Alexandra J Sinclair

Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study

Objective To observe intracranial pressure in women with idiopathic intracranial hypertension who follow a low energy diet. Design Prospective cohort study. Setting Outpatient department and the clinical research facility based at two separate hospitals within the United Kingdom. Participants 25 women with body mass index (BMI) >25, with active (papilloedema and intracranial pressure >25 cm H2O), chronic (over three months) idiopathic intracranial hypertension. Women who had undergone surgery to treat idiopathic intracranial hypertension were excluded. Intervention Stage 1: no new intervention; stage 2: nutritionally complete low energy (calorie) diet (1777 kJ/day (425 kcal/day)); stage 3: follow-up period after the diet. Each stage lasted three months. Main outcome measure The primary outcome was reduction in intracranial pressure after the diet. Secondary measures included score on headache impact test-6, papilloedema (as measured by ultrasonography of the elevation of the optic disc and diameter of the nerve sheath, together with thickness of the peripapillary retina measured by optical coherence tomography), mean deviation of Humphrey visual field, LogMAR visual acuity, and symptoms. Outcome measures were assessed at baseline and three, six, and nine months. Lumbar puncture, to quantify intracranial pressure, was measured at baseline and three and six months. Results All variables remained stable over stage 1. During stage 2, there were significant reductions in weight (mean 15.7 (SD 8.0) kg, P<0.001), intracranial pressure (mean 8.0 (SD 4.2) cm H2O, P<0.001), score on headache impact test (7.6 (SD 10.1), P=0.004), and papilloedema (optic disc elevation (mean 0.15 (SD 0.23) mm, P=0.002), diameter of the nerve sheath (mean 0.7 (SD 0.8) mm, P=0.004), and thickness of the peripapillary retina (mean 25.7 (SD 36.1) µ, P=0.001)). Mean deviation of the Humphrey visual field remained stable, and in only five patients, the LogMAR visual acuity improved by one line. Fewer women reported symptoms including tinnitus, diplopia, and obscurations (10 v 4, P=0.004; 7 v 0, P=0.008; and 4 v 0, P=0.025, respectively). Re-evaluation at three months after the diet showed no significant change in weight (0.21 (SD 6.8) kg), and all outcome measures were maintained. Conclusion Women with idiopathic intracranial hypertension who followed a low energy diet for three months had significantly reduced intracranial pressure compared with pressure measured in the three months before the diet, as well as improved symptoms and reduced papilloedema. These reductions persisted for three months after they stopped the diet.

NMR‐based metabolomic analysis of cerebrospinal fluid and serum in neurological diseases – a diagnostic tool?

We sought to evaluate the diagnostic accuracy of metabolomic biomarker profiles in neurological conditions (idiopathic intracranial hypertension (IIH), multiple sclerosis (MS) and cerebrovascular disease (CVD) compared to controls with either no neurological disease or mixed neurological diseases).

11β-Hydroxysteroid Dehydrogenase 1: Translational and Therapeutic Aspects

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner. In this review, we will discuss the enzymology and molecular biology of 11β-HSD1 and the molecular basis of cortisone reductase deficiencies. We will also address how altered 11β-HSD1 activity has been implicated in a number of disease states, and we will explore its role in the physiology and pathologies of different tissues. Finally, we will address the current status of selective 11β-HSD1 inhibitors that are in development and being tested in phase II trials for patients with the metabolic syndrome. Although the data are preliminary, therapeutic inhibition of 11β-HSD1 is also an exciting prospect for the treatment of a variety of other disorders such as osteoporosis, glaucoma, intracranial hypertension, and cognitive decline.

Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions

Idiopathic intracranial hypertension is a disorder characterised by raised intracranial pressure that predominantly affects young, obese women. Pathogenesis has not been fully elucidated, but several causal factors have been proposed. Symptoms can include headaches, visual loss, pulsatile tinnitus, and back and neck pain, but the clinical presentation is highly variable. Although few studies have been done to support evidence-based management, several recent advances have the potential to enhance understanding of the causes of the disease and to guide treatment decisions. Investigators of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) reported beneficial effects of acetazolamide in patients with mild visual loss. Studies have also established weight loss as an effective disease-modifying treatment, and further clinical trials to investigate new treatments are underway. The incidence of idiopathic intracranial hypertension is expected to increase as rates of obesity increase; efforts to reduce diagnostic delays and identify new, effective approaches to treatment will be key to meeting the needs of a growing number of patients.

Exploring the pathogenesis of IIH: An inflammatory perspective

Idiopathic intracranial hypertension (IIH) is a common blinding condition amongst the young obese female population (20 per 100,000) characterised by elevated intracranial pressure (ICP). The aetiology of IIH is not known. In this review we explore the literature investigating the pathogenesis of IIH and suggest additional hypotheses. Chronic inflammation is emerging as an aetiological factor in the pathogenesis of obesity and we propose that this may be a feature of IIH. Obesity is also related to dysregulation of cortisol production by the pre-receptor enzyme, 11beta-hydroxysteroid dehydrogenase, and we speculate that this may have a role in the pathogenesis of obesity and raised ICP seen in IIH.

