Update on Regulation of Regenerative Medicine in Taiwan.

Due to rapid development of biotechnology in recent years, the field of regenerative medicine has attracted considerable attention. Regenerative medicine-related regulations have been established in several countries to ensure the quality, safety, and efficacy of innovative treatments. Considering the diversity of regenerative medicine, the regulatory framework in Taiwan has been adjusted in response to global trend and local demand. Before 2010, cell and gene therapies were regarded as "new medical practice" under the "Medical Care Act." Along with the establishment of Taiwan Food and Drug Administration (TFDA) in 2010, regenerative medicine was regulated as "medicinal products" under the "Pharmaceutical Affairs Act." Then, the Ministry of Health and Welfare (MOHW) established a new dual-track regulatory pathway for regenerative medicine in 2016. The dual-track pathway divided regenerative medicine into medical practices and medicinal products, aiming to improve the accessibility of new treatments to patients and maintain the flexibility for clinical operations. In order to refine the regulation, the MOHW proposed two draft Acts for regenerative medicine in 2022. The two draft Acts are currently under legislative process. It is expected that the research and development of regenerative medicine can be further accelerated, thus providing early access to innovative therapies for patients in the future.

Report of the International Regulatory Forum on Human Cell Therapy and Gene Therapy Products.

The development of human cell therapy and gene therapy products has progressed internationally. Efforts have been made to address regulatory challenges in the evaluation of quality, efficacy, and safety of the products. In this forum, updates on the specific challenges in quality, efficacy, and safety of products in the view of international development were shared through the exchange of information and opinions among experts from regulatory authorities, academic institutions, and industry practitioners. Sessions identified specific/critical points to consider for the evaluation of human cell therapy and gene therapy products that are different from conventional biological products; common approaches and practices among regulatory regions were also shared. Certain elements of current international guidelines might not be appropriate to be applied to these products. Further, international discussion on the concept of potency and in vivo tumorigenicity studies, among others, is needed. This forum concluded that the continued collective actions are expected to promote international convergence of regulatory approaches of the products. The Pharmaceuticals and Medical Devices Agency and Japanese Society for Regenerative Medicine jointly convened the forum with support from the National Institutes of Biomedical Innovation, Health and Nutrition. Participants at the forum include 300 experts in and outside of Japan.

Regulation of Cell and Gene Therapy Medicinal Products in Taiwan.

Owing to the rapid and mature development of emerging biotechnology in the fields of cell culture, cell preservation, and recombinant DNA technology, more and more cell or gene medicinal therapy products have been approved for marketing, to treat serious diseases which have been challenging to treat with current medical practice or medicine. This chapter will briefly introduce the Taiwan Food and Drug Administration (TFDA) and elaborate regulation of cell and gene therapy medicinal products in Taiwan, including regulatory history evolution, current regulatory framework, application and review procedures, and relevant jurisdictional issues. Under the promise of quality, safety, and efficacy of medicinal products, it is expected the regulation and environment will be more flexible, streamlining the process of the marketing approval of new emerging cell or gene therapy medicinal products and providing diverse treatment options for physicians and patients.

Surgical treatment for thyrotoxic hypokalemic periodic paralysis: case report.

Thyrotoxic hypokalemic periodic paralysis (THPP) is a rare, potentially life-threatening endocrine emergency. It is characterized by recurrent muscle weakness and hypokalemia. Because many THPP patients do not have obvious symptoms and signs of hyperthyroidism, misdiagnosis may occur. The published studies revealed that definitive therapy for THPP is control of hyperthyroidism by medical therapy, radioactive iodine or surgery, but the long-term post-operative follow-up result was not observed. We reported two cases of medically refractory THPP with recurrent paralysis of extremities and hypokalemia, and both were combined with thyroid nodules. Both patients were treated with total thyroidectomy; the pathology revealed that one is Graves' disease with thyroid papillary carcinoma, and the other is adenomatous goiter with papillary hyperplasia. No episode of periodic paralysis was noted and laboratory evaluation revealed normal potassium level during the post-operative follow up. Our experience suggests that total thyroidectomy by experienced surgeon is an appropriate and definite treatment for medically refractory THPP, especially in cases combined with thyroid nodules.

