Alex Sinclair

A practical approach to, diagnosis, assessment and management of idiopathic intracranial hypertension

Adult patients who present with papilloedema and symptoms of raised intracranial pressure need urgent multidisciplinary assessment including neuroimaging, to exclude life-threatening causes. Where there is no apparent underlying cause for the raised intracranial pressure, patients are considered to have idiopathic intracranial hypertension (IIH). The incidence of IIH is increasing in line with the global epidemic of obesity. There are controversial issues in its diagnosis and management. This paper gives a practical approach to assessing patients with papilloedema, its investigation and the subsequent management of patients with IIH.

Idiopathic Intracranial Hypertension Associated with Iron Deficiency Anaemia: A Lesson for Management

Aim: To document the causal association of iron deficiency anaemia (IDA) and intracranial hypertension (IH). Methods: A consecutive case note review of patients with a clinical diagnosis of idiopathic intracranial hypertension (IIH) and anaemia presenting to a tertiary referral unit over a 2.5-year period. Demographics, aetiology and clinical details were recorded and analysed. Results: Eight cases were identified from 77 new cases presenting with IIH. All 8 had documented microcytic anaemia with clinical evidence of raised intracranial pressure. There was no evidence of venous sinus thrombosis on MRI and MR venography in 7 subjects and on repeated CT venography in 1. On correction of anaemia alone, 7 cases resolved. One patient with severe progressive visual loss underwent ventriculoperitoneal shunt in addition to treatment of anaemia, with good outcome. The incidence of this association is 10.3%. Conclusion: These cases present an association between IDA and IH, in the absence of cerebral sinus thrombosis. As a clinically significant proportion of cases presenting with signs of IIH have IDA, we recommend all patients presenting with IIH have full blood counts and if they are found to be anaemic, they should be treated appropriately.

Neurostimulation in the treatment of primary headaches

There is increasing interest in using neurostimulation to treat headache disorders. There are now several non-invasive and invasive stimulation devices available with some open-label series and small controlled trial studies that support their use. Non-invasive stimulation options include supraorbital stimulation (Cefaly), vagus nerve stimulation (gammaCore) and single-pulse transcranial magnetic stimulation (SpringTMS). Invasive procedures include occipital nerve stimulation, sphenopalatine ganglion stimulation and ventral tegmental area deep brain stimulation. These stimulation devices may find a place in the treatment pathway of headache disorders. Here, we explore the basic principles of neurostimulation for headache and overview the available methods of neurostimulation.

