Should Acetazolamide Be the First-Line Treatment for Patients With Idiopathic Intracranial Hypertension?

Clinical orbital MRI protocols are routinely used to study the optic nerves and exclude compressive lesions, infarctions, or inflammation. However, the small caliber and divergent oblique orientations of the optic nerves make it challenging to characterize them well with conventional MRI, especially since adjacent air-filled bony structures distort the MRI signal and motion is a problem even in cooperative, healthy volunteers. Over the past 3 years we have experimented with multiple novel MRI approaches and sequences to better characterize the optic nerves. The perfect MRI protocol would be quantitative and sensitive to subtle optic nerve pathologic changes, provide high spatial resolution, be rapidly acquired, and resistant to motion degradation. This review provides an update of recent MRI sequence innovations for the optic nerves being currently translated into clinical practice. Methods discussed include rapid MRI with compressed sensing or simultaneous multislice approaches, postprocessing techniques for quantitative T2 mapping or track density imaging, and multiple MRI sequences for measuring diffusion in the optic nerves. Recently-developed orbit-specific MRI coils, quantitative sequences, and rapid acquisition techniques can improve our future ability to study optic nerve pathologies noninvasively. As advanced MRI becomes more proficient at characterizing the optic nerves, its role in the clinical management of patients should increase.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Should Acetazolamide Be the First-Line Treatment for Patients With Idiopathic Intracranial Hypertension? David I. Kaufman, DO, Deborah I. Friedman, MD, MPH The management of patients with idiopathic intracranial hypertension (IIH) has, in the past, been guided primarily by informed opinion, clinical experience, and a small number of primarily retrospective studies. Given the results of the IIH Treatment Trial (IIHTT), there is now evidence supporting the use of acetazolamide for patients with visual loss. Two experts discuss whether acetazolamide should be considered first-line treatment for patients with IIH. Pro: David Kaufman, DO Idiopathic intracranial hypertension (IIH) is a disease occurring primarily in obese women (19.3 per 100,000) of childbearing age (1-3). It leads to increased intracranial pressure (ICP) with associated neurologic signs and symptoms. Magnetic resonance imaging is normal except for findings associated with increased ICP (1). Other than elevated pressure, cerebrospinal fluid (CSF) analysis is normal. Visual loss due to chronic papilledema is the most feared outcome. At times, this may occur from inappropriate or delayed treatment (4). In the past, the literature has provided evidence for the use of a variety of medications in treating patients with IIH (5). However, this literature is based on a case series, with data gathered retrospectively. Proposed medications included corticosteroids (6), diuretics (7-9), digoxin (10- 13), topiramate (14-16), and acetazolamide (17-19). More than 60 years ago, treatment for IIH was centered on the use of systemic corticosteroids. In 1961, Paterson et al (6) first reported a beneficial effect of steroids in 6 of 7 patients with IIH. In a review of the literature in 2010, Wall (20) stated: "Steroids are still occasionally used to treat IIH but their mechanism of action remains unclear." He went on to describe many of the side effects including weight gain in these typically obese patients. He also cautioned that "patients with visual loss treated with steroids can improve but recurrence of visual loss with tapering of these medications can be followed by return of papilledema and visual loss." He concluded "use of long-term steroids to treat IIH has largely been abandoned. Short-term use may have a role in the preoperative period before a CSF shunting Department of Neurology and Ophthalmology (DK), Michigan State University, East Lansing, Michigan; and; and Departments of Neurology and Neurotherapeutics and Ophthalmology (DF), University of Texas Southwestern Medical Center, Dallas, Texas. The authors report no conflicts of interest. Address correspondence to David Kaufman, DO, 804 Service Road, A-217 Clinical Center, Michigan State University, East Lansing, MI 48824; E-mail: [e-mail] 182 procedure." Thambisetty et al (21) discussed the use of high doses of steroids in "fulminant idiopathic intracranial hypertension." These authors reviewed the cases of 16 women with onset of visual loss within 4 weeks of initial symptoms of IIH with high-grade papilledema and mean opening pressure on lumbar puncture of 54.1 cm H2O. Four patients were treated with intravenous methylprednisolone as well as acetazolamide. All eventually underwent a neurosurgical shunting procedure. Although visual function improved in 14 patients, 8 of the 16 patients remained legally blind. Jefferson and Clark (7) discussed the use of diuretics such as furosemide as a potential treatment for IIH in the 1970s. It was well documented that furosemide could lower ICP by diuresis and reducing sodium transport into the brain (8,20). However, in a review of IIH, Ball and Clarke (5) stated, "The role of diuretics is uncertain." They added "No randomized control trials of treatment have been done and the management is controversial." Digoxin as a treatment for IIH also has been proposed. This was based on the observation by Neblett et al (10) on the effect of cardiac glycosides on CSF production. They reported that 3 patients experienced lowered ICP while on this medication. They postulated that digoxin reduced CSF production by acting on the choroid