Investigation of the Electrophysiological and Thermographic Safety Parameters of Surgical Energy Devices during Thyroid and Parathyroid Surgery in a Porcine Model.

In thyroid and parathyroid surgery, surgical energy devices (SEDs) provide more efficient hemostasis than conventional clamp-and-tie hemostasis in areas with rich blood supply. However, when a SED is activated near the recurrent laryngeal nerve (RLN), the heat generated by the SED may injure the nerve irreversibly. To safely apply SEDs in thyroid/parathyroid surgery, this article introduces experimental porcine model studies to investigate the activation and cooling safety parameters of SEDs in standardized electrophysiological (EP) and thermographic (TG) procedures, respectively. In the EP safety parameter experiments, continuous intraoperative neuromonitoring (C-IONM) is applied to demonstrate the RLN function in real-time. The EP activation study evaluates the safe activation distance of SEDs; the EP cooling study evaluates the safe cooling time of SEDs. In the TG safety parameter experiment, a thermal imaging camera is used to record the temperature change after activating the SED. The TG activation study evaluates the lateral thermal spread distance after SED activation in a dry or humid environment and whether smoke and splashing are generated; the TG cooling study evaluates the cooling time. This will help establish the safety parameters of newly developed SEDs used in thyroid/parathyroid surgery and provide safety guidelines to avoid RLN injury and related complications.

Safety Parameters of Quantum Molecular Resonance Devices During Thyroid Surgery: Porcine Model Using Continuous Neuromonitoring.

Objectives: Quantum molecular resonance (QMR) devices have been applied as energy-based devices in many head and neck surgeries; however, research on their use in thyroid surgery is lacking. This study aimed to investigate the safety parameters of QMR devices during thyroidectomy when dissection was adjacent to the recurrent laryngeal nerve (RLN). Methods: This study included eight piglets with 16 RLNs, and real-time electromyography (EMG) signals were obtained from continuous intraoperative neuromonitoring (C-IONM). QMR bipolar scissor (BS) and monopolar unit (MU) were tested for safety parameters. In the activation study, QMR devices were activated at varying distances from the RLN. In the cooling study, QMR devices were cooled for varying time intervals, with or without muscle touch maneuver (MTM) before contacting with the RLN. Results: In the activation study, no adverse EMG change occurred when QMR BS and MU were activated at distances of 2 mm or longer from the RLNs. In the cooling study, no adverse EMG change occurred when QMR BS and MU were cooled in 2-second intervals or immediately after MTM. Conclusion: QMR devices should be carefully used when performing RLN dissection during thyroid surgery. According to the activation and cooling safety parameters in this study, surgeons can avoid RLN injury by following standard procedures when using QMR devices.

A Surgeon-Centered Neuromuscular Block Protocol Improving Intraoperative Neuromonitoring Outcome of Thyroid Surgery.

