Uso do laser de baixa potência para o tratamento de parestesia: uma revisão de literatura / Use of low-level laser to treat paresthesia: a literature review

Introdução: A parestesia é uma neuropatia que afeta a função sensorial. O Laser de Baixa Potência (LBP), por sua vez, apresenta propriedades analgésicas, bioestimuladoras e reparadoras. Objetivo: Realizar um levantamento na literatura científica sobre os aspectos gerais e benefícios do LBP no manejo terapêutico da parestesia, além de identificar a classificação e métodos de obtenção do diagnóstico desta condição. Materiais e Métodos: Tratou-se de uma revisão narrativa da literatura através da busca nas plataformas PubMed, SciELO, LILACS e Google Schoolar. Após o cruzamento dos descritores com os operadores booleanos e aplicação dos critérios de inclusão/exclusão, 26 estudos foram incluídos. Resultados: A parestesia pode ser classificada em neuropraxia, axonotmese e neurotmese, subdivididas em Grau I ao V. Seu diagnóstico pode ser executado através de testes subjetivos e objetivos. O LBP compreende em um dispositivo tecnológico com efeitos analgésico, anti-inflamatório e fotobiomodulador, que estimula o reparo neural. Os estudos mostram que a dosimetria nos comprimentos de onda vermelho e infravermelho, aplicação intra e extra oral, e com mais de uma sessão semanal exerce efeito modulatório positivo do reparo neural, com retorno progressivo da atividade sensitiva. Além disso, os estudos trazem uma ampla variação no número de pontos de aplicação, bem como no tempo de irradiação e quantidade de sessões, em virtude da extensão e tempo de diagnóstico da parestesia. Considerações finais: Apesar da alta complexidade da parestesia, o LBP exerce efeitos benéficos através do retorno da sensibilidade parcial ou total, além de ser um dispositivo bem tolerado pelo organismo e minimamente invasivo.

Introduction: Paresthesia is a neuropathy that affects sensory function. The Low-Level Laser (LLL), in turn, has analgesic, biostimulating and reparative properties. Purpose: Carry out a survey at the scientific literature on the general aspects and benefits of LLL in the therapeutic management of paresthesia in addition to identifying the classification and methods for obtaining a diagnosis of this condition. Materials and Methods: It was a narrative literature review through search in platforms PubMed, SciELO, LILACS and Google Schoolar. After crossing the descriptors with boolean operators and applying the inclusion/exclusion criteria, 26 articles were included in this study. Results: Paresthesia can be classified into neuropraxia, axonotmesis and neurotmesis, subdivided into Grades I to V. Its diagnostic can be carried out through subjective and objective tests. The LLL consists in a technological device with analgesic, anti-inflammatory and photobiomodulatory effects, which stimulates neural repair. Studies show that LLL in dosimetry at red and infrared wavelengths with intra and extra oral application and with more than one-week use exerts a positive modulatory effect on neural repair, with a progressive return of sensory activity. Furthermore, the studies show a wide variation in the number of application points, as well as the irradiation time and number of sessions, due to the extent and time of diagnosis of paresthesia. Final Considerations: Despite the high complexity of paresthesia, the LLL has beneficial effects through the return of partial or total sensitivity in addition being a device well tolerated by the body and minimally invasive.

Investigating Optic Nerve Sheath Diameter in Prone Position Spinal Surgery Patients: A Pilot Study.

Purpose: This study aimed to evaluate the effect of intraoperative positioning and ocular immobility on the amount of cerebrospinal fluid around the optic nerve in patients undergoing prone spinal surgery by measuring the optic nerve sheath diameter (ONSD) using ultrasound. Methods: Consecutive participants (n = 15 patients, 30 eyes) were scanned preoperatively, intraoperatively approximately 20 minutes before the end of the surgery, and postoperatively in the post-anesthesia care unit at least 10 min after the completion of the surgery at one academic hospital. Results: On average, patients who underwent prone spinal surgery had a 21% increase in ONSD intraoperatively, with a positive time-dependent relationship with the overall length of surgery (P < 0.001). ONSDs postoperatively returned to baseline and were not significantly different from preoperative measurements. Conclusion: Our findings suggest pooling and inadequate clearance of perioptic cerebrospinal fluid during prone spinal surgery that improves following termination of the procedure and return of the patient to an upright position.