Idiopathic Intracranial Hypertension

Idiopathic intracranial hypertension (IIH) is an uncommon condition where loss of vision is the predominant morbid factor. The primary objectives of this research have been to study the population aspects of the disease, to make original observations on associated ocular motility abnormalities, to present new data on visual field survival in a cohort of patients followed prospectively and to present data on the clinical outcomes on the same cohort of patients. This constitutes the first in-depth and largest prospective study of visual function and epidemiology for the condition of IIH in the UK. Thirty-four patients have been followed over a four year period with comprehensive documentation of presentation, associated factors and conditions, assessment of visual function, ocular motility and neurological status. Risk factors for poor visual outcome have been determined for the patients in this study. The incidence figures for occurrence of IIH exist only for the USA and Libya. Only hospital based recruitment figures exist for UK studies and one of the objectives of this research has been to provide original epidemiological data for IIH in a defined UK population. The incidence of IIH in this UK population has been calculated as 0.70 per 100,000 persons and 1.38 for females. An age standardised adjustment to the national UK population provides an estimated incidence of 0.71 per 100,000 for the overall population and 1.39 for females. The incidence rates were also adjusted for the population of obese individuals and rose significantly to 12.25 per 100,000 for adult females with a body mass index of 30 or more. The diagnosis of a number of asymptomatic cases raised concerns regarding incidence calculations generally with lack of complete ascertainment of cases. This is the first study to prospectively assess overweight and obesity in a population of IIH. Obesity has been confirmed as a common association with this condition and has been identified as having a high relative risk factor in this study particularly those with a body mass index of 40 or more. Analysis of serial weight measurements demonstrate no correlation between weight change and visual outcome. When reviewing the aetiology of this condition, the association of obesity should be taken into consideration as this may play a role in the disruption of the cerebrospinal fluid absorption mechanism and development of cerebral oedema. Ocular motility disturbances have not been assessed in a prospective study and this study aims to cast light on the types of ocular motility disturbances that occur in association with the condition and those that are directly caused by the raised intracranial pressure. Ocular motility assessment was normal in 23 patients. Eleven patients, however, had an ocular motility defect and not all were due to the classic non localising sixth cranial nerve palsy associated with raised intracranial pressure. Two patients had long-standing strabismus, two had transient ocular motility restrictions following optic nerve sheath fenestration procedures, one developed a secondary exotropia following visual loss and optic atrophy, and six patients had acquired cranial nerve palsies including third and sixth nerves. The level of intracranial pressure was not significantly associated with the development of acquired ocular motility disorders. The prognosis for visual outcome is generally good with a favourable outcome achieved in most cases (82%). A significant improvement was found from initial to last assessment of visual function and the pattern of improvement was also significant over the period of follow up. It was noted that patients treated surgically responded more quickly, with improvement in visual status, than those patients treated medically. However, there was no difference in the final outcome or level of visual function between these two treatment groups. Serious loss of visual function occurs in a minority of cases and appears to relate to poor visual function prior to presentation, a high degree of obesity and features of long-standing optic nerve pathology including optic atrophy. However, in general, patients who are appropriately evaluated at regular intervals and those who are treated promptly and effectively have a favourable outcome. The recommendation for visual assessment in this study includes documentation of visual acuity, visual field assessment with automated or Goldmann perimetry with sensitive testing strategies, full Orthoptic investigation as indicated and fundus examination, and close liaison with the neurology and neurosurgery departments. The use of this regime enabled the detection of insidious and asymptomatic visual loss and therefore was of considerable prognostic value. The Humphrey 24-2 programme and a new testing strategy for Goldmann perimetry were employed for the first time in this prospective study as was the Pelli-Robson contrast sensitivity assessment. Visual field assessments using the above methods were identified as suitable and reliable testing techniques. This thesis, in addition to the clinical study, provides a review of the literature relating to papilloedema and IIH, and the pathogenesis of visual loss in IIH. Observations are made regarding the clinical data of this study and the proposed mechanisms involved in the condition and its associated visual dysfunction.

Headache management: pharmacological approaches.

Headache is one of the most common conditions presenting to the neurology clinic, yet a significant proportion of these patients are unsatisfied by their clinic experience. Headache can be extremely disabling; effective treatment is not only essential for patients but is rewarding for the physician. In this first of two parts review of headache, we provide an overview of headache management, emerging therapeutic strategies and an accessible interpretation of clinical guidelines to assist the busy neurologist.

The Ocular Glymphatic System and Idiopathic Intracranial Hypertension: Author Response to "Hypodense Holes and the Ocular Glymphatic System".

The proposal that there exists a paravascular transport system within the eye, similar and likely continuous with the glymphatic system in the central nervous system (CNS), is an exciting development with implications to the pathogenesis of a number of common ocular diseases, and one that may open up new targets for treatment. We are delighted to see in this most recent correspondence how Wostyn and colleagues present further evidence to support the existence of such a system in the optic nerve and its potential relevance to the pathogenesis of glaucoma. Building on our initial hypothesis reported in Investigative Ophthalmology & Visual Science, we have now made important progress in identifying its relevance to another sight-threatening condition with a fluiddynamic component, idiopathic intracranial hypertension (IIH). We believe that these observations corroborate the most recent findings of Wostyn and colleagues, and provide

Topiramate is more effective than acetazolamide at lowering intracranial pressure

