A Google search for Idiopathic Intracranial Hypertension (IIH) returns over 160,000 results. Using the idiopathic intracranial hypertension PubMed Medical Subject Headings returns 2,879 publications. There have been 50–100 IIH publications per year in PubMed for the past 30 years. The Journal of Neuro-Ophthalmology has a “virtual issue” found online that lists 83 manuscripts published over the years dealing with IIH. Here, one can find everything from wonderful vignettes of IIH patients in the Hoyt Lecture by Norman Schatz entitled “The Troubles I've Seen” (1) to a variety of disorders masquerading as IIH, to reviews of IIH treatment options. Despite these many articles, we know little more now than we did 30 years ago about the cause of this enigmatic disease.
If we are to propose a cause for IIH, what facts must be dealt with? First is the clear preponderance of women. In the IIH Treatment Trial (IIHTT), women account for approximately 97% of cases. This makes one wonder if the few men have other causes for intracranial hypertension. Next, we know that there is an association of IIH and being overweight. But what is it about being overweight? Is it weight per se? Is it sodium intake? Is it fluid being retained? When people gain weight do they ingest more of certain dietary constituents such as vitamin A that cause intracranial hypertension? We simply do not know the answers to these questions. The results of the IIHTT, hopefully, will shed light on the cause of IIH. In the future, stored blood and cerebrospinal fluid (CSF) from cases and controls will be analyzed based on analysis of proteomic and genetic risk factors for IIH.
In this issue of the Journal, a number of articles deal with the topic of intracranial hypertension. Although it has been suggested that steroid use can lead to increased intracranial pressure (ICP), the evidence is weak. Moodly et al. (2) describe a 29-year-old postpartum woman who developed Sheehan syndrome and intracranial hypertension. With steroid replacement, the patient's signs and symptoms resolved, reminding us that steroid withdrawal leads to increased ICP.
Szewka et al. (3) investigated the relationship between obesity and visual outcomes in IIH. They performed a retrospective chart review of adult cases of IIH and found 38% had body mass index (BMI) more than or equal to 40 kg/m2. These morbidly obese patients with BMI ≥ 40 were more likely to have severe papilledema, and there was a trend toward more severe visual loss in one or both eyes. The explanation for these findings is not clear. Is it that many of those that weighed the most had the least regard for their health? Is it that the morbidly obese had the most difficulty with weight loss? Whatever the reason, the higher the BMI of IIH patients, the more closely they should be monitored for progression of vision loss. A related finding comes from a prospective study of 50 IIH patients published more than 2 decades ago (4). Using logistic regression, marked recent weight gain was an important risk factor for poor visual outcome. So we might ask whether there is a relationship of BMI with vision loss or is it recent weight gain that is important?
Ahmed et al. (5) report 2 patients with spinal leptomeningeal lymphoma initially diagnosed as IIH. At presentation, there were no clinical signs of a spinal cord disease. In one patient, there was a very high CSF protein and in the other, no lumbar puncture was done! These cases remind us to always consider spinal cord and canal pathology (such as ependymoma, chronic inflammatory polyneuropathy, and drop metastases) when there is unexplained elevated CSF protein. Because IIH has such a characteristic presentation, some practitioners question the need for lumbar puncture to obtain CSF. The report by Ahmed et al. is a testament to always perform a spinal tap to evaluate CSF constituents. Without this, the modified Dandy criteria for IIH cannot be met and the diagnosis of IIH remains uncertain.
Finally, Falardeau et al. (6) studied the risk to offspring born to mothers with IIH taking acetazolamide during pregnancy. It is known that carbonic anhydrase inhibitors, including acetazolamide, can cause forelimb anomalies in rodents (7). There is one case of a sacrococcygeal teratoma in an infant born to a mother taking acetazolamide until the 19th week of pregnancy (8). In the Falardeau article, data were collected through questionnaires sent to IIH patients and their physicians. Acetazolamide usage before 13 weeks gestation was identified in 50 pregnancies. The risk of spontaneous abortion was similar in the treated and control groups, and there were no major complications in the newborn of women treated with acetazolamide. This article extends the findings of Lee et al. (9) who reported no untoward outcomes or events in 12 IIH patients treated with acetazolamide during pregnancy. Although these studies do not prove acetazolamide is safe during pregnancy, they suggest that birth defects from acetazolamide, if they occur, are rare.
Given the numerous questions surrounding etiology and management of IIH patients, the IIHTT is underway. This is a multicenter, randomized, double-blind, placebo-controlled study of weight reduction and low-sodium diet coupled with acetazolamide versus placebo in subjects with IIH and mild visual loss. Although the 166-subject enrollment has been completed, we have not yet followed all subjects for 6 months to reach our primary study outcome of change in perimetric mean deviation. Once we reach this point, we will determine whether there is a statistically significant difference in perimetric mean deviation between those treated with maximal dosage acetazolamide and those taking placebo. Although we do not yet have our primary outcome, we have already learned a great deal from the trial.
