-term management prognosis, and natural history-is needed. Research should adhere to the ICHD's schema for TN. Improved drugs are needed along with rigorous research into surgical options and their efficacy for different subtypes of TN.

Genetic variation in catechol-O-methyltransferase is associated with individual differences in conditioned pain modulation in healthy subjects.

BACKGROUND: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. METHODS: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. RESULTS: SNP rs4680 (val158 met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. CONCLUSIONS: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5' regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

Exercise induced hypoalgesia profile in rats is associated with IL-10 and IL-1 ß levels and pain severity following nerve injury.

BACKGROUND: Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. METHODS: Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. RESULTS: The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. CONCLUSION: EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.

Effects of melanocortin-4 receptor (MC4R) antagonist on neuropathic pain hypersensitivity in rats - A systematic review and meta-analysis.

Melanocortin-4 receptor (MC4R) has been investigated as a potential drug target for the treatment of neuropathic pain. The objective of the study was to systematically identify the effects of MC4R antagonists on hypersensitivity in rat models of neuropathic pain. A systematic search was conducted using the following databases: WoS, PubMed, SCOPUS, and MEDLINE. Inclusion criteria were: rat hypersensitivity induced by models of neuropathic pain with reported effects of MC4R antagonist. Two researchers performed the selection process and data extraction. SYRCLE risk of bias tool was used. Standard mean differences (SMD) were calculated and pooled by meta-analysis using random effect models. Ten articles met the eligibility criteria and were included in the systematic review and meta-analysis. The results reveal that, in animals exposed to neuropathic pain, administration of MC4R antagonists significantly increased paw withdrawal threshold (SHU9119 SMD = 1.67, 95% CI: [0.91, 2.44], I2  = 0%; HS014 SMD = 2.2, 95% CI: [0.53, 3.87], I2  = 71%) and heat withdrawal latency (HS014 SMD = 3.35, 95% CI: [0.56, 6.14], I2  = 83%) compared to vehicle-treated animals. MC4R antagonists are effective in the alleviation of hypersensitivity in rodent neuropathic pain models. SHU9119 and HS014 antagonists showed the most prominent results. However, further investigation is needed to determine the optimal dose and time of treatment.

Postendodontic pain: a practical approach to diagnosis and management.

OBJECTIVES: Endodontic treatment is a routine procedure performed by general dental practitioners and endodontists on a daily basis. Fortunately, most patients undergoing endodontic therapy show a favorable outcome with uneventful healing. However, some patients develop pain following endodontic therapy. A majority of these patients develop acute, nociceptive pain ("flare-up") that resolves with appropriate treatment and subsequent healing. The dental profession is very adept at successfully managing the acute pain that occurs early following endodontic treatment. A minority of patients, however, develop ongoing pain following root canal therapy, termed chronic if persisting for 3 months or more. The diagnosis and management of chronic postendodontic pain are often challenging. This article aims to review pain following endodontic therapy, ranging from acute to chronic pain and its management, with specific emphasis on chronic pain, its pathophysiology, clinical features, diagnostic criteria, and management modalities. CONCLUSION: Endodontic treatment rarely leads to chronic neuropathic pain; however, when the nerve injury occurs and results in posttraumatic trigeminal neuropathic pain (PTNP), treatment options are very limited and rarely successful. Therefore, all steps should be taken to avoid nerve injury. Prevention of endodontic treatment related PTNP is crucial and achieved through early recognition, and prompt management.

Classification algorithm for the International Classification of Diseases-11 chronic pain classification: development and results from a preliminary pilot evaluation.

ABSTRACT: The International Classification of Diseases-11 (ICD-11) chronic pain classification includes about 100 chronic pain diagnoses on different diagnostic levels. Each of these diagnoses requires specific operationalized diagnostic criteria to be present. The classification comprises more than 200 diagnostic criteria. The aim of the Classification Algorithm for Chronic Pain in ICD-11 (CAL-CP) is to facilitate the use of the classification by guiding users through these diagnostic criteria. The diagnostic criteria were ordered hierarchically and visualized in accordance with the standards defined by the Society for Medical Decision Making Committee on Standardization of Clinical Algorithms. The resulting linear decision tree underwent several rounds of iterative checks and feedback by its developers, as well as other pain experts. A preliminary pilot evaluation was conducted in the context of an ecological implementation field study of the classification itself. The resulting algorithm consists of a linear decision tree, an introduction form, and an appendix. The initial decision trunk can be used as a standalone algorithm in primary care. Each diagnostic criterion is represented in a decision box. The user needs to decide for each criterion whether it is present or not, and then follow the respective yes or no arrows to arrive at the corresponding ICD-11 diagnosis. The results of the pilot evaluation showed good clinical utility of the algorithm. The CAL-CP can contribute to reliable diagnoses by structuring a way through the classification and by increasing adherence to the criteria. Future studies need to evaluate its utility further and analyze its impact on the accuracy of the assigned diagnoses.