In-Hospital Endocrinology Consultation After Transsphenoidal Surgery: Is It Always Necessary?

BACKGROUND: Patients with sellar masses undergoing transsphenoidal surgery (TSS) frequently develop endocrine dysfunction; therefore, in-hospital endocrinology consultation (IHEC) is recommended. However, we wondered whether routine endocrinology assessment of all TSS patients is always necessary. METHODS: We developed an IHEC Physician's Guide to identify patients who would require peri-operative IHEC. An analysis of all patients undergoing TSS for a sellar mass over a 4-year period was conducted to assess the predictive value of the IHEC Physician's Guide in identifying patients who required IHEC. RESULTS: A total of 116 patients underwent TSS; 24 required IHEC. As expected, the risk of endocrine complications requiring peri-operative endocrine management was significantly higher in the IHEC group versus no-IHEC group (96% vs. 1%; p < 0.001). The negative predictive value of the IHEC Physician's Guide in identifying patients who did not require IHEC was 0.99 (95% CI 0.9409-0.9997); Fisher's exact test, p < 0.001), meaning that the IHEC Physician's Guide successfully identified all but one patient who truly required IHEC. CONCLUSION: Results from our study show that most patients do not need IHEC after TSS and that those patients requiring IHEC can be reliably predicted at surgery by using a simple IHEC Physician's Guide.

Secondary pituitary hormonal dysfunction patterns: tumor size and subtype matter.

PURPOSE: Patients with sellar masses (SM) frequently have secondary hormonal deficiency (SHD) at initial presentation. While larger SM are more likely to present with SHD, it is unclear whether SHD at presentation is influenced by the type of SM. METHODS: We conducted a retrospective analysis of patients with SM prospectively enrolled in our comprehensive provincial neuropituitary registry between November 2005 and December 2018. SM were subdivided based on size: < 1 cm, 1-1.9 cm, 2-2.9 cm, and > 3 cm. RESULTS: A total of 914 patients met the inclusion criteria, including: 346 nonfunctioning adenomas (NFA), 261 prolactinomas (PRLoma), 51 growth hormone adenomas, 36 adrenocorticotropic adenomas, 93 Rathke's cleft cysts, 70 craniopharyngiomas and 57 meningiomas. The overall rate of SHD at presentation was highest in PRLoma (62.8%) and craniopharyngiomas (64.3%) and lowest in meningiomas (14%). While larger SM were significantly more likely to have SHD, the rate of SHD within each group was significantly different despite similar size (p < 0.001). Of the two largest groups of SM (NFA and PRLoma), NFA had significantly higher odds ratio (3.34, CI 1.89-5.89) of having multiple SHDs when compare with PRLoma, even when corrected for age, gender and size of tumor (p < 0.001). CONCLUSION: Our study shows that the rate and distribution of SHD in SM vary dependent upon the size of the tumor and specific pathology; in particular, NFA are more likely to present with multiple SHDs. Our data will help clinicians in determining adequate hormonal testing strategy for different SM.

Cerebellar mutism after posterior fossa tumor resection in children: a multicenter international retrospective study to determine possible modifiable factors.

