Michael Brauckhoff

Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: International standards guideline statement

Intraoperative neural monitoring (IONM) during thyroid and parathyroid surgery has gained widespread acceptance as an adjunct to the gold standard of visual nerve identification. Despite the increasing use of IONM, review of the literature and clinical experience confirms there is little uniformity in application of and results from nerve monitoring across different centers. We provide a review of the literature and cumulative experience of the multidisciplinary International Neural Monitoring Study Group with IONM spanning nearly 15 years. The study group focused its initial work on formulation of standards in IONM as it relates to important areas: 1) standards of equipment setup/endotracheal tube placement and 2) standards of loss of signal evaluation/intraoperative problem‐solving algorithm. The use of standardized methods and reporting will provide greater uniformity in application of IONM. In addition, this report clarifies the limitations of IONM and helps identify areas where additional research is necessary. This guideline is, at its forefront, quality driven; it is intended to improve the quality of neural monitoring, to translate the best available evidence into clinical practice to promote best practices. We hope this work will minimize inappropriate variations in monitoring rather than to dictate practice options. Laryngoscope, 121:S1–S16, 2011

Intraoperative Monitoring of the Recurrent Laryngeal Nerve in Thyroid Surgery

BackgroundRecurrent laryngeal nerve (RLN) palsy ranks among the leading reasons for medicolegal litigation of surgeons because of its attendant reduction in quality of life. As a risk minimization tool, intraoperative nerve monitoring (IONM) has been introduced to verify RLN function integrity intraoperatively. Nevertheless, a systematic evidence-based assessment of this novel health technology has not been performed.MethodsThe present study was based on a systematic appraisal of the literature using evidence-based criteria.ResultsRecurrent laryngeal nerve palsy rates (RLNPR) varied widely after thyroid surgery, ranging from 0%–7.1% for transient RLN palsy to 0%–11% for permanent RLN palsy. These rates did not differ much from those reported for visual nerve identification without the use of IONM. Six studies with more than 100 nerves at risk (NAR) each evaluated RLNPR by contrasting IONM with visual nerve identification only. Recuurent laryngeal nerve palsy rates tended to be lower with IONM than without it, but this difference was not statistically significant. Six additional studies compared IONM findings with their corresponding postoperative laryngoscopic results. Those studies revealed high negative predictive values (NPV; 92%–100%), but relatively low and variable positive predictive values (PPV; 10%–90%) for IONM, limiting its utility for intraoperative RLN management.ConclusionsApart from navigating the surgeon through challenging anatomies, IONM may lend itself as a routine adjunct to the gold standard of visual nerve identification. To further reduce the number of false negative IONM signals, the causes underlying its relatively low PPV require additional clarification.

Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients.

Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are ∼

Surgery of Resectable Nonfunctioning Neuroendocrine Pancreatic Tumors

3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations. (Clin Cancer Res 2009;15(20):6378–85)

