Optic nerve and chiasm hemangioblastomas in von Hippel-Lindau disease: report of 12 cases and review of the literature.

Introduction: Optic nerve and chiasm hemangioblastomas are rare tumors, occurring sporadically or in the context of von Hippel-Lindau (VHL) disease. They have only been portrayed in isolated case reports and small cohorts. Their natural history and therapeutic strategies are only scarcely described. To better characterize these rare tumors, we retrospectively analyzed an optic nerve and chiasm hemangioblastoma series of 12 VHL patients. By combining our own experience to a review of all known cases in literature, we intended to create treatment recommendations for optic nerve and chiasm hemangioblastomas in VHL patients. Methods: We reviewed two electronic databases in the hospitals of our senior authors, searching for VHL patients with optic nerve or chiasm hemangioblastomas. Clinical data were summarized. Tumor size and growth rate were measured on contrast enhanced MRI. Comparable data were collected by literature review of all available cases in VHL patients (Pubmed, Trip, Google and Google Scholar). Results: Of 269 VHL patients, 12 had optic nerve or chiasm hemangioblastomas. In 10 of 12 patients, tumors were diagnosed upon annual ophthalmoscopic/MRI screening. Of 8 patients who were asymptomatic at diagnosis, 7 showed absent or very slow annual progression, without developing significant vision impairment. One patient developed moderate vision impairment. Two symptomatic patients suffered from rapid tumor growth and progressive vision impairment. Both underwent late-stage surgery, resulting in incomplete resection and progressive vision impairment. One patient presented with acute vision field loss. A watchful-waiting approach was adopted because the hemangioblastoma was ineligible for vision-sparing surgery. One patient developed progressive vision impairment after watchful waiting. In the literature we found 45 patient cases with 48 hemangioblastomas. Discussion: When optic nerve and chiasm hemangioblastomas are diagnosed, we suggest annual MRI follow-up as long as patients do not develop vision impairment. If tumors grow fast, threaten the contralateral eye, or if patients develop progressive vision deficiency; surgical resection must be considered because neurological impairment is irreversible, and resection of large tumors carries a higher risk of further visual decline.

Rare Thyroid Diseases Mimicking or Concealing Primitive Thyroid Neoplasms: A Call for a "Check and Double-Check" Clinical Mindset.

Clinical endocrinologists encounter in their practice patients with thyroid diseases on a daily basis. Still, diagnosis of rare structural thyroid disorders can be quite challenging. In some instances, they do not only impersonate but can also conceal, other conditions such as thyroid carcinomas. We describe a series of patients with structural thyroid disorders including 1) anaplastic thyroid carcinoma initially presenting with features of thyroid abscess; 2) unicentric hyaline vascular Castleman's disease of the thyroid embedded in a stroma of papillary thyroid carcinoma; and 3) primary thyroid lymphoma with a rapid and fulminant evolution. The common challenge in the diagnosis of these cases lies in both their low incidence and their complex presentation. We use the presentation of these cases to raise the attention related to their identification. We highlight the need for precision diagnosis to enable a patient-tailored management approach and improve patient outcomes.

Epileptic seizures and abnormal tooth development as primary presentation of pseudohypoparathyroidism type 1B.

Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterised by a non-functioning PTH. Usually, the diagnosis is made following (symptomatic) hypocalcaemia. We describe a case in which epileptic seizures and abnormalities in dental development were the main clinical manifestation of PHP type 1B. This case demonstrates the importance of screening for hypocalcaemia in patients with de novo epileptic seizures. In addition, antiepileptic medications themselves may interfere with calcium-phosphate metabolism, causing or aggravating a hypocalcaemia as well. By correcting the calcium level, a resolution of these symptoms could be obtained.

The Presence of Anti-TPO Antibodies Increase the Likelihood of Post-I131 Hypothyroidism.

