Recovery of adrenal function after chronic secondary adrenal insufficiency in patients with hypopituitarism.

OBJECTIVE: Previous studies have reported recovery of secondary adrenal insufficiency (SAI) in patients with pituitary disorders, generally immediately after pituitary surgery; however, data regarding recovery of long-term SAI are lacking. We conducted a study to assess the longer term recovery rate of SAI in patients with pituitary disorders. METHODS: We identified all SAI patients in the Halifax Neuropituitary Database from 1 November 2005 to 30 September 2014, who had required glucocorticoid therapy for ≥3 months, and had a minimum follow-up of 6 months. Patients with ACTH-secreting adenomas, those receiving glucocorticoids only in the routine peri-operative period for pituitary surgery and those on glucocorticoids for nonpituitary conditions were excluded. SAI was defined as either basal serum cortisol < 130 nm and/or a subnormal cortisol response to ACTH-(1-24) stimulation test or insulin tolerance test response. RESULTS: Fifty-one patients fulfilled the criteria. Nine (17·6%) patients had complete recovery of SAI over a median of 20 months (range: 8-51) after initiating glucocorticoid replacement. Patients with smaller tumour size had increased likelihood of hypothalamic-pituitary-adrenal (HPA) axis recovery, whereas those with secondary hypogonadism or growth hormone deficiency were less likely to recover. Those with initial cortisol >175 nm had an almost one in two chance of recovery. CONCLUSION: Results from our study show that approximately one in six patients with SAI recover adrenal function, even up to 5 years after diagnosis. We recommend that patients with SAI undergo regular testing to assess recovery in order to prevent unnecessary glucocorticoid therapy.

Effects of epidermal growth factor and erythropoietin on Müller glial activation and phenotypic plasticity in the adult mammalian retina.

Retinal Müller glia have received considerable attention with regard to their potential to function as quiescent retinal precursors. Various activation strategies induce characteristic features of retinal progenitor cells in Müller glia; however, these are often accompanied by hallmark features of reactive gliosis. We investigated the effects of an intravitreal injection of epidermal growth factor (EGF), a known mitogen, and erythropoietin (EPO) on activation and expression of developmental phenotypes within the adult retina. Using thymidine-analogue labeling as well as immunocytochemical and confocal analyses, we assayed the responses of retinal cells exposed to intravitreal administration of either EGF or EPO. We report that adult Müller glia incorporate bromodeoxyuridine (BrdU) and undergo a process of nuclear translocation to ectopic retinal layers following exposure to EGF. These cells survive within the retina for at least 23 days and express the developmental markers Pax6 and Chx10 as well as nestin and glial fibrillary acidic protein. Furthermore, we demonstrate that cotreatment with EGF and EPO suppresses aspects of EGF-induced glial reactivity, alters the retinal distribution of BrdU-positive nuclei, and serves to regulate the expression of developmental phenotypes seen in these cells. These data further our understanding of Müller cell responsiveness to intravitral, combinatorial growth factor treatments.

Changes in Musashi-1 subcellular localization correlate with cell cycle exit during postnatal retinal development.

RNA-binding proteins, and in particular, the Musashi genes, function as essential regulators of progenitor functioning in both the developing and adult organism. In this report, we characterize the differential subcellular distribution of Musashi-1 in cells engaged in either proliferating or differentiating contexts in the developing mouse retina, and in cultured Müller glia. During retinal cell differentiation, Musashi-1 immunoreactivity shifts from exclusively cytoplasmic in retinal progenitor cells, to predominantly nuclear localization in differentiating neurons. This nuclear shift is transient, with localization in the adult retina becoming predominantly perinuclear and cytoplasmic in Müller glia and photoreceptors. A correlation between cell cycle progression and subcellular distribution of Musashi-1 is observed in passageable, adult Müller glial cells in vitro. Furthermore, treatment of Müller cultures with neuron-promoting differentiation media induces asymmetric cytoplasmic Musashi-1 immunoreactivity in dividing daughter cells. The observed shifts in subcellular Musashi-1 localization are consistent with contrasting roles for Musashi-1 during cell proliferation and differentiation. These data provide evidence that nuclear, and cytoplasmic sequestering of Musashi-1 in retinal cells is context-specific, and may contribute to downstream functioning of Musashi-1.

