Eoin P. O'Sullivan

The incidence and pathophysiology of hyponatraemia after subarachnoid haemorrhage.

Background  Hyponatraemia is common following subarachnoid haemorrhage (SAH) but the pathogenesis is unclear.

Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients

Background: Hyponatraemia is a well-recognised complication of neurosurgical conditions, but the incidence and implications have not been well documented. Objective: To define the incidence, pathophysiology and clinical implications of significant hyponatraemia in several neurosurgical conditions. Methods: All patients admitted to the Irish National Neurosciences Centre at Beaumont Hospital, Dublin with traumatic brain injury, subarachnoid haemorrhage, intracranial neoplasm, pituitary disorders and spinal disorders who developed significant hyponatraemia (plasma sodium <130 mmol/l) from January 2002 to September 2003 were identified from computerised laboratory records. Data were collected by retrospective case note analysis. Results: Hyponatraemia was more common in patients with pituitary disorders (5/81, 6.25%; p = 0.004), traumatic brain injury (44/457, 9.6%; p<0.001), intracranial neoplasm (56/355, 15.8%; p<0.001) and subarachnoid haemorrhage (62/316, 19.6%; p<0.001) than in those with spinal disorders (4/489, 0.81%). The pathophysiology of hyponatraemia was: syndrome of inappropriate antidiuretic hormone secretion (SIADH) in 116 cases (62%) (31 (16.6%) drug-associated), hypovolaemic hyponatraemia in 50 cases (26.7%) (which included patients with insufficient data to assign to the cerebral salt-wasting group (CSWS)), CSWS in nine cases (4.8%), intravenous fluids in seven cases (3.7%) and mixed SIADH/CSWS in five cases (2.7%). Hyponatraemic patients with cerebral irritation had significantly lower plasma sodium concentrations (mean (SD) 124.8 (0.34) mmol/l) than asymptomatic patients (126.6 (0.29) mmol/l) (p<0.0001). Hyponatraemic patients had a significantly longer hospital stay (median 19 days (interquartile range (IQR) 12–28)) than normonatraemic patients (median 12 days (IQR 10.5–15)) (p<0.001). Conclusions: Hyponatraemia is common in intracerebral disorders and is associated with a longer hospital stay. Cerebral irritation is associated with more severe hyponatraemia. SIADH is the most common cause of hyponatraemia and is often drug-associated.

The natural history of surgically treated but radiotherapy‐naïve nonfunctioning pituitary adenomas

Background and objectives  Transsphenoidal surgery is indicated for patients with nonfunctioning pituitary adenomas (NFPAs) causing compressive symptoms. Previous studies attempting to define the rate of recurrence/regrowth of surgically treated but radiation‐naïve NFPAs were somewhat limited by selection bias and/or small numbers and/or lack of consistency of findings between studies. A better understanding of the natural history of this condition could allow stratification of recurrence risk and inform future management. We aimed to define the natural history of a large, mainly unselected cohort with surgically treated, radiotherapy (RT)‐naïve NFPAs and to try to identify predictors of recurrence/regrowth.

Acute Glucocorticoid Deficiency and Diabetes Insipidus Are Common After Acute Traumatic Brain Injury and Predict Mortality

