Quality control in cochlear implant therapy: clinical practice guidelines and registries in European countries.

PURPOSE: The treatment with a cochlear implant (CI) is the gold standard in therapy of patients with profound hearing loss or deafness. Successful hearing rehabilitation with a CI is a complex, multi-stage process. In medicine, "Clinical Practice Guidelines" (CPG) are widely accepted for the standardization of such processes. These are supplemented by medical registries in which data regarding the treatment can be collected and evaluated. The aim of this paper is to identify currently existing CI-related CPGs and registries in Europe. METHODS: Between 01/2021 and 06/2021, 42 countries on the European continent, including the United Kingdom, Russia and Turkey, were screened using an internet search (search engine: Google) and a key word search in the Pubmed database. Search terms were the respective country name combined with the following terms: "Cochlear Implant", "CI", "Cochlear implant clinical practice guideline", "CI Guideline", "Cochlear Implant Registry", "CI Registry", "Ear nose throat society". The internet search was conducted in English as well as in the corresponding national language. The objective was to identify a CI-related CPG or registry. RESULTS: A CPG was found in 16 of 42 (38%) countries. In terms of population, this accounts for 645 million out of 838 million people (77%). A registry existed in 4 of the 42 (10%) countries assessed. This corresponds to 102 million out of 838 million (12%) people. In total, 4 out of 42 countries (10%) had both a CPG and a registry. CONCLUSION: Our work shows numerous efforts in Europe to standardize CI care at the national level. While most people in Europe already live in countries with a CPG, this is not the case for CI registries. European-wide consensus on CPGs or registries does not yet exist. The present study thus provides a first assessment of the distribution of CI-related CPGs and registries.

[Effects of the SARS-CoV­2 pandemic on the otolaryngology university hospitals in the field of research, student teaching and specialist training]. / Auswirkungen der SARS-CoV­2-Pandemie auf die universitäre Hals-Nasen-Ohren-Heilkunde im Bereich der Forschung, Lehre und Weiterbildung.

BACKGROUND: From spring 2020, SARS-CoV­2 began to spread worldwide, with what is now known as the first wave of the pandemic, starting in March 2020. This resulted in restructuring and shift of resources at many hospitals. The aim of our work was to detect the effects of the pandemic on the german Oto-Rhino-Laryngology (ORL) university hospitals in terms of research, student teaching and further specialist training. MATERIAL AND METHODS: The chairmen of the 39 ORL university hospitals in Germany were asked about the effects of the pandemic on research, student teaching and ORL specialist training (residency) in the period from March to April 2020 using a structured online survey. RESULTS: All 39 chairmen took part in the survey. Of these, 74.4% (29/39) stated that their research activities had deteriorated as a result of the pandemic. In 61.5% (24/39) pandemic-related research issues were addressed. All hospitals reported a restriction for in-house teaching and 97.5% (38/39) introduced new digital teaching methods. During the observation period, 74.4% of the chairmen did not see ORL specialist training (residency)at risk. CONCLUSION: Our results provide an insight into the heterogeneous effects of the pandemic. The fast processing of pandemic-related research topics and the introduction of innovative digital concepts for student teaching impressively demonstrates the great innovative potential and the ability of the ORL university hospitals to react quickly in order to maintain their tasks in research, student teaching and ORL specialist training in the best possible way even during the pandemic.

[Development of the publication activity at the German university hospitals for Otorhinolaryngology, Head and Neck Surgery during the SARS-CoV-2-pandemic in 2020]. / Entwicklung der Publikationsleistung der Universitätskliniken für Hals-Nasen-Ohrenheilkunde, Kopf- und Hals-Chirurgie während der SARS-CoV-2-Pandemie im Jahr 2020 in Deutschland.