CHARGE syndrome in a child with a CHD7 variant and a novel pathogenic SOX2 variant: A case report.

CHARGE syndrome is a clinically heterogeneous condition that typically presents with a loss-of-function mutation in CHD7. SOX2 anophthalmia syndrome is a rare condition associated with hypogonadism and hearing loss. Herein, we describe the case of a Japanese boy presenting with a micropenis, bilateral cryptorchidism, cupped ear, right facial nerve palsy, and bilateral hearing loss, clinically meeting the diagnostic criteria for CHARGE syndrome, but with optic nerve hypoplasia, which is atypical for the syndrome. Therefore, a genetic analysis (next-generation sequencing) was performed. In addition to the missense variant p.[Arg1940Cys] in CHD7, a novel nonsense variant, p. [Tyr110*] in SOX2 was identified. Although most features, including genital abnormalities and hearing loss, were clinically compatible with CHARGE syndrome caused by a CHD7 variant, optic nerve hypoplasia may have been caused by a pathogenic SOX2 variant. Prior research has shown that SOX2 is related to the development of male genitalia and the inner ear. Therefore, the genital abnormalities and hearing loss in this patient may be attributed to both the CHD7 and SOX2 variants. Furthermore, the interactions between SOX2 and CHD7 may have affected symptoms independently or reciprocally.

CNPY2 protects against ER stress and is expressed by corticostriatal neurons together with CTIP2 in a mouse model of Huntington's disease.

Canopy Homolog 2 (CNPY2) is an endoplasmic reticulum (ER) localized protein belonging to the CNPY gene family. We show here that CNPY2 is protective against ER stress induced by tunicamycin in neuronal cells. Overexpression of CNPY2 enhanced, while downregulation of CNPY2 using shRNA expression, reduced the viability of neuroblastoma cells after tunicamycin. Likewise, recombinant CNPY2 increased survival of cortical neurons in culture after ER stress. CNPY2 reduced the activating transcription factor 6 (ATF6) branch of ER stress and decreased the expression of CCAT/Enhancer-Binding Protein Homologous Protein (CHOP) involved in cell death. Immunostaining using mouse brain sections revealed that CNPY2 is expressed by cortical and striatal neurons and is co-expressed with the transcription factor, COUPTF-interacting protein 2 (CTIP2). In transgenic N171-82Q mice, as a model for Huntington's disease (HD), the number of CNPY2-immunopositive neurons was increased in the cortex together with CTIP2. In the striatum, however, the number of CNPY2 decreased at 19 weeks of age, representing a late-stage of pathology. Striatal cells in culture were shown to be more susceptible to ER stress after downregulation of CNPY2. These results demonstrate that CNPY2 is expressed by corticostriatal neurons involved in the regulation of movement. CNPY2 enhances neuronal survival by reducing ER stress and is a promising factor to consider in HD and possibly in other brain diseases.

Axillary lesion in a young adult ends up to a peculiar diagnosis: primitive neuro-ectodermal tumor (PNET) of ulnar nerve: a rare case report.

Introduction and importance: Primitive neuro-ectodermal tumor (PNET) is a highly aggressive tumor composed of small round blue cells, mostly developing in children and young adults. Being a member of Ewing's Sarcoma Family of Tumors (ESFT); it has been discussed in two subcategories of central and peripheral PNET. PNETs of peripheral nerves are very uncommon pathologic findings, as to the best of our knowledge only 12 well-documented cases have been yet reported. Case presentation: A 30-year-old male presented with progressive paresthesia of his right hand's little finger and painless swelling of the right axilla. Magnetic resonance (MR) neurography demonstrated a heterogeneous, high-signal, round mass within the right axilla fossa in proximity to the medial aspect of brachial plexus branches. The clinical and radiological study failed to an accurate diagnosis, thus surgical resection of the tumor was done for tissue evaluation. Histopathologic study of the lesion revealed a neoplasm comprising sheets of small, round, blue cells (Hematoxylin and Eosin stain), which immunohistochemically consisted with the diagnosis of PNET. Clinical discussion: The differential diagnosis of axillary fossa masses, focusses on peripheral nerve tumors like Schwannoma and PNET. MR neurography aids in evaluation, but tissue diagnosis remains crucial. Treatment involves surgical resection, chemotherapy, and radiotherapy tailored to individual patients. Conclusion: Although pPNET is not apparently the first differential diagnosis coming to mind when encountering a rapidly growing mass in the axillary fossa with peripheral nerve origin, its highly malignant behavior, makes it crucial to be considered in the differential diagnoses.

