Generalized muscle stiffness and spontaneous electromyographic discharges in neuromuscular disease of parathyroid gland hypofunction.
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Missense germline mutations of the RET proto-oncogene have recently been identified in the hereditary cancer syndromes MEN2A, MEN2B, and FMTC, all characterized by medullary carcinoma, but also including phaeochromocytoma in MEN2A and MEN2B and parathyroid disease in MEN2A. In addition, somatic RET proto-oncogene mutations have been identified in a subset of sporadic medullary carcinomas and phaeochromocytomas. This study investigated the possibility that RET plays a role in sporadic parathyroid neoplasia. Firstly, normal and neoplastic parathyroid tissues were screened for expression of the RET proto-oncogene, using an RT-PCR approach on autopsy material. Secondly, 20 archival parathyroid adenomas were screened for somatic mutations in the transmembrane region of RET, the region associated with germline mutations in MEN2A and hence parathyroid disease, using a PCR-solid phase direct sequencing approach. RET expression was identified in all the parathyroid tissues analysed. However, no mutations were identified in any of the 20 adenomas, suggesting either that other mechanisms of RET activation occur, such as translocation, or that RET plays a more minor role in the growth control of the parathyroid cells than in C cells or phaeochromocytes.
A success rate of about 90% has been achieved after primary operations for hyperparathyroidism, compared with 60% to 80% in most series of secondary operations. The present reoperative series involved 29 patients who underwent venous catheterization with blood sampling for the determination of intact parathyroid hormone before undergoing repeat parathyroid surgery. Blood samples were taken from the internal jugular veins, innominate veins, and superior caval vein. No attempt was made to perform superselective catheterization of the small neck and mediastinal veins. The reoperations were done by four surgeons who did 1, 2, 13, and 13 of the reoperations, respectively. In all patients, distinct step-ups in parathyroid hormone concentrations were found. On average, the gradient between the highest and lowest value was about 5. Close to the location of the step-ups, diseased parathyroid tissue was found in 27 of the patients. In two cases no parathyroid tissue was found, and these patients remained hyperparathyroid postoperatively. They had been treated by the surgeon who did only two of the operations. When the step-up was observed in the left innominate vein, we could not differentiate mediastinal from low cervical adenomas. No patient developed hypoparathyroidism. To avoid this complication, autotransplantation of diseased parathyroid tissue into the abdominal subcutaneous fat was done in nine patients. No case of recurrent laryngeal nerve paralysis occurred. The introduction of reliable assays for the analysis of parathyroid hormone can make selective catheterization unnecessary when localizing remaining parathyroid glands in patients with persistent hyperparathyroidism.
HYPOTHESIS: For patients with primary hyperparathyroidism and patients with 2 localization studies showing the same single location of parathyroid disease, use of intraoperative parathyroid hormone (IOPTH) measurement does not significantly increase the success of minimally invasive parathyroidectomy. DESIGN: Retrospective cohort study. SETTING: Experience of 2 academic centers over 5 years (at Brigham and Women's Hospital, Boston, Mass) and almost 4 years (at Rhode Island Hospital, Providence). PATIENTS: A total of 569 patients with primary hyperparathyroidism who underwent technetium Tc 99m sestamibi (MIBI) parathyroid imaging and neck ultrasonography (US). MAIN OUTCOME MEASURES: Incidence of correct prediction of location and extent of disease. RESULTS: In 322 patients (57%), MIBI and US imaging identified the same single site of disease. In 319 (99%) of these 322 patients, surgical exploration confirmed a parathyroid adenoma at that site, and the IOPTH levels normalized on removal. In 3 (1%) of the 322 patients, IOPTH measurement identified unsuspected additional disease. In 3 (1%) of the remaining 319 patients, IOPTH-guided removal of a single adenoma failed to correct hypercalcemia. Therefore, the failure rate of surgery in patients with positive MIBI and positive US imaging was 1% with IOPTH measurement and 2% without IOPTH measurement (P = .50). In 201 (35%) of the 569 patients, only 1 of the 2 studies recognized an abnormality or the studies disagreed on location. In these cases, either MIBI imaging or US imaging (if MIBI imaging was negative) failed to predict the correct site or extent of disease in 76 (38%) of the 201 patients (P<.001 vs concordant studies). CONCLUSIONS: In primary hyperparathyroidism, concordant preoperative localization with MIBI and US imaging is highly accurate. Use of IOPTH measurement in these cases adds only marginal benefit. When only 1 of the 2 studies identifies disease or the studies conflict, however, IOPTH measurement remains essential during minimally invasive parathyroidectomy.