INTRODUCTION: The SARS-CoV-2 pandemic has led to profound limitations in patient care and student teaching at the University Hospitals of Otorhinolaryngology (ORL). In contrast, the impact on research has been variable. To classify the pandemic-related effect on research, the development of the number of scientific publications of the German ORL university hospitals before and during the pandemic was analyzed. MATERIAL AND METHODS: The publication performance between 2015 and 2020 of the 39 current chairmen was surveyed using a literature search (Pubmed). All entries relating to the chairmen of the university hospital as first, last or co-author were included. The absolute and relative development of each author's publication performance was determined and evaluated using nonparametric statistical methods. RESULTS: A total of 2420 publications could be documented. From 2015 to 2019, an average of 368 publications were published per year. In 2020, this number increased by 57.9 % to 581 publications. While the number of monthly publications remained constant between 2015 and 2019, a significant increase was seen from May 2020 up to a maximum of 74 publications in September 2020. In 2020, 34 articles (5.9 %) had a thematic relation to the SARS-CoV-2 pandemic, with 7 of these papers (20.6 %) resulting from cross-site publications. CONCLUSION: In 2020, the number of scientific publications was raised to more than 1.5 times the usual annual publications. This increase was clearly related in time to the reduction of elective patient care during the SARS-CoV-2 pandemic starting in mid-March 2020. Probably, free time capacities enabled this increased publication output. Our results confirm the great scientific potential of the ORL university hospitals, which has been successfully implemented despite the pandemic.

[Effects of the SARS-CoV-2 pandemic on the otorhinolaryngology university hospitals in the field of medical care]. / Auswirkungen der SARS-CoV-2-Pandemie auf die universitäre Hals-Nasen-Ohrenheilkunde im Bereich der Krankenversorgung.

INTRODUCTION: Since December 2019, the SARS-CoV-2 virus has been rapidly spreading worldwide. In Germany, an exponential increase in the number of infections was registered at the beginning of March 2020 and led to a call of the Ministry of Health to create more capacity for intensive medical treatment in hospitals. The aim of the present study was to determine the effects of the SARS-CoV-2 pandemic on Oto-Rhino-Laryngology (ORL) university hospitals regarding patient care. MATERIALS AND METHODS: An online survey was sent out to all chairmen of the 39 ORL university hospitals in Germany. The answers to the questions referred to the defined period from March 15th to April 15th 2020 and were carried out using the online survey tool "SurveyMonkey". 87 questions focused on general information, health care, and structural effects in the respective institution. RESULTS: All chairmen of the 39 university hospitals in Germany participated in the survey. The collected data prove the considerable impact on organizational, structural and medical aspects of patient care. For example, the surveyed clinics reported a decrease in outpatient cases by 73.8 % to 26.2 ±â€Š14.2 % and in surgical treatments by 65.9 % to 34.1 ±â€Š13.9 %. In contrast, emergency treatment remained unchanged or even increased in 80 % of the facilities and surgical treatment of emergency patients remained unchanged or even increased in more than 90 %. Emergency outpatient and surgical treatment of patients was provided throughout the pandemic in all facilities. In total, about 35 000 outpatients and about 12 000 surgical cases were postponed. As a result of the acute structural changes, the potential danger of falling below current treatment standards was seen in individual areas of patient care. DISCUSSION: The assessment of the impact of the SARS-CoV-2 pandemic is heterogeneous. The majority of the chairmen are critically aware of the risk of falling below current medical treatment standards or guidelines. In the phase of an exponential increase in the number of infections, significant changes in treatment processes had to be accepted for understandable reasons. However, with the currently significantly reduced number of infections, falling below treatment standards and guidelines should not be allowed to remain constant and tolerated. SUMMARY: This study shows a differentiated picture with regard to the effects of the SARS-CoV-2 pandemic on outpatient, inpatient and operative patient care at the ORL university hospitals in Germany and illustrates the importance of these institutions for ensuring patient care during this critical phase.

Vibrant Soundbridge® in preschool children with unilateral aural atresia: acceptance and benefit.

The aim of this pilot study was to determine the acceptance and benefit from the middle ear implant system Vibrant Soundbridge® (VSB, MED-EL Corporation, Austria) by means of a questionnaire, compared to a previously used conventional bone conducting hearing device, in preschool children with unilateral congenital aural atresia. Prospective cohort study. All nine children with unilateral congenital aural atresia used the VSB and had previous experience with a bone conducting hearing device. The benefit from the VSB was evaluated by questionnaires concerning acceptance of hearing aids, handling, listening effort, behavior, quality of life, and the duration of daily use and compared to the experience with the bone conducting hearing device. In addition, to quantify the benefit from the VSB use, audiological assessment (pure-tone audiometry via free field testing, speech audiometry, and localization test) was performed with and without VSB. The questionnaires and audiological test results were compared pairwise. According to all questionnaire areas, children benefited significantly more from the VSB compared to bone conducting hearing device (ps <.05). The most important finding was a significant increase in daily use from 2 h for the bone conducting hearing device to 10 h for the VSB. Children performed significantly better with the VSB than without it in the audiological assessment. Children with unilateral aural atresia benefited significantly more from the VSB compared to a conventional bone conducting hearing device according to the parents' questionnaires and yielded better results in the audiometry and localization test with the VSB than without it.