Background The management of idiopathic intracranial hypertension focuses on reducing intracranial pressure to preserve vision and reduce headaches. There is sparse evidence to support the use of some of the drugs commonly used to manage idiopathic intracranial hypertension, therefore we propose to evaluate the efficacy of these drugs at lowering intracranial pressure in healthy rats. Methods We measured intracranial pressure in female rats before and after subcutaneous administration of acetazolamide, topiramate, furosemide, amiloride and octreotide at clinical doses (equivalent to a single human dose) and high doses (equivalent to a human daily dose). In addition, we measured intracranial pressure after oral administration of acetazolamide and topiramate. Results At clinical and high doses, subcutaneous administration of topiramate lowered intracranial pressure by 32% (p = 0.0009) and 21% (p = 0.015) respectively. There was no significant reduction in intracranial pressure noted with acetazolamide, furosemide, amiloride or octreotide at any dose. Oral administration of topiramate significantly lowered intracranial pressure by 22% (p = 0.018), compared to 5% reduction with acetazolamide (p = >0.999). Conclusion Our in vivo studies demonstrated that both subcutaneous and oral administration of topiramate significantly lowers intracranial pressure. Other drugs tested, including acetazolamide, did not significantly reduce intracranial pressure. Future clinical trials evaluating the efficacy and side effects of topiramate in idiopathic intracranial hypertension patients would be of interest.

1545 Topiramate is as effective as acetazolamide at lowering intracranial pressure in healthy rodents

Background Management of Idiopathic Intracranial Hypertension (IIH) aims to reduce intracranial pressure (ICP). Acetazolamide is the most commonly used drug, with class 1 evidence demonstrating modest improvement in patients with mild visual loss. Other drugs used include Topiramate, Furosemide, Amiloride and Octreotide, despite little mechanistic or clinical evidence to support their use. The aim of this study was to ascertain which of these drugs has the greatest effect on lowering ICP in-vivo. Methods Using a validated epidural ICP recording method we measured changes in ICP in conscious female rodents after subcutaneous administration of these drugs at clinically equivalent and supra-clinical doses over 2 hours (peak plasma concentrations). Results At clinical doses, Topiramate lowered ICP by 32% (p=0.0009) compared to a 25% reduction for Acetazolamide (p=0.0081). Post-hoc analysis showed no significant difference between the two (p=0.85). Furosemide, Amiloride and Octreotide had no significant effect. Conclusion Our in-vivo studies have demonstrated that, at clinically equivalent doses, Topiramate significantly lowers ICP and is as effective as acetazolamide. Topiramate may have additional advantages in IIH, including its migraine prevention properties and weight loss effects. These findings support the need for future randomised controlled trials evaluating the therapeutic efficacy of topiramate in IIH.

GLUCAGON LIKE PEPTIDE-1 REDUCES RAISED INTRACRANIAL PRESSURE

Current therapies for reducing raised intracranial pressure (ICP) in conditions such as idiopathic intracranial hypertension (IIH) have limited efficacy and tolerability; therefore there is an urgent need to develop novel therapies. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used therapeutically to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. The GLP-1R is also present in the choroid plexus, therefore we investigated whether Exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP. We used in vitro models of the choroid plexus to demonstrate the presence of the GLP-1R and, after Exendin-4 treatment, showed a two fold increase in cAMP, a downstream signaling molecule. We also determine that treatment with Exendin-4 reduces Na+ K+ ATPase activity, a key regulator of CSF secretion. Finally, we demonstrate that administration of Exendin-4 in normal and raised ICP (hydrocephalic) rats significantly reduces ICP. These findings provide the first proof of concept that GLP-1R agonists can affect CSF secretion and ICP. Repurposing existing GLP-1 drugs may represent a novel therapeutic strategy for conditions of raised ICP including IIH, hydrocephalus and traumatic brain injury.

EHMTI-0304. Headache determines quality of life in idiopathic intracranial hypertension

No previous studies have assessed quality of life (QoL) in idiopathic intracranial hypertension (IIH) associated with a therapeutic weight loss. Our previously published prospective cohort study confirmed that weight loss significantly reduced intracranial pressure (ICP) and treated chronic active adult IIH.