Advances in the management of hereditary medullary thyroid cancer

Nonfunctioning neuroendocrine pancreatic tumors (NFNEPTs) comprise about one-third of pancreatic endocrine tumors. Based on immunohistochemistry, nonfunctioning tumors are difficult to distinguish from functioning ones; therefore the final diagnosis is basically the result of a synopsis of pathology and clinical data. Owing to their incapacity to produce hormone-dependent symptoms, NFNEPTs are detected incidentally or because of uncharacteristic symptoms resulting from local or distant growth. About two-thirds of NFNEPTs are located in the pancreatic head, so jaundice may be a late symptom of this tumor. Modern diagnostic procedures are best applied by a stepwise approach: first endoscopic ultrasonography and computed tomography/magnetic resonance imaging followed by somatostatin receptor scintigraphy or positron emission tomography (or both). Due to significant false-positive and false-negative findings, for decision-making the latter should be confirmed by a second imaging modality. Regarding indications for surgery and the surgical approach to the pancreas, three pancreatic manifestations of NFNEPTs can be distinguished: (1) solitary benign non-multiple endocrine neoplasia type 1 (non-MEN-1); (2) multiple benign MEN-1; and (3) malignant NFNEPTs. Reviewing the literature and including our experience with 18 NFNEPTs (8 benign, 10 malignant) reported here, the following conclusions can be drawn: (1) Solitary benign non-MEN-1 NFNEPTs can be removed by enucleation or by pancreas-, spleen-, and duodenum-preserving techniques in most cases. The choice of surgical technique depends on the location and site of the tumor and its anatomic relation to the pancreatic duct. (2) With multiple benign MEN-1 NFNEPTs, because of the characteristics of the underlying disease a preferred, more conservative concept (removal of only macrolesions) competes with a more radical procedure (left pancreatic resection with enucleation of head macrolesions). Further studies are necessary to clarify the best way to balance quality of life (by preserving organ function) with growth control of potentially malignant tumors in the pancreas. (3) Malignant NFNEPTs comprise more than half of all NFNEPTs. Few studies have analyzed treatment strategies for localized or metastatic tumors. Whereas radical (including multivisceral) resection of tumors without distant metastases is widely accepted, the indication for radical surgery on metastasizing tumors has been questioned, as radical removal of the primary tumor may fail to increase survival. Adjuvant regimens in these tumor stages are mandatory and should be further optimized.

Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: Clinical manifestation and course in early and late onset disease

This work draws on recent advances during the era of codon‐oriented prophylactic surgery for hereditary medullary thyroid cancer (MTC). Milestones included identification of RET (REarranged during Transfection) as the susceptibility gene, introduction of prophylactic surgery on evidence of a RET germline mutation, revelation of genotype–phenotype correlations within the MEN 2 spectrum and demonstration of age‐related progression of MTC. Novel surgical techniques, notably systemic microdissection and compartment‐oriented surgery, have greatly enhanced surgical cure. Uncovering molecular pathways from RET genotype to MEN 2 phenotype should provide treatment options for RET mutation carriers whose MTC currently is too advanced for cure.

Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas

More than 50% of patients with typical MEN-2B have a de novo M918T germline mutation of the RET protooncogene. However, even in typical MEN-2B, extrathyroidal manifestations of MEN-2B can be found to be differently expressed. We analyzed the clinical manifestation and course in 21 patients harboring a de novo RET M918T mutation. Mean age at MEN-2B diagnosis was 14.2 years (range: 1–31 years). All patients had medullary thyroid carcinoma (MTC). At the time of syndrome diagnosis, oral manifestations (bumpy lips, ganglioneuroma), ocular manifestations (corneal fibers, conjunctivitis sicca), intestinal dysfunctions, musculoskeletal manifestations, and pheochromocytoma were found in 86%, 90%, 74%, 79%, and 19% of the patients, respectively. At the time of follow-up examination, the symptoms were found at higher frequency. Severe intestinal manifestation was predominantly found in patients with prepubertal onset (≤ 12 years) of MTC (n = 4/10) compared with patients with late onset (> 12 years) of MTC (n = 0/11) (40% versus 0%; p = 0.019). Although biochemical cure was found only in four patients with early onset of MTC, the long-term prognosis for patients with early onset of MTC was poorer than for patients presenting with late onset of MTC (p = 0.005). During mean follow-up of 55.8 months (range: 3–161 months), seven patients (33%) died from MTC. In conclusion, whereas most typical MEN-2B symptoms were found to be age-related, severe intestinal manifestation was found to be predominantly expressed in patients with early onset of MTC. Furthermore, in patients with early onset of MTC who could not be biochemically cured, the long-term prognosis was found to be worse than that of non-cured patients with late onset of MTC, suggesting an additional pathological process in the younger subgroup reinforcing the very high transforming in vitro activity of the M918T RET mutation.