PURPOSE: A preliminary survey of pediatric neurosurgeons working at different centers around the world suggested differences in clinical practice resulting in variation in the risk of pediatric cerebellar mutism (CM) and cerebellar mutism syndrome (CMS) after posterior fossa (PF) tumor resection. The purposes of this study were (1) to determine the incidence and severity of CM and CMS after midline PF tumor resection in children treated at these centers and (2) to identify potentially modifiable factors related to surgical management (rather than tumor biology) that correlate with the incidence of CM/CMS. METHODS: Attending pediatric neurosurgeons at British Columbia's Children's Hospital (BCCH) and neurosurgeons who completed a pediatric neurosurgery fellowship at BCCH were invited to provide data from the center where they currently practiced. Children aged from birth to less than 18 years who underwent initial midline PF tumor resection within a contemporary, center-selected 2-year period were included. Data was obtained by retrospective chart and imaging review. Modifiable surgical factors that were assessed included pre-resection surgical hydrocephalus treatment, surgical positioning, ultrasonic aspirator use, intraoperative external ventricular drain (EVD) use, surgical access route to the tumor, and extent of resection. CM was defined as decreased or absent speech output postoperatively and CMS as CM plus new or worsened irritability. RESULTS: There were 263 patients from 11 centers in 6 countries (Canada, Germany, the Netherlands, India, Indonesia, and the USA). Median age at surgery was 6 years (range < 1 to 17 years). The overall incidence of postoperative CM was 23.5% (range 14.7-47.6% for centers with data on ≥ 20 patients). The overall incidence of CMS was 6.5% (range 0-10.3% for centers contributing data on ≥ 20 patients). A multivariate logistic regression on the full data set showed no significant association between pre-resection surgical hydrocephalus treatment, prone position, ultrasonic aspirator use, EVD use, telovelar approach, complete or near total resection, or treating center and either postoperative CM or CMS. CONCLUSIONS: While there was variation in surgical management of midline PF tumors among centers participating in this study, the factors in management that were examined did not predict postoperative CM or CMS.

Securing the position of the nasoseptal flap in endoscopic transsphenoidal surgery: No need for a Foley catheter (technical report).

BACKGROUND: The pedicled nasoseptal mucoperiosteal flap is currently widely used for the reconstruction of a skull base defect following transsphenoidal surgery. The flap is generally secured in position by a Foley catheter balloon. We describe an alternative technique using cylinders of Gelfoam™ (Pfizer Incorporated) to buttress the flap in place, obviating the need for a balloon catheter. MATERIAL AND METHODS: A review of our database identified patients who underwent endoscopic transsphenoidal surgery for a pituitary macroadenoma with nasoseptal flap, secured with small rolls of Gelfoam™ (Pfizer Incorporated) rather than a nasal Foley catheter. Minimum follow-up clinical and MRI assessments: 3 months. RESULTS: 73 patients (mean follow-up: 22 months) met the inclusion criteria: 56 non-functioning and 17 functioning pituitary adenomas. 36 patients had an intraoperative CSF leak: 30 high flow and 6 low flow leaks. The surgical repair in 35 patients included fat +/- fascia graft. One patient had a post-operative CSF leak repaired by subsequent surgery without the use of a Foley catheter. CONCLUSION: Securing the nasoseptal flap using rolls of Gelfoam™ (Pfizer Incorporated) as described can be achieved without the use of a nasal Foley catheter.

Treatment of patients with glomus jugulare tumours (GJT) and its subjective effect on quality of life (QoL) measures.

Cerebellopontine angle (CPA) tumours account for 6-10% of intracranial tumours. The most common CPA tumours are vestibular schwannomas (VS), also known as acoustic neuromas, benign tumours of the vestibulocochlear nerve. Less common but symptomatic skull base lesions are glomus jugulare tumours (GJT), of which approximately 40% are identified as CPA tumours. Initial symptoms for GJT may include hearing loss and tinnitus and progress to various cranial nerve dysfunctions. Three well-accepted treatment modalities for such tumours include surgical resection, radiotherapy and/or conservative management employing serial MR or CT imaging. Patients' quality of life may be impacted by different treatment methods, so treatment decisions should be client centered.

Quality of life related to symptomatic outcomes in patients with vestibular schwannomas: A Canadian Centre perspective.

Patients with vestibular schwannomas (VS) typically present with hearing loss and tinnitus as well as variable cranial nerve dysfunctions. Surgical resection, stereotactic radiotherapy and/or conservative management employing serial magnetic resonance or computed tomography imaging serve as the main treatment options. Quality of life (QoL) may be impacted by the extent of tumour burden and exacerbated or relieved by treatment. Subjective assessment and quality of life inventories provide valuable information in client centered approaches with important implications for treatment. The intention of QoL measurements affecting VS patients within a clinical setting is to facilitate discussions regarding treatment options and objectively evaluate patient- centered clinical outcomes in a naturalistic setting.