Background: Neuromuscular blocking agents provide muscular relaxation for tracheal intubation and surgery. However, the degree of neuromuscular block may disturb neuromuscular transmission and lead to weak electromyography during intraoperative neuromonitoring. This study aimed to investigate a surgeon-friendly neuromuscular block degree titrated sugammadex protocol to maintain both intraoperative neuromonitoring quality and surgical relaxation during thyroid surgery. Methods: A total of 116 patients were enrolled into two groups and underwent elective thyroid surgery with intraoperative neuromonitoring. All patients followed a standardized intraoperative neuromonitoring protocol with continuous neuromuscular transmission monitoring and received 0.6 mg/kg rocuronium for tracheal intubation. Patients were allocated into two groups according to the degree of neuromuscular block when the anterior surface of the thyroid gland was exposed. The neuromuscular block degree was assessed by the train-of-four (TOF) count and ratio. Patients in group I received sugammadex 0.25 mg/kg for non-deep neuromuscular block degree (TOF count = 1~4). Patients in group II were administered sugammadex 0.5 mg/kg for deep neuromuscular block degree (TOF count = 0). The quality of the intraoperative neuromonitoring was measured using the V1 electromyography (EMG) amplitude. An amplitude less than 500 µV and greater than 500 µV was defined as weak and satisfactory, respectively. Results: The quality of the intraoperative neuromonitoring was not different between groups I and II (satisfactory/weak: 75/1 vs. 38/2, P = 0.14). The quality of surgical relaxation was acceptable after sugammadex injection and showed no difference between groups [55/76 (72.3%) in group I vs. 33/40 (82.5%) in group II, P = 0.23]. Conclusions: This surgeon-centered sugammadex protocol guided by neuromuscular block degree (0.5 mg/kg for deep block and 0.25 mg/kg for others) showed comparably high intraoperative neuromonitoring quality and adequate surgical relaxation. The results expanded the practicality of sugammadex for precise neuromuscular block management during monitored thyroidectomy.

Accumulation of Experience and Newly Developed Devices Can Improve the Safety and Voice Outcome of Total Thyroidectomy for Graves' Disease.

Total thyroidectomy (TT) in patients with Graves' disease is challenging even for an experienced thyroid surgeon. This study aimed to investigate the accumulation of experience and applying newly developed devices on major complications and voice outcomes after surgery of a single surgeon over 30 years. This study retrospectively reviewed 90 patients with Graves' disease who received TT. Forty-six patients received surgery during 1990-1999 (Group A), and 44 patients received surgery during 2010-2019 (Group B). Major complications rates were compared between Group A/B, and objective voice parameters were compared between the usage of energy-based devices (EBDs) within Group B. Compared to Group B, Group A patients had higher rates of recurrent laryngeal nerve palsy (13.0%/1.1%, p = 0.001), postoperative hypocalcemia (47.8%/18.2%, p = 0.002), and postoperative hematoma (10.9%/2.3%, p = 0.108). Additionally, Group A had one permanent vocal cord palsy, four permanent hypocalcemia, and one thyroid storm, whereas none of Group B had these complications. Group B patients with EBDs had a significantly better pitch range (p = 0.015) and jitter (p = 0.035) than those without EBDs. To reduce the major complications rate, inexperienced thyroid surgeons should remain vigilant when performing TT for Graves' disease. Updates on surgical concepts and the effective use of operative adjuncts are necessary to improve patient safety and voice outcome.

Effects of 1-Year Hospital Volume on Surgical Margin and Biochemical-Failure-Free Survival in Patients Undergoing Robotic versus Nonrobotic Radical Prostatectomy: A Nationwide Cohort Study from the National Taiwan Cancer Database.

PURPOSE: To examine the effect of hospital volume on positive surgical margin (PSM) and biochemical-failure-free survival (BFS) rates in patients with prostate cancer (PC) undergoing robotic-assisted or nonrobotic-assisted radical prostatectomy (RP). PATIENTS AND METHODS: The patients were men collected in the National Taiwan Cancer Registry diagnosed as having PC without distant metastasis who received RP from 44 multi-institutes in Taiwan. The logistic regression method was used to analyze the risk from RP to PSM in included patients with hospital volume (i.e., number of patients with PC receiving robotic RP per year), and the Cox proportional hazards method was used to analyze the time from the index date to biochemical recurrence. RESULTS: After propensity score adjustment, compared with hospitals with >100 patients/year, the adjusted odds ratios (aORs; 95% confidence intervals) of PSM in the robotic RP group in hospitals with 1-25, 26-50, and 51-100 patients/year were 2.25 (2.10-3.11), 1.42 (1.25-2.23), and 1.33 (1.13-2.04), respectively (type III p < 0.0001). Sensitivity analysis indicated that the aORs of PSM were 1.29 (1.07-1.81), 1.07 (0.70-1.19), and 0.61 (0.56-0.83), respectively, for patients receiving robotic RP compared with nonrobotic RP within hospitals with 1-25, 26-50, and 51-100 patients/year, respectively. Compared with hospitals with >100 patients/year, the adjusted hazard ratios (aHRs) of biochemical failure in the robotic RP group were 1.40 (1.04-1.67), 1.34 (1.06-1.96), and 1.31 (1.05-2.15) in hospitals with 1-25, 26-50, and 51-100 patients/year, respectively. CONCLUSIONS: Hospital volume significantly affected PSM and BFS in robotic RP, but not in nonrobotic RP. When patients with PC want to receive robotic RP, it should be performed in a relatively high-volume hospital (>100 patients/year).