Neural progenitor potential in cultured Müller glia: effects of passaging and exogenous growth factor exposure.

The Müller radial glial cell is the principal support cell of the adult mammalian retina. Recent reports suggest that these cells retain the capacity to proliferate, express phenotypes reminiscent of retinal progenitor cells (RPC) and generate neuron-like progeny. We isolated rodent Müller cells and generated cultures that could be passaged under conditions used in neural stem/progenitor cell colonies. We demonstrate that during the early period of primary culture, Müller glia proliferate into sphere colonies and express a select regimen of phenotypes normally seen in RPCs. This effect correlates temporally with the loss of retinal neurons post-dissection. When chronically maintained in vitro, Müller cells can be repeatedly passaged, and up-regulate early RPC phenotypes that are suggestive of cellular de-differentiation. Furthermore, exposure of Müller glial cultures to differentiating conditions containing growth factors stimulates Müller glia to up-regulate phenotypes associated with retinal neurons. These data provide further evidence that isolated, adult Müller glia retain functional and phenotypic features of RPCs.

Injury to retinal ganglion cell axons increases polysialylated neural cell adhesion molecule (PSA-NCAM) in the adult rodent superior colliculus.

The adult mammalian central nervous system (CNS) exhibits a limited regenerative response to injury. It is well established that polysialylated neural cell adhesion molecule (PSA-NCAM) contributes to nervous system plasticity. In the visual system, PSA-NCAM participates in retinal ganglion cell (RGC) axon growth during development and specifically influences RGC innervation of its principle target tissue, the superior colliculus (SC). The goals of this study were to determine whether PSA-NCAM is expressed in the normal adult mouse SC and to evaluate PSA-NCAM expression following RGC injury. In the normal rostral, but not caudal, SC we find that PSA-NCAM is present in the retinorecipient layers; however, PSA-NCAM and RGC axons do not co-localize. In the deeper collicular layers, PSA-NCAM is observed as several distinct patches that occur at the same depth along the medial-lateral axis throughout the colliculus. RGC axotomy denervates predominantly the contralateral colliculus, where increased PSA-NCAM levels are seen at 7 and 10 days after the injury. Further evaluation of the retinorecipient layers of the partially denervated SC reveals that some intact CTB-traced RGC axons (less than 5%) labeled from the ipsilateral eye do co-localize with PSA-NCAM. This study is the first characterization of PSA-NCAM expression in the normal and partially denervated adult SC and may indicate that PSA-NCAM is involved in attempted visual system remodeling after injury.

Brain & chiasmal herniations into sella after medical treatment of prolactinoma.

BACKGROUND: Dopamine agonists are widely used in the treatment of pituitary prolactinomas. We report a case of inferior mesial frontal lobe (gyrus rectus) and chiasmal herniations into an enlarged sella following successful medical treatment of a pituitary macroadenoma. METHOD: A 71-year-old healthy man presented to medical attention with visual complaints. On examination, he was found to have bitemporal hemianopsia. Endocrine evaluation revealed an elevated prolactin level. He was treated medically with a dopamine agonist (bromocriptine). RESULTS: Evaluation after one year of medical treatment revealed stabilization of the patient's vision, with a significant bitemporal field loss. Serum prolactin levels normalized (5.16 ng/ml). The MRI of the sella showed almost complete disappearance of the tumor, resulting in right mesial frontal lobe herniation inferiorly into an enlarged sella with associated chiasmal deformation. CONCLUSIONS: We report a case where successful medical treatment of a large pituitary prolactinoma has resulted in inferior frontal lobe and chiasmal herniatons into an enlarged sella.

Administration of brain-derived neurotrophic factor suppresses the expression of heat shock protein 27 in rat retinal ganglion cells following axotomy.