Endoscopic surgery has become widely used, so much so that recent technical and mechanical advances have led to "endoscopic surgery" being synonymous with "minimally invasive surgery". In particular, endoscopic thyroid surgery has developed rapidly and been increasingly refined in recent years. The incidence of thyroid diseases is markedly higher in women than in men, and operations for these diseases result in a scar on the anterior neck that is exposed when open-necked clothing is worn. Therefore, a technique for endoscopic endocrine neck surgery that results in a better cosmetic appearance is desirable. We have developed a totally gasless endoscopic surgical technique using an anterior neck-skin lifting method for thyroid and parathyroid diseases. This technique is called the video-assisted neck surgery (VANS) method. Since our original report, we have treated more than 200 cases of thyroid and parathyroid disease using this technique. In cases of benign thyroid tumours, near total lobectomy was the most common procedure followed by total lobectomy. The maximum resected tumour size was 7.4 cm in diameter. For malignant tumours, the indication for the VANS method was limited to thyroid papillary microcarcinomas measuring less than 1 cm in diameter. Total lobectomy and prophylactic neck dissection were performed in all 10 of these cases. A subtotal thyroidectomy was performed for only a few cases of Graves' disease. The operating time and the amount of bleeding were statistically significantly reduced, as the surgeon gained experience with the technique. In conclusion, the VANS method is a feasible, practical and safe procedure, with excellent cosmetic benefits.
At St. Joseph's Health Centre in London, Ontario, the Departments of Otolaryngology and Endocrinology of the University of Western Ontario work closely together in the medical and surgical management of patients with parathyroid disease. Recently, a multidisciplinary Grand Rounds was held during which current issues in the management of these patients were discussed, with particular emphasis on the role of localization studies as well as the potential difficulty inherent in distinguishing parathyroid adenomas from parathyroid hyperplasia. The following is an edited transcript from the Grand Rounds.
The etiology of parathyroid disease remains obscure. The terms "adenoma" and "hyperplasia" imply neoplastic and nonneoplastic processes, respectively. Angiogenesis, the ability of transplanted tissue to evoke new blood vessel formation by the host, is a property generally attributed to neoplastic tissue. We tested human parathyroid tissues from six patients with clinical diagnoses of adenoma and four patients with hyperplasia for their ability to evoke angiogenesis in an established in vivo model. Six to 12 small pieces of parathyroid tissue from each patient were placed on the iris of New Zealand white rabbits, three pieces per eye. Macroscopic assessment of angiogenesis was performed on days 2 through 5 after implantation by a noninformed observer. Microscopic assessment of implant viability was made after the animal was killed on day 5. Some implants were lost to infection, necrosis, and failure to attach to the iris. Both adenomatous and hyperplastic human parathyroid tissue demonstrated angiogenesis, and with approximately the same frequency. However, there was considerable variation in response of tissue from the same patient and between patients with the same clinical diagnosis. The ability of human parathyroid tissue to evoke angiogenesis may help explain its relative ease of transplantation.