Comparison of Clinical Outcomes of Radical Prostatectomy versus IMRT with Long-Term Hormone Therapy for Relatively Young Patients with High- to Very High-Risk Localized Prostate Cancer.

That intensity-modulated radiotherapy (IMRT) plus antiandrogen therapy (IMRT-ADT) and radical prostatectomy (RP) are the definitive optimal treatments for relatively young patients (aged ≤ 65 years) with high- or very high-risk localized prostate cancer (HR/VHR-LPC), but remains controversial. We conducted a national population-based cohort study by using propensity score matching (PSM) to evaluate the clinical outcomes of RP and IMRT-ADT in relatively young patients with HR/VHR-LPC. Methods: We used the Taiwan Cancer Registry database to evaluate clinical outcomes in relatively young (aged ≤ 65 years) patients with HR/VHR-LPC, as defined by the National Comprehensive Cancer Network risk strata. The patients had received RP or IMRT-ADT (high-dose, ≥72 Gy plus long-term, 1.5-3 years, ADT). Head-to-head PSM was used to balance potential confounders. A Cox proportional hazards regression model was used to analyze oncologic outcomes. Results: High-dose IMRT-ADT had a higher risk of biochemical failure (adjusted hazard ratio [aHR] = 2.03, 95% confidence interval [CI] 1.56-2.65, p < 0.0001) compared with RP; IMRT-ADT did not have an increased risk of all-cause death (aHR = 1.2, 95% CI 0.65-2.24, p = 0.564), locoregional recurrence (aHR = 0.88, 95% CI 0.67-1.06, p = 0.3524), or distant metastasis (aHR = 1.03, 95% CI 0.56-1.9, p = 0.9176) compared with RP. Conclusion: In relatively young patients with HR/VHR-LPC, RP and IMRT-ADT yielded similar oncologic outcomes and RP reduced the risk of biochemical failure compared with IMRT-ADT.

Prognostic Indicators of Non-Transection Nerve Injury and Vocal Fold Motion Impairment After Thyroid Surgery - Correlation Between Intraoperative Neuromonitoring Findings and Perioperative Voice Parameters.