In 1978, Gücer and Vierenstein (10) demonstrated with continuous CSF monitoring that doses of 3–4 g per day of acetazolamide were needed to lower ICP. Therefore, subjects in the IIHTT on acetazolamide are given the maximum dosage tolerated. We decided to give the medication twice daily with meals. We were not sure how well both the high dosage and giving the medication twice a day would be tolerated but, in general, this protocol has worked well.
Weight loss coupled with a low-sodium diet and lifestyle modification aimed at improving health has been successful. With a target of 5%–10% weight loss at 6 months and 1 year, about half of the IIHTT subjects have lost 6% or more total body weight.
High doses of acetazolamide seem safe 3 years into the trial. Serious side effects have been rare, with renal stones in about 2% of subjects. We need longer follow-up for more accurate data.
During the IIHTT, subjects are monitored closely for worsening of disease to determine failure of treatment. With entry criteria of the worst eye having between −2 and −7 dB mean deviation with Humphrey SITA Standard 24-2 testing, and with the investigational portion of the trial about three fourths complete, we have had only 7 treatment failures. There have been a few patients who, on 1 and sometimes 2 perimetric examinations, have worsening of their mean deviation to the level of treatment failure. Because the remainder of their clinical findings were stable or improved, it was suspected that they were having a “bad day” performing perimetry. On retest, usually when well rested, and sometimes after reviewing instructions for visual field testing, the perimetric results reverted back to their better baseline levels. We have called these subjects “performance failures” and believe that they are an important group to identify, so that more aggressive forms of treatment are not used unnecessarily.
The IIHTT has an optical coherence tomography (OCT) substudy. Because OCT instruments were developed for quantitation of glaucomatous optic disc changes, it is a challenge to use them to follow papilledema. The scale of the instruments cannot display high-grade papilledema accurately but using the axial view, high definition scanning capability has added new information. The retinal pigment epithelium/Bruch's membrane layer bordering the neural canal in papilledema has an inverted U shape, skewed nasally inward toward the vitreous and, in normals and anterior ischemic optic neuropathy, it has a characteristic V shape pointing away from the vitreous. This may be an important finding to differentiate papilledema from other causes of optic disc edema and elevation (11,12).
We have learned that NORDIC (Neuro-Ophthalmologic Research Disease Investigator Consortium) is a great facilitator of neuro-ophthalmology research (13). The NORDIC infrastructure built with the help of a National Eye Institute U10 grant gives clinicians the help needed to develop and run a successful clinical trial. I urge our neuro-ophthalmologic community to take advantage of all that NORDIC offers as we develop further research proposals and clinical trials.
In reviewing the literature, including the articles appearing in this issue of the Journal, a discussion of IIH raises more questions than answers. We eagerly await the findings from the IIHTT and hope we will not only gain evidence-based treatment strategies but also insights into the cause of this potentially blinding disorder.
1. Schatz NJ. The troubles I've seen. J Neuroophthalmol. 2010;30:288–294.
2. Moodley KK, Broad R, Chung K, Riordan-Eva P, Sibtain NA, Moran NF. Sheehan syndrome associated with raised intracranial pressure. J Neuroophthalmol. 2013;33:54–57.
3. Szewka AJ, Bruce BB, Newman NJ, Biousse V. Idiopathic intracranial hypertension: relation between obesity and visual outcome. J Neuroophthalmol. 2013;33:4–8.
4. Wall M, George D. Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain. 1991;114:155–180.
5. Ahmed RM, King J, Gibson J, Buckland ME, Gupta R, Gonzales M, Halmaggi GM. Spinal leptomeningeal lymphoma presenting as pseudotumor syndrome. J Neuroophthalmol. 2013;33:13–16.
6. Falardeau J, Lobb BM, Golden S, Maxfield SD, Tanne E. The use of acetazolamide during pregnancy in intracranial hypertension patients. J Neuroophthalmol. 2013;33:9–12.
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8. Worsham F Jr, Beckman EN, Mitchell EH. Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide. JAMA. 1978;240:251–252.
9. Lee AG, Pless M, Falardeau J, Capozzoli T, Wall M, Kardon RH. The use of acetazolamide in idiopathic intracranial hypertension during pregnancy. Am J Ophthalmol. 2005;139:855–859.
10. Gücer G, Vierenstein L. Long-term intracranial pressure recording in management of pseudotumor cerebri. J Neurosurg. 1978;49:256–263.
11. Kupersmith MJ, Sibony P, Mandel G, Durbin M, Kardon RH. Optical coherence tomography of the swollen optic nerve head: deformation of the peripapillary retinal pigment epithelium layer in papilledema. Invest Ophthalmol Vis Sci. 2011;52:6558–6564.
12. Sibony P, Kupersmith MJ, Rohlf FJ. Shape analysis of the peripapillary RPE layer in papilledema and ischemic optic neuropathy. Invest Ophthalmol Vis Sci. 2011;52:7987–7995.
13. Kupersmith MJ, Miller N, Balcer L, Gordon L, Wall M, Keltner J, Friedman D, Feldon S, McDermott M, Kieburtz K. The neuro-ophthalmology research disease Investigator Consortium (NORDIC). J Neuroophthalmol. 2009;29:259–261.