Idiopathic unilateral complete oculomotor nerve palsy: a case report of diagnostic quandary.

Introduction and importance: When compared to other cranial nerve palsies idiopathic unilateral oculomotor nerve palsy with pupillary sparing is one of the least noted neurological conditions. Moreover, there lies a series of diagnostic dilemmas to come into a final diagnosis resulting in several array of clinical investigations. Hence, there is a delay in prompt management. Case summary: An elderly female without any known comorbidities presented with the complaint of headache, dizziness and dropping of left eyelid. Several arrays of diagnostic workups was done to come to a diagnosis, but even with rigorous laboratory investigations and radiological examinations, a common working diagnosis could not be made. Hence with a diagnosis of exclusion after proper neurological and neuro-ophthalmological examination, idiopathic unilateral common oculomotor nerve palsy was identified for which improvement with steroids was noted in the patient. Discussion: Idiopathic unilateral complete oculomotor nerve palsy is considered as a diagnosis of exclusion when all the diagnostic parameters fail to signify and positive results. The vague symptomatic presentation of the disease condition further compels the treating physician to carry out several panels of laboratory to radiological investigations. But if identified in time the treatment modality is straightforward. Conclusion: The diagnostic quandary in timely identification of such disease conditions needs a pertinent diagnostic guideline so as to avoid the unwanted panel of investigations.

An Incidental Diagnosis of Conjoined Nerve Root After a Work-Related Back Injury: A Case Report.

Conjoined nerve roots (CNRs) are an uncommon condition often overlooked until surgery, posing significant intraoperative risks. This case report discusses a 21-year-old male diagnosed incidentally with a left lumbosacral CNR involving the fifth lumbar (L5) and first sacral (S1) spinal nerve roots following a work-related back injury, emphasizing the importance of preoperative imaging. Accurate early diagnosis of CNRs can prevent surgical complications and guide appropriate management, highlighting the need for careful preoperative planning and patient education.

Comparison of capsule and posterior lumbar interbody fusion in cauda equina syndrome with retention: a 24-month follow-up study.

BACKGROUND AND OBJECTIVES: Cauda equina syndrome with retention (CESR) is a severe lumbar condition characterized by painless urine retention due to cauda equina nerve injury. The standard treatment, posterior lumbar interbody fusion (PLIF), often yields suboptimal results. This study aims to compare the clinical safety and efficacy of a novel technique, capsule lumbar interbody fusion (CLIF), with PLIF in CESR patients, hypothesizing that CLIF can enhance neurological recovery by reducing nerve tension. METHODS: A single-center, retrospective study was conducted on 83 patients with CESR due to lumbar disc herniation, who underwent either PLIF (n = 44) or CLIF (n = 39). Patients were assessed preoperatively and at 3, 12, and 24 months postoperatively using the Oswestry Disability Index (ODI), Visual Analogue Scale (VAS), International Consultation on Incontinence Questionnaire Short Form (ICI-Q-SF), and Rintala score. Urodynamic studies and nerve tension measurements were also performed. Statistical analysis included t tests, Mann-Whitney U tests, and Spearman's correlation. RESULTS: Both groups showed significant postoperative improvements, but the CLIF group had superior outcomes. At 12 months, the CLIF group had lower VAS scores (1.15 ± 0.84 vs. 1.68 ± 0.60, p = 0.001) and ODI scores (23.31 ± 7.51 vs. 28.30 ± 8.26, p = 0.005). At 24 months, the CLIF group continued to show better results with ODI scores (15.97 ± 6.43 vs. 22.11 ± 6.41, p < 0.001) and higher ODI recovery rates (60.41 ± 17.6% vs. 44.71 ± 18.99%, p < 0.001). The CLIF group also had better ICI-Q-SF scores (2.13 ± 1.23 vs. 3.02 ± 1.45, p = 0.004) and Rintala scores (17.97 ± 1.43 vs. 16.59 ± 1.54, p < 0.001). Lower postoperative nerve tension in the CLIF group correlated with these improved outcomes. CONCLUSIONS: CLIF demonstrated superior efficacy over PLIF in treating CESR, with significant improvements in pain relief, functional recovery, and bladder and bowel function. This study highlights the potential of CLIF as a more effective surgical option for CESR, emphasizing its importance in improving patient outcomes and reducing the burden of CESR on patients and society.

