Increased systemic and adipose 11ß-HSD1 activity in idiopathic intracranial hypertension.

Context: Idiopathic intracranial hypertension (IIH) is a disease of raised intracranial pressure (ICP) of unknown etiology. Reductions in glucocorticoid metabolism are associated with improvements in IIH disease activity. The basal IIH glucocorticoid metabolism is yet to be assessed. Objective: The objective of this study was to determine the basal glucocorticoid phenotype in IIH and assess the effects of weight loss on the IIH glucocorticoid phenotype. Design: A retrospective case-control study and a separate exploratory analysis of a prospective randomized intervention study were carried out. Methods: The case-control study compared female IIH patients to BMI, age, and sex-matched controls. In the randomized intervention study, different IIH patients were randomized to either a community weight management intervention or bariatric surgery, with patients assessed at baseline and 12 months. Glucocorticoid levels were determined utilizing 24-h urinary steroid profiles alongside the measurement of adipose tissue 11ß-HSD1 activity. Results: Compared to control subjects, patients with active IIH had increased systemic 11ß-hydroxysteroid dehydrogenase (11ß-HSD1) and 5α-reductase activity. The intervention study demonstrated that weight loss following bariatric surgery reduced systemic 11ß-HSD1 and 5α-reductase activity. Reductions in these were associated with reduced ICP. Subcutaneous adipose tissue explants demonstrated elevated 11ß-HSD1 activity compared to samples from matched controls. Conclusion: The study demonstrates that in IIH, there is a phenotype of elevated systemic and adipose 11ß-HSD1 activity in excess to that mediated by obesity. Bariatric surgery to induce weight loss was associated with reductions in 11ß-HSD1 activity and decreased ICP. These data reflect new insights into the IIH phenotype and further point toward metabolic dysregulation as a feature of IIH.

Systemic and adipocyte transcriptional and metabolic dysregulation in idiopathic intracranial hypertension.

BACKGROUNDIdiopathic intracranial hypertension (IIH) is a condition predominantly affecting obese women of reproductive age. Recent evidence suggests that IIH is a disease of metabolic dysregulation, androgen excess, and an increased risk of cardiovascular morbidity. Here we evaluate systemic and adipose specific metabolic determinants of the IIH phenotype.METHODSIn fasted, matched IIH (n = 97) and control (n = 43) patients, we assessed glucose and insulin homeostasis and leptin levels. Body composition was assessed along with an interrogation of adipose tissue function via nuclear magnetic resonance metabolomics and RNA sequencing in paired omental and subcutaneous biopsies in a case-control study.RESULTSWe demonstrate an insulin- and leptin-resistant phenotype in IIH in excess of that driven by obesity. Adiposity in IIH is preferentially centripetal and is associated with increased disease activity and insulin resistance. IIH adipocytes appear transcriptionally and metabolically primed toward depot-specific lipogenesis.CONCLUSIONThese data show that IIH is a metabolic disorder in which adipose tissue dysfunction is a feature of the disease. Managing IIH as a metabolic disease could reduce disease morbidity and improve cardiovascular outcomes.FUNDINGThis study was supported by the UK NIHR (NIHR-CS-011-028), the UK Medical Research Council (MR/K015184/1), Diabetes UK, Wellcome Trust (104612/Z/14/Z), the Sir Jules Thorn Award, and the Midlands Neuroscience Teaching and Research Fund.

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood.

BACKGROUNDMethodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism and for diagnostic workup of CSF disturbances.METHODSThe MRI contrast agent gadobutrol (Gadovist) was used as a CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the CNS and is eliminated along extravascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at the level of the cisterna magna in parallel with obtaining blood samples through 48 hours.RESULTSIn a reference patient cohort (n = 29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n = 4), idiopathic normal pressure hydrocephalus dementia (n = 7), pineal cysts (n = 8), and idiopathic intracranial hypertension (n = 4).CONCLUSIONAssessment of CSF tracer clearance is clinically feasible and may provide a way to predict extravascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hours) was preceded by far peak tracer enhancement at MRI in extracranial lymphatic structures (at about 24 hours), as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.FUNDINGThe work was supported by the Department of Neurosurgery, Oslo University Hospital; the Norwegian Institute for Air Research; and the University of Oslo.