Optic nerve transection results in the apoptotic cell death of the majority of retinal ganglion cells by 14 days. The neurotrophin brain-derived neurotrophic factor (BDNF) enhances survival of retinal ganglion cells. In addition, the small heat shock protein Hsp27, with its anti-apoptotic effects, may be important for neuron survival following axotomy or trophic factor withdrawal. We recently reported the induction and expression of Hsp27 in a subset of retinal ganglion cells following axotomy. Here we have examined the effect of BDNF administration on the expression of Hsp27 in axotomized adult rodent retinal ganglion cells. Retinal ganglion cells were pre-labeled with Fluorogold prior to optic nerve transection and concomitant intraocular injection of BDNF or vehicle. Hsp27 immunofluorescence was examined in retinal sections from 4 to 28 days following injury. Consistent with previous survival studies, the number of Fluorogold-labeled retinal ganglion cells declined from 100% at 4 days to approximately 15% by 14 days following axotomy and vehicle injection. In contrast, with BDNF administration, retinal ganglion cell survival was maintained at 100% to 7 days following axotomy. We report that the number of Hsp27-positive injured retinal ganglion cells, as detected by immunohistochemical staining, was decreased by 50% in BDNF-treated retinas, when compared with vehicle-treated controls. This decreased expression of Hsp27 in response to BDNF treatment was seen both at early (4 days) and delayed (14 days) times. BDNF following optic nerve transection significantly reduced the expression of Hsp27 in retinal ganglion cells. These results indicate that BDNF may down-regulate alternate cell survival pathways, including the stress-induced expression of Hsp27, and may help to explain the failure of chronic neurotrophin treatment to maintain long-term retinal ganglion cell survival.

Injury to retinal ganglion cells induces expression of the small heat shock protein Hsp27 in the rat visual system.

Optic nerve transection results in apoptotic cell death of most adult rat retinal ganglion cells that begins at 4 days and leaves few surviving neurons at 14 days post-injury [Berkelaar et al. (1994) J. Neurosci. 14, 4368-4374]. The small heat shock protein Hsp27 has recently been shown to play a role in sensory neuron survival following peripheral nerve axotomy [Lewis et al. (1999) J. Neurosci. 19, 8945-8953]. To investigate the role of Hsp27 in injured CNS sensory neurons, we have studied the induction and cell-specific expression of Hsp27 in rat retinal ganglion cells 1-28 days after optic nerve transection. Immunohistochemical results indicate that Hsp27 is not present at detectable levels in the ganglion cell layer of control (uninjured) or sham-operated control rats. In contrast, Hsp27 is detected in retinal ganglion cells from 4 to 28 days following axotomy. Furthermore, the percentage of surviving retinal ganglion cells that are Hsp27-positive increased over the same time period. Hsp27 is also detected in glial fibrillary acidic protein-positive astrocytes in the optic layer of the superior colliculus from 4 to 28 days after optic nerve transection. These experiments demonstrate that transection of the optic nerve results in the expression of Hsp27 in three distinct regions of the rat visual system: sensory retinal ganglion cells in the eye, glial cells of the optic tract, and astrocytes in the optic layer of the superior colliculus. Hsp27 may be associated with enhanced survival of a subset of retinal ganglion cells, providing evidence of a protective role for Hsp27 in CNS neuronal injury.

Palliative intubation of the trachea and main bronchi.

A method is presented for the endoscopic intubation of malignant tumors of the trachea and main bronchi with a Souttar tube. This is appropriate when urgent relief of respiratory obstruction is necessary and when the tumor is unsuitable for resection. Eight patients have been so treated, with relief of symptoms for up to 70 weeks in seven. The method failed in one patient. There were no operative deaths.

Pulmonary embolectomy: a 25 year experience.

For the past 25 years an emergency pulmonary embolectomy service has been offered to the hospitals serving a conurbation of 1.5 million. Fifty-five of these procedures have been performed during a short period of normothermic circulatory standstill produced by clamping the superior and inferior venae cavae. Of 36 patients who underwent pulmonary embolectomy without an episode of asystole or ventricular fibrillation, 35 survived the operation (97.2%). However, there were seven deaths during the postoperative period, three related to pulmonary embolism and four to other causes (mortality 20%). Conversely, in a group of 19 patients who had an episode of cardiac arrest, 14 died during or after the operation of pulmonary embolism and two of unrelated causes (mortality 73.7%). In properly selected patients this technique achieves a satisfactory measure of success. It can be used in hospitals that do not have cardiac surgical facilities and, because of its simplicity, it can be performed during the early period after pulmonary embolism when the risk of death is greatest.