Clinical Efficacy of Auricular Vagus Nerve Stimulation in the Treatment of Chronic and Acute Pain: A Systematic Review and Meta-analysis.

INTRODUCTION: Current guidelines for pain treatment recommend a personalized, multimodal and interdisciplinary approach as well as the use of a combination of drug and non-drug therapies. Risk factors for chronification should already be reduced in patients with acute pain, e.g., after surgery or trauma. Auricular vagus nerve stimulation (aVNS) could be an effective non-drug therapy in the multimodal treatment of chronic and acute pain. The aim of this systematic review and meta-analysis is to evaluate the clinical efficacy and safety of aVNS in treating chronic and acute pain conditions. METHODS: A systematic literature search was performed regarding the application of auricular electrical stimulation in chronic and acute pain. Studies were classified according to their level of evidence (Jadad scale), scientific validity and risk of bias (RoB 2 tool) and analyzed regarding indication, method, stimulation parameters, duration of treatment and efficacy and safety. A meta-analysis on (randomized) controlled trials (using different comparators) was performed for chronic and acute pain conditions, respectively, including subgroup analysis for percutaneous (pVNS-needle electrodes) and transcutaneous (tVNS-surface electrodes) aVNS. The visual analog pain scale (VAS) was defined as primary efficacy endpoint. RESULTS: A total of n = 1496 patients were treated with aVNS in 23 identified and analyzed studies in chronic pain, 12 studies in acute postoperative pain and 7 studies in experimental acute pain. Of these, seven studies for chronic pain and six studies for acute postoperative pain were included in the meta-analysis. In chronic pain conditions, including back pain, migraine and abdominal pain, a statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control treatment with an effect size Hedges' g/mean difference of - 1.95 (95% confidence interval [CI]: - 3.94 to 0.04, p = 0.008) could be shown and a more favorable effect in pVNS compared to tVNS (- 5.40 [- 8.94; - 1.85] vs. - 1.00 [- 1.55; - 0.44]; p = 0.015). In acute pain conditions, single studies showed significant improvements with aVNS, e.g., in kidney donor surgery or tonsillectomy but, overall, a non-statistically significant reduction in VAS pain intensity for active compared to sham aVNS or control with - 0.70 [- 2.34; 0.93] (p = 0.15) could be observed in the meta-analysis. In acute pain results vary greatly between studies depending especially on co-medication and timepoints of assessment after surgery. A significant reduction in analgesics or opiate intake was documented in most studies evaluating this effect in chronic and acute pain. In 3 of the 12 randomized controlled trials in patients with chronic pain, a sustainable pain reduction over a period of up to 12 months was shown. Overall, aVNS was very well tolerated. CONCLUSION: This systematic review and meta-analysis indicate that aVNS can be an effective and safe non-drug treatment in patients with specific chronic and acute postoperative pain conditions. Further research is needed to identify the influence of simulation parameters and find optimal and standardized treatment protocols while considering quality-of-life outcome parameters and prolonged follow-up periods. A more standardized approach and harmonization in study designs would improve comparability and robustness of outcomes.

Microscopical anatomy of the peripheral nervous system: An essential notion for understanding the pathophysiology of very early classic Guillain-Barré syndrome.

The aim of this paper is to analyze the pathophysiological mechanisms acting in very early classic Guillain-Barré syndrome (GBS) (≤4 days of symptomatic onset). In this inaugural period, both in GBS and its animal model, experimental autoimmune neuritis, the outstanding pathological feature is inflammatory edema predominating in proximal nerve trunks, particularly spinal nerves, and possibly in preterminal nerve segments. Nerve trunks external to the subarachnoid angle possess epi- perineurium that is relatively inelastic and of low compliance. Here such edema can increase endoneurial fluid pressure that, when sufficiently critical, may stretch the perineurium and constrict transperineurial microcirculation, compromising blood flow and producing the potential for ischemic nerve injury, whose consequence is rapid partial or complete loss of nerve excitability. These histopathological features correlate well with electrophysiological and imaging findings reported in early GBS stages. Spinal nerve edema and ischemia help to understand the pattern of Wallerian-like degeneration observed in the axonal form of GBS, predominating in motor spinal roots at their exit from the dura matter (spinal nerves) with centrifugal distribution in more distant motor nerve trunks, and centripetal extension to the distal portion of intrathecal roots. The similarity of initial pathogenic mechanisms between demyelinating and axonal forms of GBS explains why an early increase of serum biomarkers of axonal damage is detected in both forms. In conclusion, knowledge of the microscopic anatomy of the peripheral nervous system is an essential step for a reliable understanding of pathophysiological mechanisms operating in the early phase of any classic GBS subtype.