[Vibrant Soundbridge®: An Alternative Hearing System for Preschool Children with Aural Atresia]. / Die Vibrant Soundbridge®: Ein alternatives Hörsystem bei Vorschulkindern mit Gehörgangsatresie.

BACKGROUND: The audiological treatment of children with aural atresia makes high demands on physicians and acousticians. Conventional hearing systems are often not tolerated by children and therefore do not meet the needs of the early and efficient therapy of hearing disorders. Aim of the present study was the evaluation of the audiological functional gain in children with uni- and bilateral aural atresia provided with the middle ear implant Vibrant Soundbridge(®) (VSB(®)) below the age of 6 years as well as the analysis of parents' satisfaction assessed with questionnaires. MATERIAL AND METHODS: The VSB(®) was implanted in 16 children, 13 with unilateral and 3 with bilateral aural atresia, with the mean age of 2;11±1;6 years. 3 months after the first fitting of the audio processor, pure-tone audiometry via free field testing with and without the hearing system was performed. Furthermore, parents completed a standardized questionnaire to evaluate their satisfaction with the VSB(®) treatment quality. The questionnaire included items on the acceptance by children, handling, listening effort, behavior, satisfaction, quality of life, aesthetics, and the length of daily use. RESULTS: The use of the VSB(®) resulted in a significantly improved hearing level: 20 dB on average (Z=- 3.06; p=0.002; n=12). The analysis of parents' questionnaire demonstrated high or very high satisfaction with VSB(®) in all subjects. Primarily, the length of daily use of the VSB(®) was significantly higher than that of the hearing system used before with 10.0±2.1 vs. 2.7±2.2 h per day (Z=- 3.06; p=0.002; n=14). CONCLUSION: The VSB(®) presented a good alternative for audiological treatment of uni- and bilateral aural atresia at toddler and pre-school age.

[Secretion scale by Murray et al. for FEES®: comparison of reliability and validity of the German long and short version]. / Sekretbeurteilungsskala nach Murray et al. für FEES(®) : Reliabilitäts- und Validitätsvergleich der deutschen Lang- und Kurzversion.

BACKGROUND: Accumulation of secretions in the hypopharynx, aditus laryngis and trachea constitute a cardinal trait of oropharyngeal dysphagia. For the evaluation of the degree of severity a 4-point secretion scale by Murray et al. is used internationally in a long and a short version. However, a validated German translation of the long version of this scale does not yet exist. Also, it has not yet been scientifically proven that both versions of the scale are equally valid. OBJECTIVES: This study aimed at the validation of the German translation of the long version of the secretion scale by Murray et al. and at a comparison of reliability and validity of the short and long versions. MATERIAL AND METHODS: A total of 40 videos of fiberoptic endoscopic evaluation of swallowing (FEES(®)), 10 for each severity level, were rated by 4 otorhinolaryngologists (ENT specialists) independently and with different randomizations for examination of the reliability and validity. Two rating sessions for each of the scale versions were conducted. Intrarater and interrater reliability as well as the agreement of the ratings with a reference standard were analyzed. RESULTS: Both the intrarater reliability (Spearman correlations: ρs > 0.840***) and the interrater reliability (Krippendorff's alpha: α > 0.850) yielded very good results and the concurrent validity was highly significant (ρs > 0.981***). DISCUSSION: The German translation of the secretion scale by Murray et al. can be considered reliable and valid, with comparable test accuracy of the short and long versions. Hence, the scale can be recommend for the graduation of pharyngolaryngotracheal secretions and should be integrated into the standardized evaluation of FEES(®) diagnostics for clinical and scientific purposes.

Oral delivery of mouse [d-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, in male C57BL/6J wild-type and ob/ob mice: effects on energy balance, glycaemic control and serum osteocalcin levels.