The use of radioactive iodine in the treatment of hyperthyroidism is common practice. However, a standardized treatment protocol with regard to radioactive iodine treatment (RAI) remains subject to discussion. We retrospectively analyzed 100 patient records. Patient diagnosis, age, gender, body mass index (BMI), dose of radioactive iodine, thyroid size, the 24 h radioiodine uptake (24 h RAIU) and protein bound iodine (PBI) were deducted, as well as the use of antithyroid drugs prior to RAI. Biochemical parameters were obtained, such as TSH, fT4, fT3, Anti-TPO, Anti-TG antibodies and thyroid stimulating antibodies. After 5 years of follow-up, 46% of the patients proved to be hypothyroid, whereas 8% of the patients were not cured after one dose of RAI. One year after RAI, a larger proportion of patients with a toxic nodule developed hypothyroidism compared to patients with a multinodular goiter (MNG) (44.2% vs. 21.2%). Radioactive iodine dose, PBI, RAIU, BMI, size of the thyroid gland, diagnosis, age and TPO-antibodies showed statistically significant differences in the development of hypothyroidism. Furthermore, thiamazole pretherapy was shown to be a predictor of hypothyroidism, as well as a high PBI value, exhibiting a positive predictive value of 85.2% when the PBI exceeded 0.16. We suggest a standardized measurement of TPO-Ab's to further determine their role in the development of hypothyroidism after RAI. The empirical dosing regimen was very effective, illustrating a 92% cure rate after 1 dose.

Pituitary carcinoma - case series and review of the literature.

Although pituitary adenomas (PAs) account for 15% of intracranial tumors, pituitary carcinomas (PCs) are a rare entity. Most commonly, PCs evolve from aggressive PAs invading the surrounding structures and eventually leading to metastatic lesions. Due to the low incidence, the diagnosis and treatment remains challenging. We report a case series of five patients with pituitary carcinoma (PC) treated in our center. At first diagnosis 3 patients had an ACTH-producing adenoma, 1 a prolactinoma and 1 a double secreting adenoma (GH and prolactin). The mean time interval from initial diagnosis to diagnosis of PC was 10.7 years (range 5-20 years). All patients underwent multiple surgical resections and radiotherapy. Four patients were treated with temozolomide for metastatic disease. One patient with concomitant radiochemotherapy for local recurrence. Temozolomide led to a stable disease in 2 patients. One patient had a progressive disease after 9 cycles of temozolomide. In absence of standard treatment, immunotherapy was initiated, resulting in a stable disease. We report five cases of PCs. Three patients obtained a stable disease after tailored multidisciplinary treatment. Additionally, one patient was treated with immunotherapy, opening a new treatment option in PCs. Overall, PCs are rare intracranial neoplasms occurring several years after the initial diagnosis of aggressive PAs. Currently, the absence of predictive factors for an aggressive clinical course, provokes a challenging management.

Lymphadenopathy after COVID-19 vaccination in patients with endocrine cancer: two case reports.

Summary: The Covid-19 vaccination has been rapidly implemented among patients with cancer. We present two cases of patients with endocrine tumours who developed lymphadenopathy following a Covid-19 vaccination. In the case of a patient with multiple endocrine neoplasia (MEN) 1 syndrome, an 18-fluorodeoxyglucose (18FDG)-PET/CT showed positive axillary lymph nodes. Further work-up with fine needle aspiration showed a reactive pattern following a Covid-19 vaccination in the ipsilateral arm shortly before the 18FDG-PET/CT. A second patient, in follow-up for thyroid cancer, developed clinical supraclavicular lymphadenopathy after a Covid-19 vaccination. Follow-up ultrasound proved the lesion to be transient. These cases demonstrate lymphadenopathy in response to a Covid-19 vaccination in two patients susceptible to endocrine tumours and metastatic disease. With growing evidence about the pattern and occurrence of lymphadenopathy after mRNA Covid-19 vaccination, recommendations for scheduling and interpretation of imaging among cancer patients should be implemented to reduce equivocal findings, overdiagnosis, and overtreatment, while maintaining a good standard of care in oncological follow-up. Learning points: Reactive lymphadenopathy is very common after an mRNA vaccination against Covid-19 and should be part of the differential diagnosis in patients with endocrine tumours who recently received a Covid-19 mRNA vaccination and present with an ipsilateral lymphadenopathy. A good vaccine history is essential in assessing the risk for lymphadenopathy and if possible, screening imaging in patients with endocrine tumours should be postponed at least 6 weeks after the previous vaccination. For now, a multidisciplinary care approach is recommended to determine the necessary steps in the diagnostic evaluation of lymphadenopathy in the proximity of a Covid-19 vaccination.

