NORDIC Idiopathic Intracranial Hypertension Treatment Trial (IIHTT)


OCT Substudy: NORDIC IIHTT Study Group

Modified from Michael Wall, MD, IIHTT Study Director

IDIOPATHIC INTRACRANIAL HYPERTENSION (IIH), also called pseudotumor cerebri, is a disorder of elevated intracranial pressure of unknown case. Its incidence is 22.5 new cases each year per 100,000 overweight women of childbearing age; its incidence is rising in parallel with the obesity epidemic. It affects about 100,000 Americans. Most suffer debilitating headaches. Because of pressure on the optic nerve (papilledema), 86% have visual loss and 10% develop severe visual loss. Interventions to prevent loss of sight, all with unproven efficacy, include diet, diuretics (acetazolamide), repeated spinal taps, optic nerve sheath fenestration surgery, and CSF shunting procedures. The purported goal of these therapies is to lower intracranial pressure however, it is unclear whether these act by lowering intracranial pressure, or through some other yet un-elucidated mechanism. None of these strategies has been verified by properly designed clinical trials. Thus, there is confusion, uncertainty, and weak scientific rationales to guide treatment decisions. Our long-term goals are (1) to establish convincing, evidence-based treatment strategies for IIH to restore and protect vision (2) follow subjects up to 4 years to observe the long-term treatment outcomes and (3) to determine the cause of IIH.

Although we do not know what causes IIH, we have many clues. The condition occurs mostly in women in the childbearing years. The symptoms often start or worsen during a period of weight gain. The disease is rare in thin men. This has led some researchers to look for hormonal changes within the body. To date no consistent changes in hormones have been found. As a part of our research program, we are trying to find some hormonal changes in a newly discovered hormone.

Headache is present in nearly all patients with IIH and is the usual symptom for which patients seek medical attention. The headaches of the IIH patient are usually severe and daily; they are are often throbbing. Transient visual obscurations are episodes of transient blurred vision that usually last less than 30 seconds and are followed by full recovery of vision. Visual obscurations occur in about 3/4 of IIH patients. The attacks may be involve one or both eyes. Visual obscurations do not appear to be associated with poor visual outcome. Pulsatile intracranial noises or pulse-synchronous tinnitus is common in IIH. The sound is often unilateral. The most serious problem patients have is vision loss.  About 5% of patients go blind in at least one eye. These are usually patients who do not return for follow-up evaluation.

Although no associated conditions besides recent weight gain are usually found, many conditions have been linked to high intracranial pressure.  There are numerous disorders that blocks the flow of spinal fluid between the brain and its route to the blood, the jugular vein, that can cause raised pressure, but these are not IIH.

Measuring the spinal fluid pressure via a spinal tap after MRI is necessary for proper diagnosis. Lowering the increased intracranial pressure is essential in relieving symptoms and preventing visual field loss When a spinal tap is done, the needle is placed in the subarachnoid space to measure and relieve the pressure, particularly when the pressure causes swelling of the optic nerve head, which is termed papilledema. When the optic nerve fibers are under pressure, damage may occur with resultant visual loss. Since all the optic nerve fibers are under pressure, a visual field examination is necessary to determine whether visual loss is taking place so that the appropriate treatment can be started. Fortunately, visual loss can be reversed. However, much depends on how long the visual loss has been present. In some cases, full recovery takes place and in others partial recovery. Most patients with visual loss have some recovery with treatment.

Treatment for patient with IIH can be divided into medical treatment and surgical treatment. The cornerstone of medical treatment is weight loss. Medications that cause fluid loss, such as acetazolamide, are another form of therapy. Surgical treatments are reserved with patients who fail medical therapies and have progressive vision loss. Those in current use include optic nerve sheath fenestration (making slits in the optic nerve sheath or covering) and shunting the spinal fluid from the lumbar (low back) or ventricle (head) spaces. However, no single therapy has ever been properly studied to determine which is the best treatment for most patients.

This is why NORDIC has decided to perform the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT)

The IIHTT is a prospective clinical treatment trial on idiopathic intracranial hypertension that includes a genetic association study in search of single polymorphisms (SNPs) to identify metabolic and hormonal factors that differentiate between obese women who have IIH and obese women who do not is the first NORDIC multicenter study.

Specific Aim 1: Clinical Trial of  subjects prospectively recruited. The trial is focused on determining the efficacy of diet or acetazolamide to reduce or reverse visual loss. Change in the perimetric mean deviation (PMD) from baseline to Month 6 is the primary outcome variable. Additional outcomes measured yearly up to 4 years are: changes in papilledema grade, cerebrospinal fluid (CSF) pressure measurements, other visual field measures, and quality of life measures.  IIH patients with Mild Visual Loss (-2 to -5 dB baseline PMD) will be recrutied to participate in this randomized, double-masked, placebo-controlled trial to determine the additional benefit of acetazolamide (up to 4 gm a day) added to a low sodium, weight reduction diet. Hypothesis: Acetazolamide + diet is superior to diet alone in restoring vision or preventing visual loss in IIH patients with mild visual loss.

Specific Aim 2:  (a) To identify proteomic and genetic risk factors for IIH by screening a large cohort of IIH patients and controls, (b) To determine the serum and CSF levels of potential mediators of IIH suggested by the genetic analysis, and (c) To conduct an association study in search of single nucleotide polymorphisms (SNPs) that confer risk for developing IIH. A cohort of 154 IIH patients and 154 controls matched on body-mass index, ethnicity and gender will be genotyped at SNPs contained within genes encoding molecules likely to be involved in the etiology of IIH using the SNPlex genotyping system. Specifically, genes associated with obesity will be profiled. (d) To test the hypotheses IIH is associated with abnormal metabolism of leptin or vitamin A or both, leptin levels, vitamin A and related factors will be measured at baseline and six months.

NORDIC Idiopathic Intracranial Hypertension Treatment Trial Is Unique Because It Has Multiple Features

  • This treatment trial that offers access to all study subjects to a special weight loss program to treat obesity.  The New York Obesity Research Organization has a renowned treatment program that has a waiting list for patients not in this study.
  • The IIHTT is a randomized treatment trial where all subjects will get an intervention, weight loss management.
  • The IIHTT will develop and test multiple outcomes
    • Multiple quality of life vehicles completed via internet
    • Vision function tests – threshold perimetry, visual acuity, and contrast sensitivity
    • OCT and fundus photo imaging
    • Understand inter-relationships between structure and function outcomes and correlation with QOL measures
    • Refine methods and outcomes for future NORDIC studies
  • The IIHTT will use digital and internet data entry for all aspects of the study
    • Subject self-assessments using QOL vehicles on password protected area of NORDIC website.
    • Coordinator entry of data into secure password protected EResearch at University of Rochester DCBC site.
    • Use of FTP to upload visual field data, OCT images, and Fundus photos to Reading Centers.
  • The IIHTT will determine the efficacy of the study drug acetazolamide (Diamox) on vision, other symptoms, fundus imaging, and spinal fluid pressure.
  • The IIHTT will investigate the mechanisms and pathophysiology of this disorder.
    • Specific genome studies using single nucleotide polymorphisms for at least 50 candidate genes specific to obesity
    • Vitamin A metabolism in blood and spinal fluid
    • Obesity hormone evaluation