CONTEXT Published data demonstrates that hypopituitarism is common after traumatic brain injury (TBI). Hormone deficiencies are transient in many, but the natural history of the acute changes after TBI has not been documented. In addition, it is not clear whether there are any early parameters that accurately predict the development of permanent hypopituitarism. OBJECTIVES There were 3 main objectives of this study: 1) to describe the natural history of plasma cortisol (PC) changes and sodium balance after TBI; 2) to identify whether acute hypocortisolemia or cranial diabetes insipidus (CDI) predict mortality; and 3) to identify whether the acute pituitary dysfunction predicts the development of chronic anterior hypopituitarism. DESIGN Each TBI patient underwent sequential measurement of PC, plasma sodium, urine osmolality, and fluid balance after TBI. All other anterior pituitary hormones were measured on day 10 after TBI. The results from 15 surgical comparisons defined a PC less than 300 nmol/L as inappropriately low for an acutely ill patient. CDI was diagnosed according to standard criteria. Surviving TBI patients underwent dynamic anterior pituitary testing at least 6 months after TBI. SETTING The patients were recruited from the Irish National Neurosurgery Centre. PATIENTS One hundred sequential TBI patients were recruited. Fifteen patients admitted to Intensive Therapy Unit (ITU) after major surgery were recruited as comparison patients. MAIN OUTCOME MEASURES PC in TBI patients was compared with that of comparison patients. The mortality rate was compared between TBI patients with and without acute hypocortisolemia. Results of follow-up dynamic pituitary testing were compared between those with and without acute hypocortisolemia. RESULTS Most of the TBI patients (78%) developed inappropriately low PC after TBI. Low PC and CDI were predictive of mortality. Thirty-nine percent of the patients who had follow-up testing had at least 1 pituitary hormone deficit, all of whom had had previous acute hypocortisolemia or CDI. CONCLUSIONS Acute hypocortisolemia and CDI are predictive of mortality and long-term pituitary deficits in TBI.

Morbidity and mortality in patients with craniopharyngioma after surgery.

Objective  Craniopharyngioma (CP) is a benign tumour of the suprasellar region that is associated with increased morbidity and mortality in comparison with other causes of hypopituitarism. We aimed to establish the rate and causes of mortality and morbidity in patients with CP who attended our centre.

Similar to adiponectin, serum levels of osteoprotegerin are associated with obesity in healthy subjects

An increase in serum osteoprotegerin (OPG) is associated with type 2 diabetes mellitus, the severity of vascular calcification, and coronary artery disease. Obesity is a risk factor for diabetes and cardiovascular disease, but little is known about the relationship between OPG and obesity. The purpose of this study was to determine if changes in body mass index (BMI) and insulin sensitivity influence circulating OPG in healthy subjects. A total of 100 subjects (36 lean, 41 overweight, and 23 obese) with normal glucose tolerance, blood pressure, and electrocardiogram stress test result volunteered for this study. Insulin sensitivity was estimated using a 2-hour oral glucose tolerance test with oral glucose insulin sensitivity analysis. Osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),soluble receptor activator of nuclear factor-κβ ligand (sRANKL), and adiponectin were analyzed using commercially available enzyme-linked immunosorbent assays. Osteoprotegerin (P < .01) and adiponectin (P < .001) were significantly decreased in the obese compared with lean subjects. There was no significant difference between BMI categories for TRAIL or sRANKL. Controlling for age and sex, there was a significant correlation between OPG and adiponectin (r = 0.391, P < .001), BMI (r = -0.331, P < .001), waist circumference (r = -0.268, P < .01), homeostasis model assessment of insulin resistance (r = -0.222, P < .05), and oral glucose insulin sensitivity (r = 0.221, P < .05). Both OPG and adiponectin were negatively correlated with body weight, BMI, waist circumference, and fasting plasma insulin while being positively correlated with insulin sensitivity (P < .05). Controlling for age, sex, and BMI, TRAIL was positively related to fat mass (r = 0.373, P < .001) and waist circumference (r = 0.257, P < .05). In contrast to patients with type 2 diabetes mellitus, circulating OPG is lower in obese, but otherwise healthy subjects and is positively correlated with indices of insulin sensitivity.

Osteoprotegerin and biomarkers of vascular inflammation in type 2 diabetes

Osteoprotegerin (OPG), receptor activator for nuclear factor kappa beta ligand (RANKL) and tumour necrosis factor–related apoptosis‐inducing ligand (TRAIL) are newly discovered members of the tumour necrosis factor‐alpha receptor superfamily. While their role in bone metabolism is well described, their function within the vasculature is poorly understood. OPG inhibits vascular calcification in vitro and high serum levels have been demonstrated in type 2 diabetes, but serum RANKL and TRAIL and their potential correlation with well‐established biomarkers of subclinical vascular inflammation such as high‐sensitivity C‐reactive protein (hsCRP) and interleukin‐6 (IL‐6) have not been described.

Osteoprotegerin is higher in peripheral arterial disease regardless of glycaemic status.