OBJECTIVES/HYPOTHESIS: Critical evaluation of a directed exploration protocol used by a single surgeon in the management of surgical parathyroid disease. STUDY DESIGN: Retrospective chart review was made of patients surgically managed for hyperparathyroidism at an academic tertiary care center. METHODS: Three hundred forty-six patients were evaluated for biochemically proven hyperparathyroidism between March 1995 and February 2002. A directed exploration protocol was implemented in appropriately selected patients with primary hyperparathyroidism and in patients with secondary or tertiary hyperparathyroidism requiring repeat operation. The protocol included preoperative technetium-99m sestamibi imaging for hyperfunctional parathyroid localization, targeted neck exploration, rapid intraoperative parathyroid hormone determination, and limited-stay discharge from the ambulatory surgical recovery unit. Data collection was accomplished by entering patient evaluation, management, and outcome information prospectively into collective case report forms. A retrospective analysis of the data was conducted for the purpose of evaluating the effectiveness of the protocol. RESULTS: Sustained normocalcemia beyond 6 months postoperatively was achieved in 323 of 327 (99%) patients with primary hyperparathyroidism. Eighty-four percent (84%) of patients with secondary or tertiary hyperparathyroidism achieved normocalcemia or had resolution of symptoms as a measure of therapeutic success. The complication rate for the entire series of patients was 2.8%. Ninety-two percent of positive findings on sestamibi scan correctly predicted the location of an adenoma, whereas a negative finding accurately predicted the absence of an enlarged gland in a "usual" location in 81% of patients. Twenty-six patients (9%) had a false-positive finding on the scan, whereby a solitary adenoma was found contralateral to the side indicated by the scan. Overall, the positive predictive value for sestamibi imaging in the series was 91%. Intraoperative parathyroid hormone determination yielded an overall rate of reduction of 80% from preoperative levels during directed exploration. Sustained normocalcemia was achieved in all patients in whom intraoperative parathyroid hormone determination demonstrated a minimum decline of 50% from preoperative levels following resection of hyperfunctional parathyroid tissue (adenoma[s]). The majority (72%) of patients were managed in an outpatient (ambulatory surgery) setting and were discharged to home within 8 to 12 hours after surgery. CONCLUSION: The directed exploration protocol for surgical management of hyperparathyroidism generated surgical rates of success that were as good as and, in most cases, improved over that of traditional bilateral exploration. This achievement was associated with low morbidity and reduced time and facility utilization, conveying improved cost-effectiveness. This surgical strategy should serve to enhance the capability of the surgeon to safely and efficiently manage the majority of patients with surgical parathyroid disease.
PURPOSE: To determine the appropriate choice of imaging techniques for localization of nodular lesions of parathyroid glands. MATERIALS AND METHODS: First, computed tomographic (CT), magnetic resonance (MR), ultrasonographic (US), and technetium 99m methoxyisobutyl-isonitrile (MIBI) scintigraphic images in 49 patients with primary hyperparathyroidism were retrospectively evaluated. A single-blind, prospective study that included 16 patients with primary hyperparathyroidism was then conducted. MR, US, scintigraphic, and color Doppler US images of the neck were obtained and analyzed. RESULTS: In the retrospective study, CT, MR imaging, and US had low sensitivity (13%, 17%, and 27%, respectively) and specificity (39%, 65%, and 65%, respectively). Scintigraphy had 57% sensitivity and 85% specificity. In the prospective study, the use of latest-generation MR and US equipment and the participation of experienced operators led to improved sensitivity and specificity for these techniques. The combination of US and scintigraphy resulted in improved sensitivity (96%), specificity (83%), and positive and negative predictive values (88% and 94%, respectively), relative to the results obtained with either method alone. Doppler US was of little help in the setting of small glands. CONCLUSIONS: The combination of (99m)Tc MIBI scintigraphy and US performed by well-trained operators with up-to-date instruments appeared to be the best diagnostic tool for the preoperative diagnosis of parathyroid disease.
