In the past 18 years, the Journal of Neuro-Ophthalmology has published 83 articles that directly or indirectly deal with the clinical problem of idiopathic intracranial hypertension (IIH). In addition to individual case reports, small groups of patients, and reports of psychophysical tests, there is a superb review of unresolved “vexing” issues regarding papilledema (1), a discussion of disease definition and nomenclature (2), and 2 commentaries on surgical treatment of IIH (3,4). Various causes of visual loss are described, including subretinal hemorrhage (5,6), choroidal infarction (7,8), following liposuction (9), induced hyperopia and choroidal folds (10), and as a complication of hind brain herniation after lumboperitoneal shunt with resulting cortical blindness and simultanagnosia (11). Reports of progressive visual loss after optic nerve sheath fenestration (12–14), visual loss without papilledema, (15) and IIH without papilledema (16,17) all deal with rare problems that may present to the neuro-ophthalmologist.
The clinical issue of “normal pressure IIH” (18,19) brings up a major diagnostic problem that faces the clinician who cares for these patients; there is no noninvasive way to measure cerebrospinal fluid (CSF) pressure longitudinally. In other words, were the “normal” pressures simply sampling error? The current intraventricular (20), intraparenchymal (21) or lumbar drain CSF pressure measurements are used only briefly in dire circumstances that surround severe visual loss and urgent surgical decision making. These invasive techniques are limited to answering surgical questions and cannot be routinely used to answer questions such as how high and how continuously high are the CSF pressure. While neuroimaging abnormalities detected with magnetic resonance imaging, magnetic resonance venography, and computed tomography are highly suggestive of IIH (22–24), these changes can also be seen in patients with cerebral venous sinus thrombosis (25). Orbital ultrasonic measurement of the optic nerve sheath is a relatively insensitive noninvasive technique indicating whether the CSF pressure is elevated (sheath dilated) or not (sheath not dilated), but cannot quantitate the level of intracranial pressure (ICP).
Two articles elucidated the relationship between IIH and obstructive sleep apnea (OSA) (26,27), and suggested that OSA is not a major risk factor for visual loss (27). Severity of visual loss in patients with IIH is unrelated to obesity (28) and it appears that severe obesity, by itself, does not predispose to a high incidence of papilledema (29).
A series of studies on vitamin A and case reports (30–33), as well as an authoritative review of vitamin A metabolism, and its potential relationship to obesity, vitamin A storage, and carrier proteins in CSF and serum (34), all provide tantalizing clues relating IIH to vitamin A and its congeners. More work needs to be done to see whether there is a causal relationship between vitamin A metabolism and IIH.
Epidemiologic and familial incidence studies (35,36) and a comparison of IIH in Israeli men and women (37) were reported. There were no clear differences between the Israeli IIH incidence study and earlier studies (36). In the male and female comparisons, women were statistically more likely to be obese than men. A report of “late-onset” IIH (patients were older than 45 years) found 5 of 14 were men (64% of the total), were obese, and a third were asymptomatic (38). Unfortunately this report was a mixture of symptomatic cases (4 of 14 patients had some identifiable cause of IIH) and idiopathic cases, which will make it difficult to compare their results with other studies of older patients. This report suggests that older patients are more likely to have an identifiable cause of increased ICP.
A multitude of unusual causes of “IIH-like” conditions are reported, and such reports emphasize the need to be compulsive using the modified Dandy Criteria to make the correct diagnosis of IIH. The yearly reviews of IIH-related articles collected and summarized from other journals are worth reading (39–42).
Many questions that are asked about the CSF pressure in IIH cannot be answered. What happens to the CSF pressure with change in posture, during ambulation, in recumbency, during Valsalva maneuvers, and what is the effect of various medications, when vision changes and pulsatile tinnitus occurs?
All these questions could be answered with a noninvasive method to measure CSF pressure. IIH is a quintessential neuro-ophthalmologic problem waiting to be solved. It will take concerted planning and technical expertise to develop a noninvasive pressure monitoring device. New and not so new medications need to be studied to investigate their effectiveness. Drugs such as topiramate, octreotide, omeprazole, and others that have been used deserve to be studied. Continuous CSF pressure measurement would permit one to calculate CSF production rates as well as resistance to absorption and correlate the effects of sleep and exercise on CSF pressure. More work on the basic science of CSF production, absorption, and testing of the lymphatic drainage hypothesis may eventually allow us to understand the pathophysiology of IIH.
In 2009, a multicenter, double-blind, randomized placebo-controlled study (funded by National Institutes of Health) of the effect of weight and/or low sodium diet plus acetazolamide versus diet plus placebo in subjects with idiopathic IIH and mild visual loss was begun under the direction of Michael Wall and Mark Kupersmith (Neuro-Ophthalmology Research Disease Investigator Consortium). A group of 45 American and Canadian centers is recruiting 154 patients and an equal number of controls. The primary objective of the study is to determine the efficacy of weight reduction plus acetazolamide as compared with weight reduction and placebo in reducing or reversing visual loss. The secondary objectives are a genetic analysis (carried out by Edwin Stone, MD, PhD, at the University of Iowa Ophthalmology Laboratories) of subjects and controls for single-nucleotide polymorphisms within genes that encode molecules likely to be involved in the etiology of IIH. Vitamin A and other potential factors possibly related to the metabolism of IIH subjects will be studied by Bill Blaner, PhD, and Jennifer Libien, PhD, at NYU. Fundus photography is being studied by Steve Feldon at the University of Rochester, and the visual field scoring is being carried out under John Keltner's watchful eye at UC Davis. Hormone levels related to gender and obesity will be studied using the results of the genetic testing. Carefully designed and carried out, this study holds the promise of producing some important answers to questions of the effectiveness of current standard treatment with acetazolamide and/or diet alone in the control of this condition. In addition, it is hoped that there will be new insights into the role of obesity and gender in the etiology and pathogenesis of this strange condition. Of particular interest will be the results of the dietary treatment as carried out by Dr. Xavier Pi-Sunyer, under the aegis of the New York Obesity Research Center.
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