COVID-19 and Cushing's disease in a patient with ACTH-secreting pituitary carcinoma.

SUMMARY: The pandemic caused by severe acute respiratory syndrome coronavirus 2 is of an unprecedented magnitude and has made it challenging to properly treat patients with urgent or rare endocrine disorders. Little is known about the risk of coronavirus disease 2019 (COVID-19) in patients with rare endocrine malignancies, such as pituitary carcinoma. We describe the case of a 43-year-old patient with adrenocorticotrophic hormone-secreting pituitary carcinoma who developed a severe COVID-19 infection. He had stabilized Cushing's disease after multiple lines of treatment and was currently receiving maintenance immunotherapy with nivolumab (240 mg every 2 weeks) and steroidogenesis inhibition with ketoconazole (800 mg daily). On admission, he was urgently intubated for respiratory exhaustion. Supplementation of corticosteroid requirements consisted of high-dose dexamethasone, in analogy with the RECOVERY trial, followed by the reintroduction of ketoconazole under the coverage of a hydrocortisone stress regimen, which was continued at a dose depending on the current level of stress. He had a prolonged and complicated stay at the intensive care unit but was eventually discharged and able to continue his rehabilitation. The case points out that multiple risk factors for severe COVID-19 are present in patients with Cushing's syndrome. 'Block-replacement' therapy with suppression of endogenous steroidogenesis and supplementation of corticosteroid requirements might be preferred in this patient population. LEARNING POINTS: Comorbidities for severe coronavirus disease 2019 (COVID-19) are frequently present in patients with Cushing's syndrome. 'Block-replacement' with suppression of endogenous steroidogenesis and supplementation of corticosteroid requirements might be preferred to reduce the need for biochemical monitoring and avoid adrenal insufficiency. The optimal corticosteroid dose/choice for COVID-19 is unclear, especially in patients with endogenous glucocorticoid excess. First-line surgery vs initial disease control with steroidogenesis inhibitors for Cushing's disease should be discussed depending on the current healthcare situation.

Undetectable thyroglobulin makes 123I whole-body scan and stimulated thyroglobulin obsolete in follow-up care of differentiated thyroid cancer: a retrospective study.

BACKGROUND: Differentiated thyroid cancer (DTC) is a common malignancy with increasing incidence. Follow-up care for DTC includes thyroglobulin (Tg) measurement and ultrasound (US) of the neck, combined with 131I remnant ablation when indicated. Diagnostic precision has evolved with the introduction of the new high-sensitive Tg-assays (sensitivity ≤0.1 ng/mL). The aim of the study was to determine the prognostic utility of high-sensitive Tg and the need for other diagnostic tests in DTC. METHODS: This was a retrospective, observational study. Patients with pathologically confirmed DTC, treated with total thyroidectomy and 131I remnant ablation, who had their complete follow-up care in our institution were selected (October 2013-December 2018). Subjects with possible thyroglobulin autoantibody interference were excluded. Statistical analysis was performed using the IBM SPSS® Statistics 24 software package. RESULTS: Forty patients were eligible for analysis. A total of 24 out of the 40 patients (60%) had an undetectable high-sensitive Tg 6 months after total thyroidectomy. None of these patients had a stimulated Tg above 1 ng/mL, or remnant on the 123I Whole-Body Scan (WBS) after 1 year of follow-up. Ultrasound of the neck, performed between 6 and 12 months postoperative, was negative in 21 out of the 24 patients. CONCLUSIONS: This study shows that an undetectable high-sensitive Tg can change the management of patients with DTC and decrease the use and need of stimulated Tg and 123I WBS.