Radiological Growth Patterns of Prolactinomas and Nonfunctioning Adenomas.

OBJECTIVES: To compare growth patterns of nonfunctioning and prolactin-producing pituitary macroadenomas, and to find whether their specific growth patterns are associated with clinically significant effects on vision. MATERIALS AND METHODS: From our comprehensive provincial neuropituitary registry, we retrospectively identified 35 randomly selected patients each with nonfunctioning adenomas and prolactinomas >10 mm in any dimension. MRI scans were analyzed to determine the superior and inferior growth, volume, and maximum craniocaudal height of the adenomas. Patients underwent visual field testing at diagnosis. Continuous variables were compared using Student's t test, the Mann-Whitney U test, and ANOVA. Categorical variables were compared using the chi-square test. RESULTS: The mean height of prolactinomas (23.2±11.3 mm) was similar to nonfunctioning adenomas (22.3±9.3 mm, p=0.8), and so were mean tumor volumes (prolactinoma=5.9±8 ml vs. nonfunctioning adenoma=4.8±5 ml, p=0.47). However, the mean suprasellar growth for prolactinomas was 2.9±5.3 mm and 7.3±4.7 mm for nonfunctioning adenomas (p<0.001), and the mean infrasellar growth was 10.2±8.0 and 5.0±6.6 mm, respectively (p=0.04). The inferior growth pattern of prolactinomas was associated with a significantly lower likelihood of having visual field abnormalities (11.4 vs. 57.1%, p<0.001). CONCLUSIONS: Prolactinomas have predominantly inferior growth compared to nonfunctioning adenomas and are less likely to cause vision changes.

Hearing preservation in vestibular schwannoma management.

OBJECTIVE: To compare hearing preservation between stereotactic radiotherapy (SRT) and conservative treatment of patients with unilateral vestibular schwannoma. DATA SOURCES: Retrospective case series comparing hearing outcomes of patients with a unilateral vestibular schwannoma managed conservatively or with stereotactic radiotherapy in a tertiary care academic centre. PATIENTS: Tumor database patients with American Academy of Otolaryngology Head and Neck Surgery Class A or B hearing at the onset of study. Stereotactic radiotherapy patients were predominantly those who failed conservative management. INTERVENTIONS: Audiometric pure tone averages and speech discrimination scores as well as patient demographics, tumor location, size and growth were extracted. MAIN OUTCOME MEASURES: Hearing outcome measures were: 1) Hearing Preservation, i.e. no drop from Class A/B to Class C/D hearing, 2) Hearing Survival of Class A/B hearing in months, 3) Audiometric Pure Tone Averages, Difference between post-treatment and pre-treatment, and 4) Speech Discrimination Score Difference (pre-treatment-post treatment). Survival analysis and non-parametric tests were used for hearing outcome measures, with multiple covariates tested. RESULTS: Overall, serviceable hearing preservation among the 123 patients was 51%. The median hearing survival time was 46 months (mean 59 months). The Pure Tone averages and Speech Discrimination score differences were 16 dB and 82% respectively over a median follow-up time of 43 months. No significant difference was found between the conservative and SRT groups in any hearing outcome. Class A patients showed far better hearing survival than Class B patients. CONCLUSIONS: No significant difference was demonstrated as to measures of hearing outcomes between stereotactic radiotherapy and conservative management. Excellent existing hearing appears to be the best predictor of long term hearing survival in the cohort studied.

Presentation of atrial fibrillation following oral dexamethasone treatment in a NF2 patient.

Atrial fibrillation (A-fib) is the most common cardiac arrhythmia which is associated with an increased risk of mortality secondary to stroke and coronary artery disease. Intravenous glucocorticoid therapy (such as dexamethasone and hydrocortisone) is frequently used peri-operatively in patients undergoing cardiac surgery to prevent A-fib. Dexamethasone is also frequently used in patients with single or bilateral vestibular schwannomas (VS), to reduce tumor swelling both before and after radiation treatment. We describe a case of A-fib in a 50 year-old female patient with neurofibromatosis type 2 (NF-2), who was prescribed dexamethasone for post-radiation tumor edema.