Objectives: In patients with recurrent laryngeal nerve (RLN) injury after thyroid surgery, unrecovered vocal fold motion (VFM) and subjective voice impairment cause extreme distress. For surgeons, treating these poor outcomes is extremely challenging. To enable early treatment of VFM impairment, this study evaluated prognostic indicators of non-transection RLN injury and VFM impairment after thyroid surgery and evaluated correlations between intraoperative neuromonitoring (IONM) findings and perioperative voice parameters. Methods: 82 adult patients had postoperative VFM impairment after thyroidectomy were enrolled. Demographic characteristics, RLN electromyography (EMG), and RLN injury mechanism were compared. Multi-dimensional voice program, voice range profile and Index of voice and swallowing handicap of thyroidectomy (IVST) were administered during I-preoperative; II-immediate, III-short-term and IV-long-term postoperative periods. The patients were divided into R/U Group according to the VFM was recovered/unrecovered 3 months after surgery. The patients in U Group were divided into U1/U2 Group according to total IVST score change was <4 and ≥4 during period-IV. Results: Compared to R Group (42 patients), U Group (38 patients) had significantly more patients with EMG >90% decrease in the injured RLN (p<0.001) and thermal injury as the RLN injury mechanism (p=0.002). Voice parameter impairments were more severe in U Group compared to R Group. Compared to U1 group (19 patients), U2 Group (19 patients) had a significantly larger proportion of patients with EMG decrease >90% in the injured RLN (p=0.022) and thermal injury as the RLN injury mechanism (p=0.017). A large pitch range decrease in period-II was a prognostic indicator of a moderate/severe long-term postoperative subjective voice impairment. Conclusion: This study is the first to evaluate correlations between IONM findings and voice outcomes in patients with VFM impairment after thyroid surgery. Thyroid surgeons should make every effort to avoid severe type RLN injury (e.g., thermal injury or injury causing EMG decrease >90%), which raises the risk of unrecovered VFM and moderate/severe long-term postoperative subjective voice impairment. Using objective voice parameters (e.g., pitch range) as prognostic indicators not only enables surgeons to earlier identify patients with low voice satisfaction after surgery, and also enable implementation of interventions sufficiently early to maintain quality of life.

Comparison of Surgical Complications Rates Between LigaSure Small Jaw and Clamp-and-Tie Hemostatic Technique in 1,000 Neuro-Monitored Thyroidectomies.

Over the past decade, the use of neuromonitoring in thyroid surgery has become well established and is increasing accepted across the world. In addition, new developments in energy devices have significantly improved efficacy in achieving hemostasis in thyroid surgery. Few studies focused on the complication rates in energy device-assisted sutureless neuro-monitored thyroidectomy. This study investigates a novel LigaSure Small Jaw (LSJ) technique for sutureless thyroidectomy and compares the surgical complication rates between LSJ and conventional clamp-and-tie technique in one thousand consecutive neuro-monitored thyroidectomy patients. Five hundred patients received sutureless thyroidectomy performed with LSJ (Group L), and 500 patients received surgery performed with conventional clamp-and-tie technique (Group C). Complication rates of postoperative hematoma, hypocalcemia and recurrent laryngeal nerve (RLN) palsy were compared between groups. The overall complication rates of hematoma, hypocalcemia (temporary/ permanent), and RLN (temporary/ permanent) palsy were 0.9%, 24.9% (24.6%/0.3%), and 1.7% (1.5%/0.2%), respectively. Group L and Group C significantly differed in postoperative hematoma rate (0.0% vs. 1.8%, respectively; p = 0.0026) and in postoperative hypocalcemia rate (20.1% vs. 30.0%, respectively; p = 0.0032). The incidence of RLN palsy did not significantly differ between Group L and Group C (1.38% vs. 2.08%; p = 0.2652). The overall surgical complication rates are low in neuro-monitored thyroidectomy. The LSJ is feasible for performing completely sutureless thyroidectomy and obtains superior outcomes of postoperative hematoma and hypocalcemia in comparison with clamp-and-tie hemostatic technique. The novel LSJ technique using double or overlapped sealing is useful for sutureless thyroidectomy. However, surgeons must carefully observe the tissue contraction that may reduce the LSJ-RLN distance and increase the risk of thermal injury during the LSJ activation.

Precision Neuromuscular Block Management for Neural Monitoring During Thyroid Surgery.