Revisiting the Muscles and Nerves of Anterior Compartment of the Arm: A Case Report.

During routine dissection of the anterior compartment of the arm region, we encountered several variations in the muscular and neural structures in the right upper extremity of a female cadaver. We observed one superiorly positioned extramuscular head with fibers originating from both the biceps brachii (BB) and coracobrachialis (CB) muscles and one inferiorly positioned extramuscular head with fibers solely from the BB muscle. The musculocutaneous nerve did not penetrate the CB muscle, but instead provided a muscular branch that communicated with the median nerve (MN). Both the MN and brachial artery (BA) flow beneath the extra head. This case suggests that the described variations may contribute to the entrapment of the MN and compression of the BA. Understanding these variations is crucial before surgical intervention. The failure to recognize such anatomical nuances could lead to inadvertent nerve injury or compromised vascular perfusion, emphasizing the need for preoperative planning and intraoperative vigilance.

Anatomic-Based Technique for Sensing Lead Placement in Hypoglossal Stimulator Implantation.

Placement of the sensing lead can be challenging in obese and Down syndrome patients. This article presents an alteration in technique for its placement for these patient populations. Laryngoscope, 2024.

Role of paraoxonase 1 in organophosphate G-series nerve agent poisoning and future therapeutic strategies.

Chemical warfare nerve agents (CWNA) are neurotoxic chemicals unethically used as agents of mass destruction by terrorist outfits and during war. The available antidote against CWNA-mediated toxicity is not sufficiently effective and possesses several limitations. As a countermeasure, paraoxonase 1 (PON1), a catalytic bioscavenger, is being developed as a prophylactic treatment. However, the catalytic activity and substrate specificity of human PON1 are insufficient to be used as a potential antidote. Several laboratories have made different approaches to enhance the CWNA hydrolytic activity against various nerve agents. This review explores the holistic view of PON1 as a potential prophylactic agent against G-series CWNA poisoning, from its initial development to recent advancements and limitations. Apart from this, the review also provides an overview of all available PON1 variants that could be used as a potential prophylactic agent and discusses several possible ways to counteract immunogenicity.

Lithium alleviates paralysis in experimental autoimmune neuritis in Lewis rats by modulating glycogen synthase kinase-3ß activity.

IMPORTANCE: Guillain-Barré syndrome (GBS)-like neuropathy mimics the leading cause of sporadic acute nontraumatic limb paralysis in individuals from developed countries. Experimental autoimmune neuritis (EAN) is an animal model of GBS and of syndromes such as acute canine polyradiculoneuritis, seen in dogs and cats. OBJECTIVE: The involvement of glycogen synthase kinase (GSK)-3ß, a pro-inflammatory molecule, in rat EAN is not fully understood. This study evaluated the potential role of GSK-3ß in EAN through its inhibition by lithium. METHODS: Lewis rats were injected with SP26 antigen to induce EAN. Lithium was administered from 1 day before immunization to day 14 post-immunization (PI). Then the rats were euthanized and their neural tissues were prepared for histological and Western blotting analyses. RESULTS: Lithium, an inhibitor of GSK-3, significantly ameliorated EAN paralysis in rats, when administered from day 1 to day 14 PI. This corresponded with reduced inflammation in the sciatic nerves of EAN rats, where phosphorylation of GSK-3ß was also upregulated, indicating suppression of GSK-3. CONCLUSIONS AND RELEVANCE: These findings suggest that lithium, an inhibitor of GSK-3ß, plays a significant role in ameliorating rat EAN paralysis, by suppressing GSK-3ß and its related signals in EAN-affected sciatic nerves.

Current approaches to facial nerve schwannoma surgery.