Inhibitor of apoptosis protein (IAP) profiling in experimental autoimmune encephalomyelitis (EAE) implicates increased XIAP in T lymphocytes.

In multiple sclerosis (MS) and its widely accepted animal model, experimental autoimmune encephalomyelitis (EAE), the failure of autoreactive immune cells to undergo apoptosis is thought to contribute to CNS tissue damage and disease progression. Promoting apoptosis of myelin-reactive immune cells in diseases such as MS, may delay disease progression and decrease the frequency and severity of relapses. X-linked inhibitor of apoptosis (XIAP) is a potent anti-apoptotic protein that inhibits intrinsic, extrinsic, and c-Jun amino-terminal kinase mediated apoptosis and was the only member of the inhibitor of apoptosis (IAP) family upregulated in whole blood from EAE mice. Similar increases in XIAP were also observed in both peripheral and encephalitogenic T lymphocytes. Increased XIAP expression in T cells within areas of demyelination in the CNS suggests that XIAP may be enhancing cell survival and thereby contributing to disease pathology.

Increased X-linked inhibitor of apoptosis protein (XIAP) expression exacerbates experimental autoimmune encephalomyelitis (EAE).

Dysregulated apoptotic signaling has been implicated in most forms of cancer and many autoimmune diseases, such as multiple sclerosis (MS). We have previously shown that the anti-apoptotic protein X-linked inhibitor of apoptosis (XIAP) is elevated in T cells from mice with experimental autoimmune encephalomyelitis (EAE). In MS and EAE, the failure of autoimmune cells to undergo apoptosis is thought to exacerbate clinical symptoms and contribute to disease progression and CNS tissue damage. Antisense-mediated knockdown of XIAP, in vivo, increases the susceptibility of effector T cells to apoptosis, thus attenuating CNS inflammation and thereby alleviating the clinical signs of EAE. We report for the first time, generation of transgenic mice whereby the ubiquitin promoter drives expression of XIAP (ubXIAP), resulting in increased XIAP expression in a variety of tissues, including cells comprising the immune system. Transgenic ubXIAP mice and wild-type (WT) littermates were immunized with myelin oligodendrocyte glycoprotein (MOG35-55) in complete Freund's adjuvant and monitored daily for clinical symptoms of EAE over a 21-day period. The severity of EAE was increased in ubXIAP mice relative to WT-littermates, suggesting that XIAP overexpression enhanced the resistance of T cells to apoptosis. Consistent with this finding, T cells derived from MOG35-55-immunized ubXIAP mice and cultured in the presence of antigen were more resistant to etoposide-mediated apoptosis compared to WT-littermates. This work identifies XIAP is an important apoptotic regulator in EAE and a potential pharmacological target for treating autoimmune diseases such as MS.

PDEs as drug targets for CNS immune disorders.

PDEs are important second messenger systems governing a host of cellular functions involved in neural signal transduction in the CNS and inflammatory cell signaling in the immune system. The contributions of PDE family members as novel treatments that target neuroinflammation as a pathophysiological process in the neuropathogenesis of diverse neurological and psychiatric brain disorders with prominent immune system correlates are discussed.

Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice.