INTRODUCTION: Titration of neuromuscular block (NMB) plays a key role in intraoperative recurrent laryngeal nerve monitoring during thyroid surgery. The combination of neuromuscular blocking agent and timely partial reversal of NMB was investigated in both animal experiments and clinical neuro-monitored thyroidectomy. METHODS: In animal experiments, 8 piglets received sugammadex to assess the laryngeal EMG recovery after rocuronium-induced NMB. In clinical monitored thyroidectomy, 40 patients each were allocated to conventional group and sugammadex group. Conventional group received rocuronium 0.3 mg/kg at anesthesia induction, while sugammadex group received partial NMB recovery protocol- 0.6 mg/kg of rocuronium at anesthesia induction and 0.5 mg/kg of sugammadex. Main outcome was assessed by first (V1) and final (V2) EMG signal induced by vagal stimulation. RESULTS: In the porcine model, 50% recovery of laryngeal EMG amplitude was achieved at 16.8 ± 1.9 and 6 ± 2.7 minutes respectively after 0.5 and 1 mg/kg of sugammadex (p < 0.01). In monitored thyroidectomy, EMG amplitudes at V1 in group S and group C were 1214 ± 623 and 915 ± 476 µV, respectively (p = 0.02). Positive and adequately high EMG amplitudes were observed at the early surgical stage for all patients. Sugammadex groups were superior to conventional group in EMG tube placement (p < 0.001). CONCLUSION: Both porcine model and clinical application showed that precise NMB management by low-dose sugammadex was effective for intraoperative neural monitoring (IONM). The regimen ensured optimal conditions for tracheal intubation and timely neuromuscular function restoration for high-quality EMG signal.

Laryngeal Neural Monitoring during Pediatric Thyroid Cancer Surgery-Is Transcartilage Recording a Preferable Method?

The use of transcartilage (TC) intraoperative neuromonitoring (IONM) in a pediatric population has not been reported. This study evaluated the feasibility and the benefit of using TC-IONM for thyroid cancer surgery in a pediatric population. This retrospective single-center study enrolled 33 pediatric patients who had received an IONM-assisted thyroidectomy. Demographic characteristics, standardized IONM laryngeal examinations and stimulation information (L1-V1-R1-R2-V2-L2) were compared between endotracheal tube (ET) and TC methods. In the 15 cancer patients (30 nerves), TC-IONM provided significant higher electromyography (EMG) amplitude (p < 0.001), signal stability (lower V1/V2 signal correlation, r = 0.955 vs. r = 0.484, p = 0.004), signal quality (higher ratio of V1 or V2 amplitude <500 µV, 0.0% vs. 43.8%, p = 0.005) and lower R1-R2p change (7.1% vs. 37.5%, p = 0.049) compared to ET-IONM. In the 18 benign patients (28 nerves), TC-IONM provided significantly higher EMG amplitude (p < 0.001), signal stability (r = 0.945 vs. r = 0.746, p = 0.0324) and non-significant higher signal quality and R1-R2p change. This report is the first to discuss the use of TC-IONM in pediatric thyroid surgery. In contrast with ET-IONM, TC-IONM had superior amplitude, stability and quality of EMG signals, which greatly facilitates the meticulous recurrent laryngeal nerve dissection in pediatric thyroidectomies. The TC-IONM method can be considered a feasible, effective and preferable method of monitored thyroidectomy in pediatric thyroid cancer.

Correlation Between Objective and Subjective High-Pitched Voice Impairment in Patients After Thyroid Surgery.

Objectives: High-pitched voice impairment (HPVI) is not uncommon in patients without recurrent laryngeal nerve (RLN) or external branch of superior laryngeal nerve (EBSLN) injury after thyroidectomy. This study evaluated the correlation between subjective and objective HPVI in patients after thyroid surgery. Methods: This study analyzed 775 patients without preoperative subjective HPVI and underwent neuromonitored thyroidectomy with normal RLN/EBSLN function. Multi-dimensional voice program, voice range profile and Index of voice and swallowing handicap of thyroidectomy (IVST) were performed during the preoperative(I) period and the immediate(II), short-term(III) and long-term(IV) postoperative periods. The severity of objective HPVI was categorized into four groups according to the decrease in maximum frequency (Fmax): <20%, 20-40%, 40-60%, and >60%. Subjective HPVI was evaluated according to the patient's answers on the IVST. Results: As the severity of objective HPVI increased, patients were significantly more to receive bilateral surgery (p=0.002) and have subjective HPVI (p<0.001), and there was no correlation with IVST scores. Among 211(27.2%) patients with subjective HPVI, patients were significantly more to receive bilateral surgery (p=0.003) and central neck dissection(p<0.001). These patients had very similar trends for Fmax, pitch range, and mean fundamental frequency as patients with 20-40% Fmax decrease (p>0.05) and had higher Jitter, Shimmer, and IVST scores than patients in any of the objective HPVI groups; subjective HPVI lasted until period-IV. Conclusion: The factors that affect a patient's subjective HPVI are complex, and voice stability (Jitter and Shimmer) is no less important than the Fmax level. When patients have subjective HPVI without a significant Fmax decrease after thyroid surgery, abnormal voice stability should be considered and managed. Fmax and IVST scores should be interpreted comprehensively, and surgeons and speech-language pathologists should work together to identify patients with HPVI early and arrange speech therapy for them. Regarding the process of fibrosis formation, anti-adhesive material application and postoperative intervention for HPVI require more future research.