BACKGROUND: We have recently shown that intranasal administration of mouse [d-Leu-4]-OB3 reconstituted in Intravail to male Swiss Webster mice resulted in significantly higher bioavailability than commonly used injections methods of delivery. The absorption profile associated with intranasal delivery of mouse [d-Leu-4]-OB3 showed an early peak representing absorption across the nasal mucosa, and a later peak suggesting a gastrointestinal site of uptake. AIM AND METHODS: In the present study, we examined the effects of orally administered (by gavage) mouse [d-Leu-4]-OB3 on energy balance, glycaemic control and serum osteocalcin levels in male C57BL/6J wild-type and ob/ob mice allowed food and water ad libitum or calorie restricted by 40% of normal intake. RESULTS: In wild-type mice fed ad libitum, oral delivery of mouse [d-Leu-4]-OB3 reduced body weight gain, food intake and serum glucose, by 4.4, 6.8 and 28.2% respectively. Serum osteocalcin levels and water intake were essentially the same in control and treated wild-type mice. In ob/ob mice fed ad libitum, mouse [d-Leu-4]-OB3 reduced body weight gain, food intake, water intake and serum glucose by 11.6, 16.5, 22.4 and 24.4% respectively. Serum osteocalcin in ob/ob mice treated with mouse [d-Leu-4]-OB3 was elevated by 62% over controls. Calorie restriction alone caused significant weight loss in both wild-type (9.0%) and ob/ob (4.8%) mice, and mouse [d-Leu-4]-OB3 did not further enhance this weight loss. As expected, serum glucose levels in wild-type and ob/ob mice were significantly reduced by calorie restriction alone. Mouse [d-Leu-4]-OB3 further reduced serum glucose in wild-type mice and normalized levels in ob/ob mice. Calorie restriction alone reduced serum osteocalcin levels by 44.2% in wild-type mice and by 19.1% in ob/ob mice. Mouse [d-Leu-4]-OB3 prevented this decrease in groups of mice. CONCLUSIONS: The results of this study suggest that oral delivery of mouse [d-Leu-4]-OB3 in Intravail is possible and may have potential not only as an alternative therapy in the treatment of human obesity and some of its associated metabolic dysfunctions, but also may help to prevent and/or reverse at least some of the bone loss which accompanies osteoporosis, anorexia nervosa and other wasting diseases.

Intranasal delivery of mouse [D-Leu-4]-OB3, a synthetic peptide amide with leptin-like activity, improves energy balance, glycaemic control, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice.

BACKGROUND: We have recently shown that intranasal administration of mouse [D-Leu-4]-OB3 reconstituted in Intravail(®) to male Swiss Webster mice resulted in significantly higher uptake and bioavailability when compared with commonly used injection methods of delivery. AIM AND METHODS: In this study, we examined the effects of intranasal delivery of mouse [D-Leu-4]-OB3 in Intravail(®) on energy balance, glucose regulation, insulin secretion and serum levels of osteocalcin, a specific and sensitive marker of bone formation. Genetically obese C57BLK/6-m db/db mice were allowed food and water ad libitum and given either Intravail(®) alone or mouse [D-Leu-4]-OB3 in Intravail(®) for 14 days by intranasal instillation. RESULTS: Mouse [D-Leu-4]-OB3 reduced body weight gain, daily food intake, daily water intake and serum glucose by 11.5, 2.2, 4.0 and 61.9%, respectively. Serum insulin levels in db/db mice given mouse [D-Leu-4]-OB3 were approximately threefold lower than those in mice receiving Intravail(®) alone. Mouse [D-Leu-4]-OB3 elevated serum osteocalcin in db/db mice by 28.7% over Intravail(®) treated control mice. CONCLUSIONS: The results of our study indicate that intranasal delivery of biologically active mouse [D-Leu-4]-OB3 in Intravail(®) is feasible and has significant effects on regulating body weight gain, food and water intake, serum glucose, insulin sensitivity and bone formation in leptin-resistant C57BLK/6-m db/db mice.

Clinical feasibility test on a minimally invasive laser therapy system in microsurgery of nerves.