INTRODUCTION Peripheral arterial disease (PAD) and type 2 diabetes mellitus (DM) are both associated with excessive vascular calcification and elevated levels of inflammatory markers IL-6 and hsCRP. The recently identified Osteoprotegerin(OPG)/RANKL/TRAIL pathway has been implicated in vascular calcification, but data on levels in PAD and effect of co-existent DM are lacking. MATERIALS AND METHODS 4 groups of patients were recruited - 26 with PAD and DM, 35 with DM alone, 22 with PAD alone, and 21 healthy individuals. Serum OPG, RANKL, TRAIL, hsCRP and IL-6 were measured using commercial ELISA assays. Presence and severity of PAD was defined using ankle brachial index (ABI). RESULTS Serum OPG (7.4±0.3 vs.5.8±0.2 pmol/l, p<0.0001), TRAIL (95.5±5.2 ng/ml vs. 76.2±4.4 ng/ml, p=0.006), hsCRP (2.6±0.3 vs. 1.8±0.3 mg/l, p=0.048), and IL-6 (4.1±0.4 vs. 2.9±0.4 pg/ml, p=0.06) were higher in patients with PAD. There was no difference in RANKL. Only OPG was significantly higher in PAD and DM (7.2±0.3 pmol/l) and PAD alone (7.7±0.4 pmol/l) compared to DM only (5.8±0.3 pmol/l) and healthy controls (5.6±0.4 pmol/l), p<0.01, but OPG was no higher in those with DM plus PAD versus those with PAD alone (p<0.3). Only OPG was associated with PAD severity, correlating negatively with ABI (r=-0.26, p=0.03), independent of age, gender, glycaemic status, hsCRP and IL-6. CONCLUSIONS PAD is associated with higher serum OPG, regardless of the co-existence of DM. This finding, in addition to its correlation with severity of PAD, suggests that OPG may be a novel marker for the presence and severity of PAD, possibly by reflecting the degree of underlying vascular calcification.

A comparison of osteoprotegerin with adiponectin and high-sensitivity C-reactive protein (hsCRP) as a marker for insulin resistance

OBJECTIVE Insulin resistance (IR) is associated with low adiponectin and elevated high sensitivity C-reactive protein (hsCRP). Osteoprotegerin (OPG) has been shown to be elevated in type 2 diabetes, but whether it reflects underlying IR is unclear. We aimed to compare the ability of serum OPG with adiponectin and hsCRP to act as a marker for IR in individuals with normal and abnormal glucose tolerance. MATERIALS/METHODS 115 men underwent a 75 g oral glucose tolerance test. OPG, hsCRP and adiponectin were measured using ELISA. IR was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS Men with abnormal glucose tolerance (n=38) were older (58.3±11.2 vs 47.3±11.4 years, P<.001), had higher body mass index (BMI) (31.1±2.9 vs 27.9±3.2 kg/m(2), P<.001) and were more insulin resistant (median (I.Q.) HOMA-IR 5.88 (3.38) vs 1.13 (1.14), P<.001) than those with normal glucose tolerance (n=77). After adjustment for age and BMI, OPG (6.28 (2.32) vs 5.16 (1.86) pmol/L, P<.001) and hsCRP (2.07 (5.47) vs 0.78 (1.05) mg/L, P<.001) were higher and adiponectin (3.02±1.17 vs 4.78±2.38 μg/mL, P<.001) was lower in those with AGT. After adjustment for age and BMI, adiponectin (r=-0.317, P<.001) and hsCRP (r=0.318, P<.001), but not OPG (r=0.126, P=.196) correlated with HOMA-IR. On multiple linear regression analysis, adiponectin and hsCRP but not OPG were independent predictors of HOMA-IR. CONCLUSIONS OPG is higher in individuals with abnormal glucose tolerance, but unlike adiponectin and hsCRP, does not correlate with HOMA-IR, suggesting its elevation within this cohort of individuals is due to factors other than insulin resistance.

Somnolence in adult craniopharyngioma patients is a common, heterogeneous condition that is potentially treatable

Context and Objective  Somnolence and obesity are prevalent in craniopharyngioma patients.