A focused 35-minute whole body MRI screening protocol for patients with von Hippel-Lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor syndrome. Affected patients develop central nervous system hemangioblastomas and abdominal tumors, among other lesions. Patients undergo an annual clinical screening program including separate magnetic resonance imaging (MRI) of the brain, whole spine and abdomen. Consequently, patients are repeatedly subjected to time-consuming and expensive MRI scans, performed with cumulative Gadolinium injections. We report our experience with a 35-min whole body MRI screening protocol, specifically designed for detection of VHL-associated lesions. METHODS: We designed an MRI protocol dedicated to the typical characteristics of VHL-associated lesions in different imaging sequences, within the time frame of 35 min. Blank imaging of the abdomen is carried out first, followed by abdominal sequences with Gadolinium contrast. Next, the full spine is examined, followed by imaging of the brain. A single dose of contrast used for abdominal imaging is sufficient for further highlighting of spine- and brain lesions, thus limiting the Gadolinium dosage. We used 1.5 Tesla equipment, dealing with fewer artifacts compared to a 3 Tesla system for spine- and abdominal imaging, while preserving acceptable quality for central nervous system images. In addition, imaging on a 1.5 Tesla scanner is slightly faster. RESULTS: From January 2016 to November 2018, we performed 38 whole body screening MRIs in 18 VHL patients; looking for the most common types of VHL lesions in the abdomen, spine, and brain, both for new lesions and follow-up. The one-step approach MRI examinations lead to 6 surgical interventions for clinically significant or symptomatic hemangioblastomas in the brain and spine. One renal cell carcinoma was treated with radiofrequency ablation. In comparison with previous conventional MRI scans of the same patients, all lesions were visible with the focused protocol. CONCLUSIONS: Annual screening in VHL disease can be done in a rapid, safe and sensitive way by using a dedicated whole body MRI protocol; saving MRI examination time and limiting Gadolinium dose.

A Systematic Review and Meta-Analysis of Endocrine-Related Adverse Events Associated with Immune Checkpoint Inhibitors.

Monoclonal antibodies targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4), programed cell death 1 (PD-1), or its ligand (PD-L1) have become the mainstay for advanced malignancies. The incidence of endocrine adverse events provoked by these immune checkpoint inhibitors (ICI) is based on data from randomized controlled trials, which have their drawbacks. PubMed was searched through August 22nd, 2017, by 2 reviewers independently (J.d.F. and C.E.A.). Early phase I/II, phase III experimental trials, prospective and retrospective observational studies were included. The weighted incidence and risk ratio were estimated for hypophysitis, primary thyroid disease, primary adrenal insufficiency, and diabetes mellitus. Their management is discussed in a systematic review. A total of 101 studies involving 19 922 patients were included. Ipilimumab-treated patients experienced hypophysitis in 5.6% (95% CI, 3.9-8.1), which was higher than nivolumab (0.5%; 95% CI, 0.2-1.2) and pembrolizumab (1.1%; 95% CI, 0.5-2.6). PD-1/PD-L1 inhibitors had a higher incidence of thyroid dysfunction - particularly hypothyroidism (nivolumab, 8.0%; 95% CI, 6.4-9.8; pembrolizumab, 8.5%; 95% CI, 7.5-9.7; PD-L1, 5.5%; 95% CI, 4.4-6.8; ipilimumab, 3.8%; 95% CI, 2.6-5.5). Combination therapy was associated with a high incidence of hypothyroidism (10.2-16.4%), hyperthyroidism (9.4-10.4%), hypophysitis (8.8-10.5%), and primary adrenal insufficiency (5.2-7.6%). Diabetes mellitus and primary adrenal insufficiency were less frequent findings on monotherapy. Our meta-analysis shows a high incidence of endocrine adverse events provoked by single agent checkpoint blockade, further reinforced by combined treatment.

Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV.

Human Bartter syndrome IV is an autosomal recessive disorder characterized by congenital deafness and severe renal salt and fluid loss. It is caused by mutations in BSND, which encodes barttin, a beta-subunit of ClC-Ka and ClC-Kb chloride channels. Inner-ear-specific disruption of Bsnd in mice now reveals that the positive potential, but not the high potassium concentration, of the scala media depends on the presence of these channels in the epithelium of the stria vascularis. The reduced driving force for K(+)-entry through mechanosensitive channels into sensory hair cells entails a profound congenital hearing loss and subtle vestibular symptoms. Although retaining all cell types and intact tight junctions, the thickness of the stria is reduced early on. Cochlear outer hair cells degenerate over several months. A collapse of endolymphatic space was seen when mice had additionally renal salt and fluid loss due to partial barttin deletion in the kidney. Bsnd(-/-) mice thus demonstrate a novel function of Cl(-) channels in generating the endocochlear potential and reveal the mechanism leading to deafness in human Bartter syndrome IV.