Timing and Extent of Surgery in Patients with Familial Medullary Thyroid Carcinoma/Multiple Endocrine Neoplasia 2A-related RET Mutations Not Affecting Codon 634

Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can occur either sporadically or in the context of hereditary tumor syndromes. Whereas the genetic background of hereditary pheochromocytomas is becoming rather well-defined, very little is known about the more common sporadic form of the disease which constitutes ∼70% of all cases. In this study, we elucidate some of the molecular mechanisms behind sporadic pheochromocytoma by performing a comprehensive analysis of copy number alterations, gene expression, promoter methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127 and MAX, which have been associated with hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an altered copy number in at least one of the known susceptibility genes, often in association with an altered messenger RNA (mRNA) expression. Specifically, 11 sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which significantly correlated with a reduced NF1 mRNA expression. Subsequent sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with NF1 loss. Our results thus suggest that the NF1 gene constitutes the most frequent (24%) target of somatic mutations so far known in sporadic pheochromocytomas.

Identification of the non-recurrent inferior laryngeal nerve using intraoperative neurostimulation

In hereditary medullary thyroid carcinoma (MTC), recommendations regarding timing and extent of surgery are mainly based on the data of patients with the codon 634 RET mutation, which is the most often affected codon. Little is known about whether these recommendations may also be applied to patients with less common RET mutations. We ascertained the data from 140 patients with FMTC/MEN2A-related RET mutation not affecting codon 634 who have been treated at three specialized centers. The several RET mutations found affected codons 611 (n = 17), 618 (n = 22), 620 (n = 17), 768 (n = 9), 790 (n = 24), 791 (n = 21), 804 (n = 23), and 891 (n = 7). For each codon, the age of the youngest patient with MTC only (41, 7, 18, 29, 13, 47, 20, and 15 years, respectively), MTC with lymph node metastases (46, 24, 21, 34, 46, 47, 50, and 76 years, respectively), and MTC with distant metastases (52, 69, 43, 68, 57, - , - , and 75 years, respectively) was determined. All patients with lymph node metastases had elevated basal calcitonin levels. Based on these data, a more individual recommendation regarding timing and extent of surgery can be given. Because neither gender nor the type of nucleotide substitution for a specific codon appeared to have a significant influence on the age of onset, this recommendation should be based on the affected codon, the age of the patient, and the calcitonin level. Recurrent laryngeal nerve palsy (n = 6) and hypoparathyroidism (n = 3) were rather rare and were found only in patients older than 30 and 43 years, respectively, giving evidence that surgery in young patients can be performed safely.

Papillary Thyroid Carcinoma in Patients with RET Proto-Oncogene Germline Mutation

Introduction: The non-recurrent inferior laryngeal nerve occurs at a frequency of about 0.5% and usually on the right side. The identification of a non-recurrent laryngeal nerve may be difficult. We describe a new method for its identification using intraoperative neurostimulation. Methods: We examined nine patients with a non-recurrent inferior laryngeal nerve and five patients with a normal inferior laryngeal nerve anatomy who were operated on trans-sternally. Neurostimulation of the vagal nerve producing electromyographic signal in the intrinsic laryngeal musculature was performed at different points proximally and distally. Results: Electromyographic signals were found proximally but not distally of the separation of the inferior laryngeal nerve from the vagus in 14 patients. In nine patients with a non-recurrent inferior laryngeal nerve, we performed neurostimulation of the vagus opposite the lower and the upper thyroid poles. In all patients we found no electromyographic signals at the distal stimulation point. In contrast, proximal neurostimulation of the vagus opposite the upper thyroid pole produced positive electromyographic signals. Conclusion: Neurostimulation of the vagal nerve distally of the separation of the inferior laryngeal nerve did not produce electromyographic signals in the intrinsic laryngeal musculature, perhaps due to the different modalities in the vagal fascicles. Negative electromyographic signals following neurostimulation of the distal vagal nerve opposite the lower thyroid pole should lead to proximal neurostimulation of the vagus opposite the upper thyroid pole. Positive electromyographic signals proximally and negative electromyographic signals distally predict the occurrence of a non-recurrent inferior laryngeal nerve which allows its diagnosis before surgical dissection of the thyroid gland and may prevent nerve palsy.