Reoperative parathyroid surgery is associated with a high mortality and morbidity. Morbidity consists of uncorrected hypercalcemia, hypoparathyroidism, and recurrent nerve injury. Initial operative failure is most frequently a result of not identifying four parathyroid glands. On reoperation, parathyroid glands are most often found in the neck and are usually hyperplastic. It is recommended that before attempting rexploration for parathyroid disease, all the patient's records especially the operative note and the previous pathology material should be reviewed. Preoperative localization by selective venous catheterization is of great use in the management of this type of patient.
UNLABELLED: This study evaluated the accuracy of (99m)Tc-sestamibi scintigraphy and neck ultrasonography in patients with primary hyperparathyroidism (PHPT) and the role of intraoperative hand-held gamma-probes in minimally invasive radioguided surgery (MIRS) of patients with a high likelihood of a solitary parathyroid adenoma (PA). The study was undertaken under the aegis of the Italian Study Group on Radioguided Surgery and Immunoscintigraphy (GISCRIS). METHODS: Clinical records were reviewed for 384 consecutive PHPT patients undergoing radioguided surgery using a low dose of (99m)Tc-sestamibi. Selection of patients for MIRS instead of traditional bilateral neck exploration was based on preoperative imaging indicating a solitary PA. (99m)Tc-Sestamibi (37-110 MBq, or 1-3 mCi) was injected in the operating theater 10-30 min before the start of the intervention. Either 11-mm collimated (309 patients) or 14-mm collimated (75 patients) gamma-probes were used. Intraoperative quick parathyroid hormone (IQPTH) assay was used on 308 patients (80.2%). RESULTS: MIRS was successfully performed on 268 (96.8%) of 277 patients. Conversion to bilateral neck exploration was necessary in 9 patients (3.3%) because of either persistently high IQPTH levels after removal of the preoperatively visualized PA (4 patients), intraoperative frozen-section diagnosis of parathyroid carcinoma (2 patients), or hard-to-remove PA (3 patients). MIRS, which was performed under locoregional anesthesia in 72 patients, required a mean operating time of 37 min and a mean hospital stay of 1.2 d. MIRS was successfully performed also on 32 (78.0%) of 41 patients who had previously undergone thyroid or parathyroid surgery. No major surgical complications were observed in the MIRS group, and there were only 24 cases (11%) of transient postoperative hypocalcemia. The probe was of little help in patients with concomitant (99m)Tc-sestamibi-avid thyroid nodules and not helpful at all in patients with negative scan findings preoperatively. IQPTH measurement helped to disclose some cases of multigland parathyroid disease. CONCLUSION: (99m)Tc-Sestamibi scintigraphy, especially if combined with neck ultrasonography, is highly accurate in selecting PHPT candidates for MIRS. The low-dose (99m)Tc-sestamibi protocol (which entails a low-to-negligible radiation exposure to the surgical team) is safe and effective for MIRS. MIRS plays a limited role in patients with concomitant (99m)Tc-sestamibi-avid thyroid nodules and should be discouraged in patients with negative (99m)Tc-sestamibi finding preoperatively. IQPTH can be recommended during MIRS to facilitate intraoperative identification of previously undiagnosed multigland parathyroid disease.
