Michael A. Burdon

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).

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.

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.

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.

Corticosteroids, 11β-Hydroxysteroid Dehydrogenase Isozymes and the Rabbit Choroid Plexus

The epithelial cells of the choroid plexus (CP) are responsible for cerebrospinal fluid (CSF) secretion into the ventricles of the brain. The balance between CSF production and drainage, in part, facilitates a normal intracranial pressure. The secretion of Na+ and anions by the CP creates an osmotic gradient driving water into the ventricles. This is opposite to classical Na+ transporting tissues, such as the kidney, where Na+ and water reabsorption is mediated by 11β‐hydroxysteroid dehydrogenase type 2 that protects the mineralocorticoid receptor by abrogating active cortisol to inactive cortisone. In the human ocular ciliary epithelium, Na+ and water secretion is dependent on a novel mediator of ciliary epithelial Na+ transport, 11β‐HSD type 1 (11β‐HSD1), that generates intraocular cortisol. In a mechanism analogous to that of the embryologically related ocular ciliary epithelium, we propose that autocrine regulation of intracranial cortisol is dependent on 11β‐HSD1 expression in the CP epithelial cells. By conducting immunolocalisation studies on brains from New Zealand White Albino rabbits, we defined the expression of 11β‐HSD1 in the secretory CP epithelial cells. Enzyme assays performed on intact rabbit CP whole tissue explants confirmed predominant 11β‐HSD1 activity, generating cortisol that was inhibited by glycyrrhetinic acid (an 11β‐HSD inhibitor). Using the real time‐polymerase chain reaction, rabbit CP tissue was found to express levels of 11β‐HSD1, glucocorticoid receptor α and serum and glucocorticoid‐regulated kinase 1 mRNA comparable to that expressed in rabbit ocular ciliary body, thereby highlighting the similarity between these two tissues. Furthermore, an enzyme‐linked immunosorbent assay of rabbit CSF revealed a median cortisol concentration of 1.7 nmol/l (range 1.4–4.3 nmol/l, n = 9). Our data have identified a functional 11β‐HSD1 within the CP, mediating intracranial cortisol bioavailability. Expression of 11β‐HSD1 may be fundamental in the regulation of CSF secretion and the local generation of cortisol may represent a pathophysiological mechanism underlying cortisol‐dependent neuroendocrine diseases.

Idiopathic intracranial hypertension: consensus guidelines on management

The aim was to capture interdisciplinary expertise from a large group of clinicians, reflecting practice from across the UK and further, to inform subsequent development of a national consensus guidance for optimal management of idiopathic intracranial hypertension (IIH). Methods Between September 2015 and October 2017, a specialist interest group including neurology, neurosurgery, neuroradiology, ophthalmology, nursing, primary care doctors and patient representatives met. An initial UK survey of attitudes and practice in IIH was sent to a wide group of physicians and surgeons who investigate and manage IIH regularly. A comprehensive systematic literature review was performed to assemble the foundations of the statements. An international panel along with four national professional bodies, namely the Association of British Neurologists, British Association for the Study of Headache, the Society of British Neurological Surgeons and the Royal College of Ophthalmologists critically reviewed the statements. Results Over 20 questions were constructed: one based on the diagnostic principles for optimal investigation of papilloedema and 21 for the management of IIH. Three main principles were identified: (1) to treat the underlying disease; (2) to protect the vision; and (3) to minimise the headache morbidity. Statements presented provide insight to uncertainties in IIH where research opportunities exist. Conclusions In collaboration with many different specialists, professions and patient representatives, we have developed guidance statements for the investigation and management of adult IIH.