11ßHSD1 Inhibition with AZD4017 Improves Lipid Profiles and Lean Muscle Mass in Idiopathic Intracranial Hypertension.

BACKGROUND: The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11ß-HSD1 inhibitors. We examined the impact of the reversible competitive 11ß-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH). METHODS: We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry. RESULTS: Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass. CONCLUSIONS: These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11ß-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.

Blood-Brain Barrier Dysfunction in Idiopathic Intracranial Hypertension.

Idiopathic intracranial hypertension (IIH) is traditionally considered benign and characterized by symptoms related to increased intracranial pressure, including headache and impaired vision. We have previously demonstrated that brains of IIH patients exhibit patchy astrogliosis, increased perivascular expression of the water channel aquaporin-4 (AQP4) as well as degenerating pericyte processes and capillary basement membranes. Given the established association between pericyte degeneration and blood-brain barrier (BBB) dysfunction, we investigated blood protein leakage by light microscopic immunohistochemistry. We also assessed perivascular AQP4 expression by immunogold transmission electron microscopy. The study included 14 IIH patients and 14 reference (REF) subjects undergoing neurosurgery for epilepsy, aneurysm, or tumor. Evidence of BBB dysfunction, measured as area extravasated fibrinogen/fibrin, was significantly more pronounced in IIH than REF individuals. The extent of extravasated fibrinogen was positively correlated with increasing degree of astrogliosis and vascular AQP4 immunoreactivity, determined by light microscopy. Immunogold transmission electron microscopy revealed no overall changes in AQP4 expression at astrocytic vascular endfeet in IIH (n = 8) compared to REF (n = 11) individuals. Our results provide evidence of BBB leakage in IIH, signifying that IIH is a more serious neurodegenerative disease than previously considered.

A unique androgen excess signature in idiopathic intracranial hypertension is linked to cerebrospinal fluid dynamics.

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, characterized by elevated intracranial pressure frequently manifesting with chronic headaches and visual loss. Similar to polycystic ovary syndrome (PCOS), IIH predominantly affects obese women of reproductive age. In this study, we comprehensively examined the systemic and cerebrospinal fluid (CSF) androgen metabolome in women with IIH in comparison with sex-, BMI-, and age-matched control groups with either simple obesity or PCOS (i.e., obesity and androgen excess). Women with IIH showed a pattern of androgen excess distinct to that observed in PCOS and simple obesity, with increased serum testosterone and increased CSF testosterone and androstenedione. Human choroid plexus expressed the androgen receptor, alongside the androgen-activating enzyme aldoketoreductase type 1C3. We show that in a rat choroid plexus cell line, testosterone significantly enhanced the activity of Na+/K+-ATPase, a surrogate of CSF secretion. We demonstrate that IIH patients have a unique signature of androgen excess and provide evidence that androgens can modulate CSF secretion via the choroid plexus. These findings implicate androgen excess as a potential causal driver and therapeutic target in IIH.

Cortical astrogliosis and increased perivascular aquaporin-4 in idiopathic intracranial hypertension.

The syndrome idiopathic intracranial hypertension (IIH) includes symptoms and signs of raised intracranial pressure (ICP) and impaired vision, usually in overweight persons. The pathogenesis is unknown. In the present prospective observational study, we characterized the histopathological changes in biopsies from the frontal brain cortical parenchyma obtained from 18 IIH patients. Reference specimens were sampled from 13 patients who underwent brain surgery for epilepsy, tumors or acute vascular diseases. Overnight ICP monitoring revealed abnormal intracranial pressure wave amplitudes in 14/18 IIH patients, who underwent shunt surgery and all responded favorably. A remarkable histopathological observation in IIH patients was patchy astrogliosis defined as clusters of hypertrophic astrocytes enclosing a nest of nerve cells. Distinct astrocyte domains (i.e. no overlap between astrocyte processes) were lacking in most IIH biopsy specimens, in contrast to their prevalence in reference specimens. Evidence of astrogliosis in IIH was accompanied with significantly increased aquaporin-4 (AQP4) immunoreactivity over perivascular astrocytic endfeet, compared to the reference specimens, measured with densitometry. Scattered CD68 immunoreactive cells (activated microglia and macrophages) were recognized, indicative of some inflammation. No apoptotic cells were demonstrable. We conclude that the patchy astrogliosis is a major finding in patients with IIH. We propose that the astrogliosis impairs intracranial pressure-volume reserve capacity, i.e. intracranial compliance, and contributes to the IIH by restricting the outflow of fluid from the cranium. The increased perivascular AQP4 in IIH may represent a compensatory mechanism to enhance brain fluid drainage.