The clinical feasibility test described here evaluates the basis for a laser therapy system that enables tumour tissue to be separated from nerves in a minimally invasive manner. It was first investigated whether, using an Er:YAG laser, laser-induced nerve (specifically, facial nerve) responses in the rabbit in vivo can be reliably detected with the hitherto standard monitoring techniques. Peripherally recordable neuromuscular signals (i.e. compound action potentials, CAPs) were used to monitor nerve function and to establish a feedback loop. The first occurrence of laser-evoked CAPs was taken as the criterion for deciding when to switch off the laser. When drawing up criteria governing the control and termination of the laser application, the priority was the maintenance of nerve function. Five needle-electrode arrays specially developed for this purpose, each with a miniature preamplifier, were then placed into the facial musculature instead of single-needle electrodes. The system was tested in vivo under realistic surgical conditions (i.e. facial-nerve surgery in the rabbit). This modified multi-channel electromyography (EMG) system enabled laser-evoked CAPs to be detected that have amplitudes 10 times smaller than those picked up by commercially available systems. This optimization, and the connection of the neuromuscular unit with the Er:YAG laser via the electrode array to create a feedback loop, were designed to make it possible to maintain online control of the laser ablation process in the vicinity of neuronal tissue, thus ensuring that tissue excision is both reliable and does not affect function. Our results open up new possibilities in minimally invasive surgery near neural structures.

Homograft patch repair in carotid artery rupture.

The case of a 24-year-old man with a rupture of the left common carotid artery and history of intravenous drug abuse is presented. Due to absence of a suitable autologous vein segment the carotid bulb was repaired with a human allograftpatch.

Inhibitory effects of leptin-related synthetic peptide 116-130 on food intake and body weight gain in female C57BL/6J ob/ob mice may not be mediated by peptide activation of the long isoform of the leptin receptor.

We recently reported that intraperitoneal administration of leptin-related synthetic peptide 116-130 [LEP-(116-130)] resulted in reduced food intake and significant weight loss in homozygous female C57BL/6J ob/ob mice. In this study, we used two in vitro bioassays to show that the interaction of LEP-(116-130) with the long form of the leptin receptor (OB-Rb), the receptor isoform that is predominantly expressed in the hypothalamus, is not required for the observed in vivo effects of the peptide on energy balance. LEP-(116-130) was unable to compete the binding of alkaline phosphatase-leptin fusion protein to OB-R. Moreover, LEP-(116-130) was unable to activate signal transduction by OB-Rb in vitro. In homozygous female C57BLKS/J-m db/db mice that do not express OB-Rb, intraperitoneal administration of LEP-(116-130) reduced body weight gain and blood glucose levels but not food intake, which further supports a mechanism of action that does not require peptide interaction with OB-Rb.

Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature.

Sporadic single case reports linking glucocorticoidlike activity to megestrol acetate have been reported in the literature. These findings have important implications for patient care. Adverse drug experience reports to the US Food and Drug Administration from 1984 through 1996 and a MEDLINE search of the literature from 1984 through 1996 provided the case reports. Five cases of Cushing syndrome, 12 cases of new-onset diabetes, and 16 cases of adrenal insufficiency were identified in association with megestrol therapy. Twelve cases in which preexisting diabetes was exacerbated and 17 cases of possible adrenal insufficiency were identified. Therapy with megestrol can result in clinical manifestations of glucocorticoidlike activity, including Cushing syndrome, diabetes, and adrenal insufficiency. Clinicians need to be aware of this association as these complications can be life-threatening if not recognized.

Design of a synthetic leptin agonist: effects on energy balance, glucose homeostasis, and thermoregulation.

We have previously reported that a synthetic peptide amide corresponding to amino acid residues 116-130 of mouse leptin, LEP-(116-130), reduces body weight gain, food intake, and blood glucose levels in ob/ob and db/db mice. In the present study we show that the activity of LEP-(116-130) resides in a restricted sequence between amino acid residues 116-122. A synthetic peptide corresponding to this sequence (Ser-Cys-Ser-Leu-Pro-Gln-Thr) has been named OB3. Single point D-amino acid substitution was used to study the structure-function relationship of each residue in OB3. D-Amino acid analogs of OB3 were synthesized by the solid phase method, purified to 98+%, and administered (1 mg/day, ip) for 7 days to female C57BL/6J ob/ob mice. The effects of the peptides on body weight gain, food and water intake, glucose homeostasis, and thermoregulation were assessed. In most cases, the efficacy of OB3 on all parameters tested was reduced by substitution of an L-amino acid with its corresponding D-isoform. A statistically significant increase (2.6-fold) in the weight-reducing effect of OB3, however, was observed by inversion of the configuration of the leucine residue at position 4 (Leu-4) of OB3 by substitution with its D-amino acid isoform [D-Leu-4]. Compared with OB3, mice treated with [D-Leu-4]-OB3 consumed 7.9% less food and 16.5% less water. Blood glucose was normalized to levels comparable to those in wild-type control mice within 2 days after initiation of [D-Leu-4]-OB3 treatment. Unlike native leptin, however, neither OB3 nor any of its D-amino acid-substituted analogs had any apparent effect on thermogenesis. Our results indicate that synthetic peptide strategies may be useful in the development of potent and stabile pharmacophores with potential therapeutic significance in the treatment of human obesity and its related metabolic dysfunctions.