Correlation between Electrophysiological Change and Facial Function in Parotid Surgery Patients.

This observational study investigated intraoperative electrophysiological changes and their correlation with postoperative facial expressions in parotidectomy patients with visual confirmation of facial nerve (FN) continuity. Maximal electromyography(EMG) amplitudes of the facial muscles corresponding to temporal, zygomatic, buccal and mandibular branches were compared before/after FN dissection, and facial function at four facial regions were evaluated before/after parotidectomy in 112 patients. Comparisons of 448 pairs of EMG signals revealed at least one signal decrease after FN dissection in 75 (67%) patients. Regional facial weakness was only found in 13 of 16 signals with >50% amplitude decreases. All facial dysfunctions completely recovered within 6 months. EMG amplitude decreases often occur after FN dissection. An amplitude decrease >50% in an FN branch is associated with a high incidence of dysfunction in the corresponding facial region. This study tries to establish a standard facial nerve monitoring (FNM) procedure and a proper facial function grading system for parotid surgery that will be useful for the future study of FNM in parotid surgery.

New Developments in Anterior Laryngeal Recording Technique During Neuromonitored Thyroid and Parathyroid Surgery.

A recurrent laryngeal nerve (RLN) injury resulting in vocal fold paralysis and dysphonia remains a major source of morbidity after thyroid and parathyroid surgeries. Intraoperative neural monitoring (IONM) is increasingly accepted as an adjunct to the standard practice of visual RLN identification. Endotracheal tube (ET) surface recording electrode systems are now widely used for IONM; however, the major limitation of the clinical use of ET-based surface electrodes is the need to maintain constant contact between the electrodes and vocal folds during surgery to obtain a high-quality recording. An ET that is malpositioned during intubation or displaced during surgical manipulation can cause a false decrease or loss of electromyography (EMG) signal. Since it may be difficult to distinguish from an EMG change caused by a true RLN injury, a false loss or decrease in EMG signal may contribute to inappropriate surgical decision making. Therefore, researchers have investigated alternative electrode systems that circumvent common causes of poor accuracy in ET-based neuromonitoring. Recent experimental and clinical studies have confirmed the hypothesis that needle or adhesive surface recording electrodes attached to the thyroid cartilage (transcartilage and percutaneous recording) or attached to the overlying neck skin (transcutaneous recording) can provide functionality similar to that of ET-based electrodes, and these recording methods enable access to the EMG response of the vocalis muscle that originates from the inner surface of the thyroid cartilage. Studies also indicate that, during surgical manipulation of the trachea, transcartilage, percutaneous, and transcutaneous anterior laryngeal (AL) recording electrodes could be more stable than ET-based surface electrodes and could be equally accurate in depicting RLN stress during IONM. These findings show that these AL electrodes have potential applications in future designs of recording electrodes and support the use of IONM as a high-quality quantitative tool in thyroid and parathyroid surgery. This article reviews the major recent developments of newly emerging transcartilage, percutaneous, and transcutaneous AL recording techniques used in IONM and evaluates their contribution to improved voice outcomes in modern thyroid surgery.