The laboratory profile in idiopathic intracranial hypertension.

While overweight and female gender play an undisputable role in the pathogenesis of idiopathic intracranial hypertension (IIH), the contribution of other factors is still unclear. We have evaluated the laboratory findings of patients with IIH in an attempt to find the influence of abnormalities on the disease course. Included were 82 females after menarche and males older than 18 years who were followed up for at least 1 year. A wide range of laboratory parameters were examined at the time of presentation. The most frequent abnormal laboratory findings were elevated C reactive protein (CRP) (51 %), thrombophilia (31 %), increased plasma cortisol levels (29 %) and elevated lactate dehydrogenase (LDH) (20 %). Patients with elevated CRP and patients with thrombophilia had an unfavorable visual outcome. Increased cortisol levels and abnormal calcium correlated with a higher rate of recurrence. The visual outcome of patients with elevated LDH was better than those with normal LDH. It seems that certain metabolic, inflammatory and coagulation abnormalities may influence the course of IIH. If confirmed in further studies, these findings could contribute to elucidation of the etiology and prognosis of IIH.

The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension.

Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension.

Idiopathic intracranial hypertension: can studies of obesity provide the key to understanding pathogenesis?

The pathogenesis of idiopathic intracranial hypertension (IIH) is poorly understood. Several mechanisms have been suggested, but no one mechanism has been able to account for all manifestations of the disease. Although IIH predominantly affects obese, premenopausal women, little is known about whether or how the obesity contributes to the IIH. Obesity is a heterogeneous condition, consisting of different phenotypes that are influenced by the regional distribution of adipose tissue. This review explores the literature to integrate current knowledge on the relationships between obesity and IIH. The review evaluates the hypotheses that dysregulation of insulin, glucose metabolism, sex hormones, adipokines, glucocorticoids, lipids and free fatty acids in obesity could predispose to IIH. One potential common pathway linking metabolic disorders to the pathogenesis of IHH is a thrombotic tendency due to dysregulation of haemostatic risk factors. This could cause either occult cerebral sinus thrombosis or partial thrombosis of the parasagittal venous lacunae, with subsequent impaired resorption of cerebrospinal fluid and venous hypertension. Investigations that evaluate obesity, fat metabolism, endocrinological dysregulation and thrombotic tendency in patients with IIH are required so that pathogenic mechanisms can be clarified and management strategies in IIH can be improved.

Flavoprotein autofluorescence detection of early ocular dysfunction.

Metabolic stress occurs at disease onset and causes altered flavoprotein redox activity that increases flavoprotein autofluorescence (FA). Using a new method to measure ocular FA, we studied women with subtle visual dysfunction due to pseudotumor cerebri. Each FA value was greater in the more affected eye of each woman with pseudotumor cerebri, permitting identification of that eye in each case. Flavoprotein autofluorescence values averaged 60% greater in more affected eyes of women with pseudotumor cerebri, but not between eyes of healthy women (control subjects). These results demonstrate the clinical utility of FA and may permit early detection and monitoring of retinal and optic nerve diseases.

Neurologic manifestations of iron deficiency in childhood.