Estradiol improves cerebellar memory formation by activating estrogen receptor beta.

Learning motor skills is critical for motor abilities such as driving a car or playing piano. The speed at which we learn those skills is subject to many factors. Yet, it is not known to what extent gonadal hormones can affect the achievement of accurate movements in time and space. Here we demonstrate via different lines of evidence that estradiol promotes plasticity in the cerebellar cortex underlying motor learning. First, we show that estradiol enhances induction of long-term potentiation at the parallel fiber to Purkinje cell synapse, whereas it does not affect long-term depression; second, we show that estradiol activation of estrogen receptor beta receptors in Purkinje cells significantly improves gain-decrease adaptation of the vestibulo-ocular reflex, whereas it does not affect general eye movement performance; and third, we show that estradiol increases the density of parallel fiber to Purkinje cell synapses, whereas it does not affect the density of climbing fiber synapses. We conclude that estradiol can improve motor skills by potentiating cerebellar plasticity and synapse formation. These processes may be advantageous during periods of high estradiol levels of the estrous cycle or pregnancy.

Otolith deprivation induces optokinetic compensation.

According to the multisensory integration theory vestibular, optokinetic and proprioceptive inputs act in concert to maintain a stable retinal image of the visual world. Yet, it remains elusive to what extent the otolith organs contribute to this process and whether a specific loss of otolith input is compensated for. Here we investigated the compensatory eye movements in tilted mice, which lack otoconia because of a mutation in otopetrin 1. Tilted mice showed very small displacements of the eyes in the orbit during static roll paradigms, suggesting the absence of functional otolith organs. Independent of head position with respect to gravity, the gain and phase lead of angular vestibuloocular reflex of tilted mice were decreased and increased, respectively (frequencies 0.2 to 1 Hz and peak accelerations 8 to 197 degrees /s2, respectively). Furthermore, lack of otolith input increases the dependency of the vestibular system on stimulus frequency. In contrast, the gain of optokinetic reflex in tilted mice was significantly higher in the low-frequency range than in control mice, regardless of the position of the mice in space or the plane of the eye movements. To explain these results, a simple model was used in which a multisensory integration unit was embedded. With this model, we were able to simulate all the behaviors observed. Thus our data and the model support the presence of the multisensory integration system and revealed a compensatory enhanced optokinetic reflex in tilted mice, indicating an adaptive synergism in the processing of otolith and visually driven signals.

A behavioral and histological study of the effects of long-term exposure of adult rats to aluminum.

Aluminum (Al) has been etiologically and epidemiologically related to several neurologic conditions, including Alzheimer's disease (AD). The effects of Al long-term exposure were investigated to describe the associated behavioral and brain modifications. Adult rats were intraperitoneally injected three times a week for 6 months with ecological doses of Al gluconate (0.85 mg/kg). The Al overload was confirmed by the significantly increased level of Al in serum. We assessed fear conditioning, spatial memory and emotional reactivity by shuttle-box task, Morris water maze, and open-field, respectively. The performance of the experimental animals at the shuttle-box task was significantly lower (p <.01) compared to that of control. The experimental animals had impaired spatial memory, with lower and more fluctuant performance at Morris water maze. The noxious-driven behavior of the experimental animals was also altered, with significantly lower activity scores (p <.05), and high emotionality scores (p <.01) at the open-field. We recovered and processed the brain for aluminum and amyloid deposits. The brains of experimental animals, studied by optical microscopy, displayed a massive cellular depletion in the hippocampal formation, particularly, the CAl field, and also in the temporal and parietal cortex. We observed numerous ghost-like neurons with cytoplasmic and nuclear vacuolations, and with Al deposits. The hippocampus contained extracellular accumulations of Al and amyloid surrounded by nuclei of degenerating cells, which we interpreted as neuritic plaques. The cerebrovasculature was distorted, with a significant thickening of the wall of capillaries, associated with amyloid deposits. These behavioral and neuropathological modifications associated with long-term exposure to Al are reminiscent of those observed in AD.