Intracranial dermoid cyst presenting as an isolated fourth nerve palsy

Sirs: A 68-year-old man presented with 4 months of painless vertical diplopia on left gaze. Examination revealed a right fourth nerve palsy, which was confirmed by the Bielschowsky head tilt test and demonstrated on the Hess chart. There was a normal vertical fusion range, no corrective head posture or further neurological abnormality detected. Systemic examination found borderline hypertension (145/ 91 mmHg) and a normal fasting glucose. He denied any history of trauma. His only medical history was treatment for dyslipidemia. MRI scan revealed a 1–2 cm strongly hyperintense welldefined rounded mass on T1and T2-weighted images (Figs. 1, 2). The lipid-containing mass was applied to the dorsum of the tectum and left of the midline. Its appearance was hypointense on the fat-suppressed pulse sequence images (Fig. 3). These findings are characteristic of dermoid cysts. On consultation with the neurosurgical team, the decision was made to observe this intracranial dermoid cyst. At 16 months follow-up there has been no clinical progression. He remains under neuro-ophthalmic review. A space-occupying lesion is an uncommon cause of any isolated pupil sparing third, fourth or sixth cranial nerve palsy. A presumed microvascular palsy is a common aetiology and the majority of these resolve within 6 months. It has been recommended that sudden onset and isolated cranial nerve palsy can be observed, using neuroimaging if there is an insidious onset, progression (i.e. is no longer isolated) or non-resolution [1, 2]. In the case presented the onset of vertical diplopia was over the period of 4 months, and hence due to the insidious onset was scanned urgently. The radiological differential diagnosis of the hyperintense mass on T1-weighted images (Fig. 2) would include haematomas, aneurysms and lipid rich masses. High signal intensity on T1-weighted images and a hypointense T2 appearance, in this location, would be demonstrated by a dermoid cyst, a thrombosed berry aneurysm, an intracranial tetratoma or a quadrigeminal cistern lipoma. Fat suppression and inversion recovery sequences are therefore helpful to narrow the differential diagnosis and prove the mass is lipid containing (Fig. 3) [3]. Further image characteristics, such as chemical shift artefact, can differentiate between a dermoid cyst and a lipoma. Dermoids are typically well-circumscribed lesions that can contain lipid metabolites, hair and hair follicles, calcifications, sebaceous and sweat glands and decomposed epithelial cells containing cholesterol and keratin [4]. The composition determines their appearance: a typical high signal intensity on T1-weighted images, due to the high fat content; and a heterogeneous signal on T2-weighted sequences, due to the mixed content of the lesion [3]. Dermoid cysts are rare, congenital, non-neoplastic lesions that account for 0.7–1.8% of all intracranial tumours, with the posterior cranial fossa being the commonest location [4]. Supratentorial lesions have been reported presenting as an isolated third nerve palsy and other symptoms, with infratentorial dermoids causing sixth nerve palsy and cerebellar signs [5]. To our knowledge, an intracranial dermoid presenting as an isolated trochlear nerve palsy has not been described. R. Tailor S. P. Mollan (&) M. A. Burdon Birmingham and Midland Eye Centre, City Hospital, Dudley Road, Birmingham B18 7QH, UK e-mail: soozmollan@doctors.org.uk

INTRACRANIAL ARTERIOVENOUS MALFORMATION PRESENTING WITH PAPILLOEDEMA

Intracranial arteriovenous malformations (AVM) typically present clinically with haemorrhage, seizures or focal neurological deficit. AVM do not usually have a substantial mass effect or cause raised intracranial pressure. Rarely shunting of arterial blood into the venous system can cause raised venous pressure and consequently raised CSF pressure. The case described here is of a 37 year old man with an AVM who presented with headache and papilloedema secondary to raised CSF pressure. Following partial embolisation, to reduce fistulous flow, and stereotactic radiosurgery (SRS), to reduce the size of the AVM, both the headache and papilloedema resolved.

074 Rating papilloedema: an evaluation of the Frisen classification in idiopathic intracranial hypertension

Optic disc appearance is a key measure of disease status in Idiopathic Intracranial Hypertension (IIH). Frisen classification describes stages of papilloedema (grades 0–5) and is used internationally, in clinical and research practice. No studies have evaluated Frisen classification since its original description. We assess the inter-rater reproducibility and sensitivity of Frisen classification, compared with our system of ranking papilloedema severity, in IIH. Six masked neuro-ophthalmologists reviewed paired disc photographs (before and after treatment) from 47 patients with IIH (25 acute and 22 chronic) and assigned a Frisen grade. Additionally paired discs were ranked in order of papilloedema severity, (disc ranking). 188 discs were reviewed. Agreement among all reviewers was noted in only three instances (1.6%) when using Frisen classification, compared with 40 instances of exact agreement (44.6%) for disc ranking. The probability of agreement between any two reviewers was 36.1% for Frisen grade and 70.0% for disc ranking. Disc ranking had significantly greater sensitivity, identifying a difference in 75.3% of paired photographs compared to 53.2% for Frisen grade (p<0.001). We demonstrate the limited sensitivity and reproducibility of Frisen classification in IIH. Simple optic disc ranking was more sensitive and reproducible. The use of disc ranking in clinical practice and research studies is recommended until alternative schemes, specific to IIH, have been developed.