Phosphodiesterase 10A (PDE10A) mRNA and protein levels decline in the striatum of R6/1 and R6/2 Huntington's disease (HD) mice prior to motor symptom development. In human HD, PDE10A protein levels are significantly decreased in the caudate-putamen of patients with grade 3 HD compared to age-matched controls. To test whether the loss of PDE10A activity in the striatum was detrimental to normal brain function, we treated wild-type (WT) mice with chronic administration of papaverine, which is a specific inhibitor of PDE10A. At 7 weeks of age, mice were introduced to a weekly battery of motor tests, including assessment of weight, locomotion, gait, and coordination. Beginning at 8 weeks of age, mice received 0, 5, 10 or 20 mg/kg papaverine once daily until the completion of behavioral testing. Following 14 days of papaverine injections, mice were assessed for deficits in cognitive performance as measured in the Morris water maze (MWM). All behavioral tests occurred either immediately prior to or 30 min following a subcutaneous papaverine challenge dose. Twenty-four hours following completion of the 2-3 week MWM protocol, mice were given a dose of papaverine and 30 min later psychological function assessed in the Light-Dark (LD) Test. Chronic administration of papaverine for 42 days was associated with distinct motor perturbations, mild cognitive disturbance and anxiety-like behaviors. Subsequently, we assessed the effect of 14 days papaverine (i.e. sub-chronic) treatment on psychological function of WT and R6/1 HD mice. While sub-chronic papaverine induced anxiety-like behavior in WT mice, it appeared to have little effect on the behavior of R6/1 HD mice. Finally, a separate group of 6-week old WT and R6/2 HD mice were treated for 21 days with saline or 10 mg/kg fluoxetine, an agent with anxiolytic and anti-depressant effects, in order to compare the effects of papaverine and fluoxetine on anxiety-like behavior in the LD test. CREB and PDE10A protein levels in striatum and hippocampus were determined by western blot. While papaverine treatment reduced CREB protein levels in the hippocampus and striatum, fluoxetine increased CREB in the hippocampus. These data suggest that papaverine and fluoxetine may produce quite different effects on behavior; these behaviors may be linked to CREB expression in brain regions associated with motor and cognitive functions. PDE10A protein levels were decreased by both papaverine and fluoxetine. Chronic PDE10A inhibition produced a variety of behavioral and central neurochemical deficits and these effects were exacerbated by stress. The unique localization of PDE10A and its apparent role in basal ganglia function may underlie its role in psychiatric and neurological disorders involving the basal ganglia.

Role of phosphodiesterases in neurological and psychiatric disease.

Cyclic nucleotides such as cAMP and cGMP play a central role in neuronal cell function and are regulated by changes in synthesis and/or degradation. Degradation is regulated by phosphodiesterases (PDEs), a group of enzymes consisting of at least 11 families, several of which have multiple isoforms. As inhibition of PDEs can have profound effects on cell function, there is considerable interest in selective antagonists of these enzymes. Recent work has also revealed that PDEs are heterogeneously distributed, thus making them interesting targets for drug development. In particular, PDE10A may play a role in disorders that involve striatal neurons, such as Huntington's disease and psychosis.

Targeting apoptosis to treat multiple sclerosis.

Accumulating evidence implicates a failure of myelin-reactive immune cells to undergo apoptosis in the pathological events contributing to multiple sclerosis (MS). We have recently demonstrated that members of the inhibitor of apoptosis (IAP) family of anti-apoptotic genes are elevated in peripheral blood immune cells (monocytes, T cells) of patients with aggressive forms of MS (secondary progressive) or those with relapsing-remitting MS suffering a disease replase. These findings suggest that the IAPs may be novel diagnostic markers for distinguishing subtypes of MS. Moreover, antisense-mediated knockdown of the IAP family member known as X-linked IAP (XIAP) reverses paralysis in an animal model of MS suggesting that treatments targeting XIAP, and perhaps other IAPs, may have utility in the treatment of MS.

Shared decision making and decisional conflict in the Management of Vestibular Schwannoma: a prospective cohort study.