Iron deficiency is a common disorder in pediatric patients. Although the most common manifestation is that of anemia, iron deficiency is frequently the source of a host of neurologic disorders presenting to general pediatric neurologic practices. These disorders include developmental delay, stroke, breath-holding episodes, pseudotumor cerebri, and cranial nerve palsies. Although frequent, the identification of iron deficiency as part of the differential diagnosis in these disorders is uncommon and frequently goes untreated. The purpose of the current review is to highlight what is understood regarding iron deficiency and it's underlying pathophysiology as it relates to the brain, and the association of iron deficiency with common neurologic pediatric disease.

[A clinicopathological study of demyelination pseudotumors of the brain].

OBJECTIVE: To study the clinicopathological characteristics diagnosis, differential diagnosis and etiology of demyelination pseudotumors of the brain. METHODS: The clinical features, CT, MRI scan findings, corticosteroid therapeutic effects and follow-up data of 3 cases of demyelination pseudotumors of the brain were analysed, and pathological changes were observed by histologic (HE, Luxol fast blue and Bodian) and immunohistochemical (S-P method) techniques. RESULTS: The acute onset of demyelination pseudotumors appeared to be more predominant in our data. Clinical manifestations included headache, vomiting, a depressed conscious level, dysphasia, and paresis. CT, MRI scans showed solitary or multiple lesions in cerebral hemisphere. All the patients presented excellent response to steroid treatment. Follow-up for a period of 6 to 31 months, revealed the absence of progression or recurrence. The pathological changes were mainly located in both cerebral hemispheres, in which there were relative axonal preservation in foci loss of myelin, reactive gliosis, profuse perivascular lymphocytic infiltration and mixtures of foamy macrophages. CONCLUSION: Demyelination pseudotumor is a distinct clinicopathologic encephalitic entity. The findings of this study suggest that the cause of tumefactive demyelination may be related to an allergic reaction triggered by viral infection.

Safety issues in children and adolescents during growth hormone therapy--a review.

The action of growth hormone (GH) via its receptor involves many organ systems and metabolic pathways. These diverse actions are reviewed in this paper in the context that they may represent unwanted side-effects of GH therapy for growth promotion. The monitoring of GH therapy in large multicentre international databases has demonstrated a low frequency of adverse events. Tumour recurrence or new malignancy are not increased. Headaches, especially in the first few months of therapy, require close evaluation as benign intracranial hypertension is found infrequently, especially in children with GH deficiency and chronic renal failure (CRF). Children at risk for slipped capital femoral epiphysis and scoliosis require close monitoring during therapy. Decreased insulin sensitivity that is dose-dependent is observed during GH therapy. Glucose homeostasis, however, is not affected, but a recent report of increased incidence of Type 2 diabetes mellitus in children undergoing GH therapy requires prospective surveillance.

Multimodal monitoring in patients with head injury: evaluation of the effects of treatment on cerebral oxygenation.

BACKGROUND: Recently, invasive intensive care unit monitoring of cerebral oxygenation has become feasible. The purpose of this study was to investigate the effects of standard therapeutic interventions used in the treatment of intracranial hypertension on cerebral oxygenation and other physiologic parameters in comatose patients. METHODS: In the neurosurgical intensive care unit, Ptio2, and jugular bulb oxygen saturation (Sjvo2), arterial blood pressure, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) were prospectively studied (0.1 Hz acquisition rate) with a multimodal monitoring system in 21 patients with severe traumatic brain injury during various treatment modalities: dopamine and mannitol infusion, head positioning, and induced arterial hypocapnia. RESULTS: For baseline CPP values below 40 mm Hg, dopamine infusion was more effective in decreasing ICP and improving Ptio2 and Sjvo2 than for initial CPP values above 60 mm Hg. Treatment with mannitol, although improving CPP and lowering ICP, did not affect Ptio2 and Sjvo2. CPP in this group, however, was always above 60 mm Hg. Forced hyperventilation to an end-tidal Pco2 of 21 mm Hg normalized ICP and CPP, but significantly reduced cerebral oxygenation. CONCLUSION: A CPP > 60 mm Hg emerges as the crucial factor guaranteeing sufficient brain oxygenation. Any intervention used to further elevate CPP does not improve cerebral oxygenation, to the contrary, forced hyperventilation even bears the risk of inducing brain ischemia.