Results of valve replacement with the Omniscience prosthesis.

Clinical experience with the Omniscience prosthesis from two regional cardiac units in England is presented. Actuarial analysis suggests a prohibitive incidence of prosthetic thrombosis of the mitral valve, this complication occurring in 14 of a total of 96 (15%) patients studied over a mean period of approximately 1 1/2 years. Aortic valve implantations were frequently complicated by prosthetic dehiscence, which occurred in nine of a total of 88 (10%) patients who received this valve. Our results with this prosthesis contrasts markedly with our favorable experience with other types of prostheses and lead us to question the suitability of the Omniscience valve for further clinical use.

Spontaneous spinal epidural hematoma causing paraplegia: resolution and recovery without surgical decompression.

Spontaneous spinal epidural hematomas are well-recognized but rare entities. The standard treatment for these hematomas has been prompt surgical evacuation. The authors report a case of a 76-year-old man who precipitously became paraplegic secondary to a spontaneous spinal epidural hematoma and then experienced the complete resolution of his neurological deficit and the hematoma. We conclude that conservative (nonoperative) management of spontaneous spinal epidural hematomas may be appropriate in those instances in which there is early and sustained neurological recovery confirmed by radiological resolution of the lesion.

Prolonged administration of NT-4/5 fails to rescue most axotomized retinal ganglion cells in adult rats.

The survival of axotomized RGCs was increased by intravitreal NT-4/5 given by repeated injections or osmotic minipumps, but the effects were less complete than predicted. Compared to a single injection of the neurotrophin on day 0, second injections on days 3 or 7 only sustained an additional 10-20% of the RGCs on day 10. Minipumps augmented RGC survival up to 4-fold (50%) at 2 weeks but most RGCs were lost by 1 month. Thus, specific neurotrophins can rescue many RGCs soon after injury but long-term neuronal survival may require a better understanding of changes in neurotrophin receptors and interactions with other molecules.

Meningeal melanocytoma of the planum sphenoidale. Case report and review of the literature.

Meningeal melanocytoma is a rare benign primary melanotic tumor of the meninges, most commonly found in the spinal canal and the posterior fossa. The authors report the 19th published case of a supratentorial meningeal melanocytoma and the first reported case in which the tumor arose from the planum sphenoidale. The patient's presenting symptoms were characteristic of a large bifrontal lesion and included headaches, personality change, lethargy, and urinary and fecal incontinence. Computerized tomography and magnetic resonance imaging studies revealed an extraaxial lesion arising from the planum sphenoidale. The patient underwent successful gross total removal of the tumor without neurological sequelae. Based on the findings shown in this case report, meningeal melanocytoma should be included in the differential diagnosis of extraaxial lesions arising from the area of the planum sphenoidale.

Stereotactic transtentorial hiatus ventriculoperitoneal shunting for the sequestered fourth ventricle. Technical note.

The authors describe a technique of stereotactic transtentorial hiatus ventriculoperitoneal shunting for the treatment of the sequestered fourth ventricle, used successfully in the care of four patients. They recommend it as a safe, effective treatment of patients suffering from an isolated fourth ventricle.

Meningeal melanocytoma. Report of a case and a historical comparison.