BACKGROUND: Patients with vestibular schwannomas (VS) are faced with complex management decisions. Watchful waiting, surgical resection, and radiation are all viable options with associated risks and benefits. We sought to determine if patients with VS experience decisional conflict when deciding between surgery or non-surgical management, and factors influencing the degree of decisional conflict. METHODS: A prospective cohort study in two tertiary ambulatory skull-base clinics was performed. Patients with newly diagnosed or newly growing vestibular schwannomas were recruited. Patients were given a demographic form and the decisional conflict scale (DCS), a validated measure to assess the degree of uncertainty when making medical decisions. The degree of shared decision making (SDM) experienced by the patient and physician were assessed via the SDM-Q-10 and SDM-Q-Doc questionnaires, respectively. Non-parametric statistics were used. Questionnaires and demographic information were correlated with DCS using Spearman correlation coefficient and Mann-Whitney U. Logistic regression was performed to determine factors independently associated with DCS scores. RESULTS: Seventy-seven patients participated (55% female, aged 37-81 years); VS ranged in size from 2 mm-50 mm. Significant decisional conflict (DCS score 25 or greater) was experienced by 17 (22%) patients. Patients reported an average SDM-Q-10 score of 86, indicating highly perceived level of SDM. Physician and patient SDM scores were weakly correlated (p = 0.045, Spearman correlation coefficient 0.234). DCS scores were significantly negatively correlated with a decision to pursue surgery, presence of a trainee, and higher SDM-Q-10 score. DCS was higher with female gender. Using logistic regression, the SDM-Q-10 score was the only variable associated with significantly reduced DCS. CONCLUSIONS: About one fifth of patients deciding how to manage their vestibular schwannoma experienced a significant degree of decisional conflict. Involving the patients in the process through shared decision-making significantly reduced the degree of uncertainty patients experienced.

Oligodendrocyte progenitor enrichment in the connexin32 null-mutant mouse.

Before the establishment of chemical synapses, neural progenitors are often coupled by connexin-mediated gap junctions providing a robust mechanism for cell-cell communication in developing brain. The present study was undertaken to determine whether alterations in junctional coupling also affect neural progenitor proliferation, survival, and differentiation in adult brain. We localized the connexin32 gap junction protein to a subset of NG2+ and platelet-derived growth factor alpha receptor+ early oligodendrocyte progenitors in the dentate gyrus of adult mice. In connexin32-deficient mice, we found an increase in the total number of proliferating nestin+ and NG2+ progenitors in the subgranular zone, hilus, and polymorphonuclear layer of the dentate gyrus in vivo and in the total number of nestin+ progenitors capable of clonogenic expansion in vitro. By bromodeoxyuridine labeling, lineage analysis, and terminal deoxynucleotidyl nick end labeling, we demonstrate that turnover of these cells is constitutively enhanced in the connexin32 knock-out dentate gyrus reflecting a dynamic defect in oligodendrogenesis in this population. Analyses of surviving bromodeoxyuridine-labeled cells at 1, 3, 7, and 28 d after injection demonstrate that this transient amplifying population fails to terminally differentiate and is deleted by an apoptotic-like mechanism within 3 d of labeling. These data provide empirical evidence to support the hypothesis that connexin expression influences adult progenitor number and specifically implicate connexin32-mediated signaling in the activation, survival, and differentiation of a subset of early oligodendrocyte progenitors in postnatal brain.

Cholecystokinin and endogenous opioid peptides: interactive influence on pain, cognition, and emotion.

It is well documented that stressful life experiences contribute to the etiology of human mood disorders. Cholecystokinin (CCK) is a neuropeptide found in high concentrations throughout the central nervous system, where it is involved in numerous physiological functions. A role for CCK in the induction and persistence of anxiety and major depression appears to be conspicuous. While increased CCK has been associated with motivational loss, anxiety and panic attacks, an increase in mesocorticolimbic opioid availability has been associated with coping and mood elevation. The close neuroanatomical distribution of CCK with opioid peptides in the limbic system suggests that there may be an opioid-CCK link in the modulation and expression of anxiety or stressor-related behaviors. In effect, while CCK induces relatively protracted behavioral disturbances in both animal and human subjects following stressor applications, opioid receptor activation may change the course of psychopathology. The antagonistic interaction of CCK and opioid peptides is evident in psychological disturbances as well as stress-induced analgesia. There appears to be an intricate balance between the memory-enhancing and anxiety-provoking effects of CCK on one hand, and the amnesic and anxiolytic effects of opioid peptides on the other hand. Potential anxiogenic and mnemonic influences of site-specific mesocorticolimbic CCK and opioid peptide availability, the relative contributions of specific CCK and opioid receptors, as well as the time course underlying neuronal substrates of long-term behavioral disturbances as a result of stressor manipulations, are discussed.