When primary hyperparathyroidism was a more symptomatic disease, it was often associated with increased cardiovascular risk. As the clinical manifestations of the disease have changed to a milder, more asymptomatic disorder, investigation is shifting to more subtle cardiovascular abnormalities. We measured arterial stiffness in 39 patients with mild primary hyperparathyroidism [serum calcium, 2.66 +/- 0.2 mmol/liter (10.7 +/- 0.6 mg/dl); PTH, 21.7 +/- 9.5 pmol/liter (89 +/- 39 pg/ml)] and in 134 controls. Arterial stiffness was measured mathematically at the radial artery with a noninvasive device as the "augmentation index" (AIx). The AIx measures the difference between the second and first systolic peaks in the pressure waveform and correlates with increased cardiovascular risk. When physiological variables affecting augmentation index and potentially confounding cardiovascular risk factors (age, gender, heart rate, height, blood pressure, diabetes mellitus, smoking, and hyperlipidemia) were adjusted for, primary hyperparathyroidism was an independent predictor of increased augmentation index (B = 3.37; P < 0.03). A matched-pair analysis showed that 15% of the variance in AIx was uniquely accounted for by the presence of primary hyperparathyroidism. The presence of primary hyperparathyroidism was a stronger predictor of elevated AIx than age, gender, smoking, hypertension, hyperlipidemia, or diabetes mellitus. AIx was also directly correlated with evidence of more active parathyroid disease, including higher PTH levels (r = +0.42; P < 0.05) and lower bone mineral density at the distal one-third radius (r = -0.33; P < 0.05). The diagnosis of primary hyperparathyroidism was therefore an independent predictor of increased AIx, an early measure of arterial stiffness, and the increase was associated with evidence of more active parathyroid disease.
In a well-defined geriatric population the prevalence of primary hyperparathyroidism was 1.5%. From a clinical material consisting of 400 patients treated surgically for primary hyperparathyroidism during a 10-year period 158 patients (38%) above the age of 64 were studied. Neuromuscular symptoms were present in 80%, renal insufficiency or kidney stones in each 16%, constipation and/or anorexia in 38%. 10% were considered clinically asymptomatic. In 80% the primary hyperparathyroidism was caused by a solitary adenoma. Normocalcaemia was achieved in 94%. Hypocalcaemia requiring vitamin D treatment occurred in 3%, and in 2% hypercalcaemia persisted or recurred. All of these had multiglandular parathyroid disease. The therapeutic effect of the surgical treatment was considered good or fair in most of the cases. No mortality occurred. Primary hyperparathyroidism occurs with a high prevalence in the elderly. It can be treated successfully by surgical therapy with a low cost of morbidity, mortality and medical care.
BACKGROUND: Patients treated for primary hyperparathyroidism run an increased risk of death. The aim of this study was to analyse several factors that may influence their risk of death. METHODS: General, laboratory, physical and clinical variables, altogether 34 variables, were defined as possible risk factors for death and were studied in a patient series of 845 patients operated on during the period 1953-82. Mean follow-up time was 10.5 years (SD 5.9); 253 patients were deceased at follow-up. Cox's proportional hazard model was used. RESULTS: We found seven variables with independent influence on the risk of death: age, sex, diabetes, cardiovascular disease, glomerular filtration rate, renal tubular concentration capacity and amount of diseased parathyroid tissue. The remaining 27 variables were separately tested, one at a time, using the same method and with the influence of age and sex eliminated. In this test situation, the year of surgery, peak serum calcium, serum creatinine level, body mass index, hypertension, psychiatric symptoms and a history of crisis were all significantly related to the risk of death. The analyses also gave information on the direction and magnitude of the effect of the variables on the risk of death. CONCLUSION: Primary hyperparathyroidism itself is a risk factor for death, but it was concluded that well-preserved renal function at surgery seems to have a protective role. We also found that the greater the amount of diseased parathyroid tissue the lesser the renal function and, furthermore, that hyperparathyroidism of substantial degree or long duration may bring about renal impairment that is not necessarily disclosed by the creatinine value alone.
The records of 100 patients operated on for primary hyperparathyroidism, from Jan 21, 1982 to June 11, 1984, were reviewed. In each patient, hypercalcemia had been documented on at least two separate occasions. A history, physical examination, chest roentgenogram, complete blood cell count with differential, 18-factor automated blood chemistry analysis, and urinalysis were used to screen for other causes of hypercalcemia. Of the 100 patients who had surgery, 88 had a preoperative parathyroid hormone level determination. Preoperative parathyroid hormone levels were normal in 41% of patients with parathyroid disease demonstrated at surgery. Parathyroid hormone assays produce variable results even from the best laboratories. A serum calcium determination remains the best test for diagnosing primary hyperparathyroidism.
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