Background: Facial nerve schwannomas (FNSs) are exceedingly rare benign tumors. This study aims to report on a series of excised FNSs, providing clinical information and details on their surgical management, including novel approaches. Methods: We retrospectively reviewed patients who underwent surgical excision of FNSs in a private otology clinic and public tertiary referral center. The main outcome measures were facial nerve function, complete tumor removal, postoperative complications, tumor recurrence, and hearing. Results: Seventeen patients (10 men and 7 women) with a mean age of 44.23 years (SD, 12.21) underwent surgery during the study period. The most common symptom was facial nerve dysfunction (58.8%). Facial and otoneurologic symptoms (hearing loss, tinnitus, and vertigo) were observed in 88.8% and 77.7% of patients, respectively. The middle cranial fossa (MCF) was the most common approach (six patients, 35.2%), followed by translabyrinthine (TL), transmastoid (TM), and combined TM-MCF (three patients, 17.6% each). Exclusive endoscopic transcanal suprageniculate (ETS) and mastoid combined with cervical approaches were applied once in two patients, 5.8% each. Total tumor removal was achieved in all cases. No significant postoperative complications were observed. The mean follow-up period was 193.2 months (SD, 119.5) and no tumor recurrence was observed. Conclusion: This study provides further evidence for the safety and efficacy of various surgical approaches for FNS, and incorporates the endoscopic transcanal approach. Level of evidence: 4.

Multiple sporadic schwannomas in a previously radiated field.

Peripheral nerve sheath tumors are a heterogenous group of predominantly benign tumors of neurogenic origin that arise outside of the central nervous system and include schwannomas and neurofibromas. These tumors often occur sporadically, however multiple lesions are generally associated with genetic syndromes such as neurofibromatosis (type 1 and 2) and schwannomatosis, and occasionally these tumors and their malignant variations are associated with a history of radiation treatment. Multiple benign schwannomas in an irradiated field have seldom been reported in the literature. We describe a case of a 49-year-old male with a history of right sided irradiated testicular cancer who presented with 2 histologically confirmed benign schwannomas in the right pelvic wall and right psoas muscle.

Anatomical landmarks and procedure technique of Levator Scapulae Plane Block (LeSP block): Case report: Ultrasound-guided block of the superficial, deep and distal planes of the levator scapulae muscle for treatment of shoulder girdle myofascial pain.

Neck pain is a prevalent issue associated with musculoskeletal disorders. This study describes the interfascial Levator Scapulae Plane Block (LeSP Block) technique, using ultrasound guidance for local anesthetic administration to treat chronic neck pain. Two patients, 1 77-year-old female and 1 50-year-old female, underwent the LeSP Block. Immediate postprocedure pain relief was achieved in both, with 1 patient experiencing complete pain remission (VAS = 0) and the other showing significant improvement (VAS = 2) after 30 days. The LeSP Block demonstrated effectiveness and ease of use, suggesting its inclusion in pain management strategies for shoulder girdle and scapular pain. Further anatomical studies aimed at improving the anatomical description of the accessory spinal nerve are recommended to refine the technique.

Suspected local anesthetic resistance after intrathecal, perineural, intraarticular and subcutaneous injections: a case report.

Background: Local anesthetic (LA) resistance is an exceedingly rare phenomenon. Incidence is unknown given the rarity of disease. Often, inadequate response to LA can be attributed to many factors including suboptimal dosing, maldistribution, or poor procedural technique. However, in the absence of these technical factors, true LA resistance can be attributed to mutations in the voltage gated sodium channel and is strongly associated with hypermobility conditions such as Ehlers Danlos and muscular dystrophies such as Emery-Dreifuss. There have also been reports describing LA resistance after scorpion bites, although the underlying mechanism for this type of resistance is unknown. We aim to present a case of suspected LA resistance in the setting of multiple failed LA delivery. Case Description: In this case report, we describe a patient with suspected LA resistance after failed intrathecal, perineural, intraarticular and subcutaneous delivery of LA. Our patient was unresponsive to three different LAs at varying doses. Conclusions: Patients with failure to achieve adequate anesthesia with more than one route of LA administration should be evaluated for LA resistance. A thorough medical history and physical examination, along with a focus on identifying prior LA failure such as with dental procedures, and physical examination findings suggestive of connective tissue disorders may help establish the diagnosis with confirmatory genetic testing.