Meningeal melanocytomas are rare tumors of the central nervous system that are found almost exclusively in the posterior fossa and spinal cord and whose natural history is poorly defined. In this report, the authors review the clinical presentation, radiological appearance, operative findings, and histological features in two cases of meningeal melanocytoma: one cranial and one spinal. Two women, aged 21 and 30 years, were admitted to the hospital 60 years apart: the first because of progressive paraplegia and the second because of slowly progressive hearing loss. The first patient had an extradural tumor that was treated by laminectomy, subtotal resection, and postoperative radiotherapy in 1936. Her symptoms recurred 16 years later and she underwent reoperation of the residual tumor, which was found to have an intradural component. The authors' patient, who presented 60 years later, underwent plain and enhanced computerized tomography and magnetic resonance imaging that demonstrated a large posterior fossa lesion indicative of either an acoustic neuroma or a meningioma. She underwent posterior fossa decompression but only partial excision of the tumor could be accomplished because vigorous bleeding limited the extent of the resection. Surgery was followed by radiotherapy. The residual tumor enlarged despite these measures and required repeated resection 6 months later. At the second operation the tumor was much less vascular, perhaps reflecting the effects of radiotherapy, and was removed almost entirely. The patient died 6 months later from an anticoagulant-related cerebellar hemorrhage. In both cases the lesions were jet black, and histological examination revealed melanin-containing hypercellular tumors with rare mitotic figures. Meningeal melanocytomas are being diagnosed with increased frequency in parallel with improvements in neuroimaging and clarification of histological features. Clinical presentation of patients with these tumors typically occurs in their fifth decade and women are affected twice as often as men. The posterior fossa lesions can mimic acoustic neuromas and meningiomas in location and radiological appearance; however, the internal auditory canal is normal. In the spine, meningeal melanocytomas present with the clinical features of myeloradiculopathy. Diagnosis is made intraoperatively from the gross, jet-black appearance of the tumor and from histological examination. Vascularity, size, and location may render complete resection unfeasible. Because of the tumor's propensity to recur, radiotherapy has been recommended but its role remains to be elucidated.

Median sternotomy dehiscence: a modified wire suture closure technique.

Over a 7-year period, sternal wound dehiscences occurring in 26 patients were treated by a modified wire closure technique. This method is described and the results presented.

Colo-pericardial and colo-caval fistula. Late complication of colon interposition.

We report the first recorded case of a colo-pericardial fistula and of a colo-caval fistula following interposition of colon after resection of the oesophagus.

Newborn apnea caused by a neurofibroma at the craniocervical junction.

The authors report, for the first time, the finding by magnetic resonance imaging of a neurofibroma at the craniocervical junction with upper cervical cord and lower brainstem compression causing complete apnea from birth. Subsequent subtotal resection of the neurofibroma resulted in the successful extubation of a previously ventilator-dependent patient. After a two month period of breathing spontaneously, the newborn developed an upper respiratory tract infection and was reintubated. The patient, unable to be weaned off of the respirator, was extubated and expired shortly thereafter, at the age of five months. The authors suggest that in newborns with unexplained apnea, MRI of the cranio-cervical junction is indicated. Certain patients may be discovered who have less compromised cervico-medullary function and are afflicted by less aggressive forms of neurofibromatosis type 1. These patients may benefit permanently from a surgical decompression.

Endovascular treatment of a "blister-like" aneurysm of the internal carotid artery.

BACKGROUND: "Blister-like" aneurysms of the supraclinoid internal carotid artery have recently been recognized as having unique pathological and clinical features. Little is known regarding their optimal treatment modality. METHODS: We report a case of a "blister-like" aneurysm of the internal carotid artery treated with Guglielmi detachable coil (GDC) embolization. CASE REPORT: A 55-year-old man presented with a Hunt & Hess grade II subarachnoid hemorrhage. Computed tomography revealed diffuse subarachnoid blood. Cerebral angiography demonstrated a broad-based bulge on the medial wall of the right distal internal carotid artery. The patient was taken to the operating room and underwent a right pterional craniotomy and wrapping of this unclippable aneurysm. On postoperative day 11, he developed signs of vasospasm, and repeat angiography showed remarkable growth of the aneurysm. The aneurysm was believed to be amenable to endovascular therapy and was treated by GDC embolization. The patient recovered well and remained neurologically intact on follow-up examinations. Repeat cerebral angiography was performed three and nine months following his initial presentation and revealed a significant aneurysm neck remnant. This neck remnant was treated by repeat GDC embolization 13 months following his subarachnoid hemorrhage. CONCLUSIONS: "Blister-like" aneurysms of the internal carotid artery are important to recognize and are difficult to manage using traditional surgical approaches. Early repeated cerebral angiography is indicated and, where appropriate, endovascular therapy should be considered in the management of these patients.