In vivo effects of leptin-related synthetic peptides on body weight and food intake in female ob/ob mice: localization of leptin activity to domains between amino acid residues 106-140.

In C57BL/6J ob/ob mice, a single base mutation of the ob gene in codon 105 results in the replacement of arginine by a premature stop codon and production of a truncated inactive form of leptin. These observations suggest that leptin activity may be localized, at least in part, to domains distal to amino acid residue 104. To investigate this possibility, we synthesized six overlapping peptide amides corresponding to residues 106-167 of leptin, and examined their effects on body weight and food intake in female C57BL/6J ob/ob mice. When compared with vehicle-injected control mice, weight gain by mice receiving 28 daily 1-mg i.p. injections of LEP-(106-120), LEP-(116-130), or LEP-(126-140) was significantly (P < 0.01) reduced with no apparent toxicity. Weight gain by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167) was not significantly different from that of vehicle-injected control mice. The effects of LEP-(106-120), LEP-(116-130), or LEP-(126-140) were most pronounced during the first week of peptide treatment. Within 7 days, mice receiving these peptides lost 12.3%, 13.8%, and 9.8%, respectively, of their initial body weights. After 28 days, mice given vehicle alone, LEP-(136-150), LEP-(146-160), or LEP-(156-167) were 14.7%, 20.3%, 25.0%, and 24.8% heavier, respectively, than they were at the beginning of the study. Mice given LEP-(106-120) or LEP-(126-140) were only 1.8% and 4.2% heavier, respectively, whereas mice given LEP-(116-130) were 3.4% lighter. Food intake by mice receiving LEP-(106-120), LEP-(116-130), or LEP-(126-140), but not by mice receiving LEP-(136-150), LEP-(146-160), or LEP-(156-167), was reduced by 15%. The results of this study indicate 1) that leptin activity is localized, at least in part, in domains between residues 106-140; 2) that leptin-related peptides have in vivo effects similar to those of native leptin; and 3) offer hope for development of peptide analogs of leptin having potential application in human or veterinary medicine.

Pituitary adenomas in childhood and adolescence.

A clinicopathological study of 56 pediatric patients with non-ACTH-secreting pituitary adenomas removed by a transsphenoidal neurosurgical approach was undertaken to better define the clinical presentation, to assess demographic factors, to determine the immunohistochemical staining characteristics of the tumors, and to evaluate the outcome of transsphenoidal surgical treatment and other adjuvant therapies. A separate analysis of prolactinoma patients was performed. All tumors were confirmed histologically and immunophenotyped for pituitary hormones. Forty-one patients had tumors that stained for PRL alone, eight patients had tumors that stained for PRL and GH, six patients had plurihormonal adenomas, and one patient had a tumor that stained for glycoprotein hormones. No tumors contained GH alone. Macroadenomas exceeded microadenomas (1.4:1). There were no male patients with microadenomas of any type. Females outnumbered males (3.3:1). Patients presented most frequently with headache, menstrual dysfunction (in females), galactorrhea, and hypopituitarism. All but one of the patients with hypopituitarism at presentation had macroadenomas. Tumor staining characteristics did not always correlate well with clinical status, especially with regard to GH-containing tumors. Pediatric pituitary tumors did not appear to be more invasive or more aggressive than adult pituitary tumors, contrary to some previous reports. The patients with microadenomas had a 70% operative cure rate and a 65% long term cure rate; the recurrence rate for microadenoma patients was 25%. Macroadenoma patients had a 33% operative cure rate, a 55% long term cure rate, and a recurrence rate of 33%. Thus, microadenoma and macroadenoma patients had similar long term cure rates, but macroadenoma patients required more aggressive adjuvant therapy (second surgery, radiation, or bromocriptine) and had higher rates of hypopituitarism (52% of macroadenoma patients vs. 0% of microadenoma patients required long term hormone replacement).