How the Severity and Mechanism of Recurrent Laryngeal Nerve Dysfunction during Monitored Thyroidectomy Impact on Postoperative Voice.

Intraoperative neuromonitoring can qualify and quantify RLN function during thyroid surgery. This study investigated how the severity and mechanism of RLN dysfunction during monitored thyroid surgery affected postoperative voice. This retrospective study analyzed 1021 patients that received standardized monitored thyroidectomy. Patients had post-dissection RLN(R2) signal <50%, 50-90% and >90% decrease from pre-dissection RLN(R1) signal were classified into Group A-no/mild, B-moderate, and C-severe RLN dysfunction, respectively. Demographic characteristics, RLN injury mechanisms(mechanical/thermal) and voice analysis parameters were recorded. More patients in the group with higher severity of RLN dysfunction had malignant pathology results (A/B/C = 35%/48%/55%, p = 0.017), received neck dissection (A/B/C = 17%/31%/55%, p < 0.001), had thermal injury (p = 0.006), and had asymmetric vocal fold motion in long-term postoperative periods (A/B/C = 0%/8%/62%, p < 0.001). In postoperative periods, Group C patients had significantly worse voice outcomes in several voice parameters in comparison to Group A/B. Thermal injury was associated with larger voice impairments compared to mechanical injury. This report is the first to discuss the severity and mechanism of RLN dysfunction and postoperative voice in patients who received monitored thyroidectomy. To optimize voice and swallowing outcomes after thyroidectomy, avoiding thermal injury is mandatory, and mechanical injury must be identified early to avoid a more severe dysfunction.

Full percutaneous intraoperative neuromonitoring technique in remote thyroid surgery: Porcine model feasibility study.

BACKGROUND: In remote thyroid surgery, a reliable intraoperative neuromonitoring (IONM) procedure is an important tool for reducing injury to recurrent laryngeal nerve (RLN). This study proposes an alternative or adjunct technique for performing full percutaneous (PC) IONM and confirms its feasibility in animal experiments. METHODS: This prospective porcine model study enrolled four piglets with eight nerve sides. Evoked electromyography (EMG) was stimulated from PC ball-tip probe, and recorded from EMG endotracheal tube (ETT) and from PC paired long-needle electrodes on the perichondrium of the lateral aspect of thyroid cartilage. RESULTS: In all RLNs and vagus nerves, typical laryngeal EMG waveforms were successfully evoked by PC probe stimulation and recorded by both ETT and PC needle electrodes. CONCLUSIONS: This study confirms the feasibility of the full PC IONM techniques in porcine model. However, further clinical studies are needed to compare the practicality of different remote-access approaches for thyroid surgery.

Improving Voice Outcomes After Thyroid Surgery - Review of Safety Parameters for Using Energy-Based Devices Near the Recurrent Laryngeal Nerve.

Technological advances in thyroid surgery have rapidly increased in recent decades. Specifically, recently developed energy-based devices (EBDs) enable simultaneous dissection and sealing tissue. EBDs have many advantages in thyroid surgery, such as reduced blood loss, lower rate of post-operative hypocalcemia, and shorter operation time. However, the rate of recurrent laryngeal nerve (RLN) injury during EBD use has shown statistically inconsistent. EBDs generate high temperature that can cause iatrogenic thermal injury to the RLN by direct or indirect thermal spread. This article reviews relevant medical literatures of conventional electrocauteries and different mechanisms of current EBDs, and compares two safety parameters: safe distance and cooling time. In general, conventional electrocautery generates higher temperature and wider thermal spread range, but when applying EBDs near the RLN adequate activation distance and cooling time are still required to avoid inadvertent thermal injury. To improve voice outcomes in the quality-of-life era, surgeons should observe safety parameters and follow the standard procedures when using EBDs near the RLN in thyroid surgery.