Cerebrospinal fluid and lumbar puncture: a practical review

Cerebrospinal fluid is vital for normal brain function. Changes to the composition, flow, or pressure can cause a variety of neurological symptoms and signs. Equally, disorders of nervous tissue may alter cerebrospinal fluid characteristics. Analysis of cerebrospinal fluid can provide information on diagnosis, may be therapeutic in certain conditions, and allows a research opportunity into neurological disease. However, inappropriate sampling, inaccurate technique, and incomplete analysis can contribute to significant patient morbidity, and reduce the amount of accurate information obtained. In this article, we will review how cerebrospinal fluid is produced, circulated, and resorbed. We will also review lumbar puncture technique, equipment, and cerebrospinal fluid analysis. We also discuss how to minimize the risks and address the complications associated with lumbar puncture.

Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance?

Objective  The aetiology of idiopathic intracranial hypertension (IIH) is not known, but its association with obesity is well‐recognized. Recent studies have linked obesity with abnormalities in circulating inflammatory and adiposity related cytokines. The aim of this study was to characterize adipokine and inflammatory cytokine profiles in IIH.

Evolving evidence in adult idiopathic intracranial hypertension: pathophysiology and management

Idiopathic intracranial hypertension (IIH) is a rare but important disease associated with significant morbidity. There is an expected rise in prevalence in line with the escalating global burden of obesity. Modern revisions in the terminology and diagnostic criteria for IIH help guide clinicians in investigations and researchers in standardising recruitment criteria for clinical trials. The pathophysiology of IIH is incompletely characterised; suggested underpinning mechanisms include the role of cerebrospinal fluid regulation as well as metabolic and endocrinological perspectives. Recent treatment trials are providing insights into the management but debate still surrounds key areas in treatment. This review will provide an up-to-date discussion on the potential pathogenic mechanisms and management of IIH.

Cerebrospinal Fluid Corticosteroid Levels and Cortisol Metabolism in Patients with Idiopathic Intracranial Hypertension: A Link between 11β-HSD1 and Intracranial Pressure Regulation?

CONTEXT The etiology of idiopathic intracranial hypertension (IIH) is unknown. We hypothesized that obesity and elevated intracranial pressure may be linked through increased 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. OBJECTIVE The aim was to characterize 11β-HSD1 in human cerebrospinal fluid (CSF) secretory [choroid plexus (CP)] and drainage [arachnoid granulation tissue (AGT)] structures, and to evaluate 11β-HSD1 activity after therapeutic weight loss in IIH. DESIGN AND SETTING We conducted in vitro analysis of CP and AGT and a prospective in vivo cohort study set in two tertiary care centers. PATIENTS OR OTHER PARTICIPANTS Twenty-five obese adult female patients with active IIH were studied, and 22 completed the study. INTERVENTION Fasted serum, CSF, and 24-h urine samples were collected at baseline, after 3-month observation, and after a 3-month diet. MAIN OUTCOME MEASURES Changes in urine, serum, and CSF glucocorticoids (measured by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry) after weight loss were measured. RESULTS 11β-HSD1 and key elements of the glucocorticoid signaling pathway were expressed in CP and AGT. After weight loss (14.2±7.8 kg; P<0.001), global 11β-HSD1 activity decreased (P=0.001) and correlated with reduction in intracranial pressure (r=0.504; P=0.028). CSF and serum glucocorticoids remained stable, although the change in CSF cortisone levels correlated with weight loss (r=-0.512; P=0.018). CONCLUSIONS Therapeutic weight loss in IIH is associated with a reduction in global 11β-HSD1 activity. Elevated 11β-HSD1 may represent a pathogenic mechanism in IIH, potentially via manipulation of CSF dynamics at the CP and AGT. Although further clarification of the functional role of 11β-HSD1 in IIH is needed, our results suggest that 11β-HSD1 inhibition may have therapeutic potential in IIH.

The role of metabolomics in neurological disease

Metabolomic analysis has the potential to generate disease-specific metabolite signatures unique to individuals. Autoimmune illnesses, such as inflammatory uveitis, have highlighted the discriminative power of metabolomics by allowing disease sub-classification. Elucidating surrogate markers for neurological disease is particularly important, given the constraints in accessing central nervous system tissue in vivo. Metabolomic analysis, using either (1)H NMR spectroscopy or mass spectroscopy can be performed using biofluids such as urine, blood or cerebrospinal fluid and may permit the identification of disease specific metabolite signatures which may be useful as disease biomarkers. This is particularly relevant to complex diseases such as multiple sclerosis where promising preliminary work has been carried out. Future work in this field may well generate metabolite profiles to monitor disease evolution, prognosticate and guide therapeutic decisions.