Long term follow-up of transsphenoidal surgery for the treatment of Cushing's disease in childhood.

Transsphenoidal removal of pituitary adenomas has become the accepted treatment for Cushing's disease. As Cushing's disease is rare in childhood, few reports describe extended follow-up after transsphenoidal surgery for this disease in children. Twenty-two patients less than 19 yr of age were diagnosed with Cushing's disease by standard testing. All patients underwent transsphenoidal surgery (TSS) as primary treatment at Mayo Clinic between 1975 and 1990. Follow-up was available in all patients and averaged 6.7 yr. Adenomas were identified pathologically in 19 patients and visualized by the surgeon in the remainder. There was 1 macroadenoma. Ten patients are considered cured with a mean follow-up of 5.5 yr. Five patients had evidence of persistent disease within 6 months of TSS and required further treatment. Seven patients had remission lasting greater than 6 months with subsequent relapse (mean time to recurrence, 7.0 yr). In children treated with TSS for Cushing's disease, the rate of cure with extended follow-up is only approximately 50%. This rate is much lower than that in adults and may indicate that Cushing's disease is more aggressive in childhood. As TSS is associated with low morbidity, we feel it is still the treatment of choice for Cushing's disease in children.

The clinical evaluation of patients with subclinical hyperthyroidism and free triiodothyronine (free T3) toxicosis.

PURPOSE: To develop a strategy to identify cases of endogenous subclinical hyperthyroidism and free triiodothyronine (free T3) thyrotoxicosis in otherwise healthy ambulatory patients. PATIENTS AND METHODS: In a retrospective study we reviewed the records of ambulatory patients who had thyroid stimulating hormone (TSH) levels determined between October 1, 1991 and August 31, 1992. Each patient also had a simultaneous free thyroxine (free T4) measurement. Patients were excluded from consideration if they had active, concurrent non-thyroidal illness, psychiatric disease, known hypothalamic/pituitary lesions, were under treatment for hyper- or hypothyroidism, were on drugs known to affect TSH levels, or were pregnant. Patients without exclusions were diagnosed with free T3 toxicosis if they had: (1) a markedly subnormal TSH level (less than or equal to 0.1 mU/L), (2) a normal free T4, (3) a normal total T3, (4) evidence of a primary thyroid abnormality (e.g., autonomous function on a thyroid scan), and (5) an elevated free T3 level by tracer equilibrium dialysis. Patients meeting conditions 1-4, but with normal free T3 levels, were considered to have subclinical hyperthyroidism. RESULTS: One thousand twenty-five patients had TSH and simultaneous free T4 determinations, and 148 of these had markedly subnormal TSH but normal free T4 levels. Three patients met the criteria for free T3 toxicosis and three had subclinical hyperthyroidism. All six patients had either multinodular glands or a single nodule on thyroid exam. Four patients were treated with radioactive iodine or surgery, resulting in reversal of the TSH suppression in three cases. CONCLUSION: Apparently healthy ambulatory patients with subnormal TSH levels should be worked up with measurements of free T4 and total T3. If these are normal, a T3 level (by tracer equilibrium dialysis) be obtained to distinguish subclinical hyperthyroidism from overt free T3 toxicosis. A thyroid scan and radioiodine uptake measurement can be obtained to substantiate the diagnosis. Some patients with these conditions will benefit from treatment.

Cushing's disease in children.

As with adults, the diagnosis of Cushing's disease in childhood can be difficult. The clinical presentation in children is distinctive in terms of the effects on growth and pubertal development. The biochemical diagnosis can usually be made with standard dexamethasone suppression testing, similar to such testing in adults. The clinical course of Cushing's disease in children tends to be more aggressive than in adults, as evidenced by higher rates of Nelson's syndrome after bilateral adrenalectomy and higher rates of recurrence after removal of corticotrope adenomas. TSS is well tolerated in children and has fewer side effects than other modalities. Currently, pituitary irradiation is best reserved as adjunctive therapy. Newer stereotactic computer assisted linear accelerator techniques (e.g., proton knife) may provide increased effectiveness with fewer side effects and be particularly useful in childhood Cushing's disease. Appropriate treatment of children with Cushing's disease can be compatible with satisfactory psychosocial adjustment and fertility in adulthood.