plexus through modification of ouabainsensitive sodium/potassium ATPase receptors. In a single patient, Schott and Holt (11) found no such effect and documented that digoxin did not enter the CSF in large amounts. Some including Hannerz (12) believed that weight loss due to digoxin might be a more plausible explanation, whereas others pointed out that the mechanism of action of digoxin in IIH remains uncertain (13). Acetazolamide was first approved as a diuretic in 1953. In the 1970s, Lubow and Kuhr (17) documented its use in a series of 40 patients (39 female with "primary idiopathic pseudotumor"). They discussed 10 cases in detail, treating Kaufman and Friedman: J Neuro-Ophthalmol 2017; 37: 182-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point many of them with acetazolamide 500-1,500 mg/day in divided doses. In some patients, they instituted a 1,200 calorie diet for weight loss. McCarthy and Reed (9) showed that acetazolamide decreased CSF flow but not until more than 99.5% of the choroid plexus carbonic anhydrase was inhibited. Tomsak et al (18) reported a series of 4 women treated with acetazolamide and found "rapid resolution of papilledema using 1,000 mg/day orally in divided doses with resolution first noted within 20-57 days (mean of 40 days)." Gradually, acetazolamide became a preferred medical treatment of patients with IIH. Although a variety of anecdotal reports were published dealing with the use of acetazolamide in IIH, none were prospective, properly powered, or placebo controlled as noted in a Cochrane Database Systematic Review published in 2005 (22). In 2002, Pagan et al (14) described 3 patients with IIH who would not tolerate or failed "standard" therapy with acetazolamide but had a favorable outcome with topiramate. The authors noted that topiramate has an inhibiting effect on carbonic anhydrase and a welcome side effect of weight loss. The following year, Friedman and Eller (15) also highlighted the use of topiramate as part of the medical regimen in 22 patients with IIH. Celebisoy et al (16), in an open-label study of 40 patients published in 2007, suggested that this medication might have value in IIH. This team noted "each group had a statistically significant improvement detected." They added that weight loss was recorded in the topiramate group. These authors then hypothesized topiramate might be effective in the treatment of IIH based on weight reduction and on the reduction of CSF formation as a possible mechanism of action. The controversy surrounding the best medication to use in IIH led the Neuro-Ophthalmologic Research Disease Investigator Consortium (NORDIC) to organize a treatment trial. A multicenter, randomized, doublemasked, placebo-controlled study called the IIH Treatment Trial (IIHTT) was sponsored by the National Eye Institute (NEI). Its aim was to determine the value of acetazolamide and diet vs diet and placebo. The IIHTT was launched in 2010 and 165 participants were recruited from throughout North America with "mild visual impairment" that met the modified Dandy criteria for IIH. Data were acquired from March 2010 to November of 2012. The participants typically were followed-up for at least 6 months with the last visit in June 2013. The planned primary outcome was the change in perimetric mean deviation (PMD) obtained with automated visual field testing. Individuals included in the IIHTT had a PMD between 22 and 27 dB (1,2). The results of the IIHTT demonstrated that the mean improvement in PMD was greater with acetazolamide (1.43 dB from 23.53 to 22.10 dB at Month 6; n = 86) than with placebo (0.71 dB from 23.5 to 22.82 dB; n = 79); the difference was 0.71 dB (95 CI, 0-1.43 dB; P = 0.050)" (2). In addition, there was improvement in both papilledema and vision-related quality-of-life scores in the acetazolamide group (1,2). The results of the IIHTT demonstrated that "in patients with IIH and mild visual loss, the use of acetazolamide with a low-sodium weight reduction diet compared with diet alone resulted in modest improvement in visual field function" (1,2). Since publication of the findings of the IIHTT, a number of neuro-ophthalmologists have emphasized the importance of the study (19,23). The results provide Level 1 evidence for the efficacy of acetazolamide in the treatment of patients with IIH. Given this evidence, it seems logical that when medication is being considered in patients with IIH with mild visual field loss, acetazolamide along with diet promoting weight loss must be considered the first-line therapeutic strategy in most cases. Con: Deborah Friedman, MD Although the recent IIH Treatment Trial (IIHTT) was a milestone study in the field of neuro-ophthalmology, it was directed at a specific population of patients with IIH, those with a PMD between 22 and 27 dB. However, there are a number of other clinical scenarios and alternate treatment modalities that the clinician must consider. Some patients with IIH are asymptomatic and come to medical attention when papilledema is discovered during a routine eye examination. These individuals often have normal visual function, including intact visual fields. This may occur in children, where IIH often is self-limited (24). As these patients are at low risk of losing vision and feel well overall, is it always necessary to start treatment with acetazolamide in dosages used in the IIHTT? Can you make an Kaufman and Friedman: J Neuro-Ophthalmol 2017; 37: 182-186 asymptomatic patient better? The management of such patients is controversial. Once a mass lesion or other cause of papilledema is excluded, some physicians will initiate treatment with acetazolamide and others will follow the patient closely until the papilledema resolves. Most reported patients with asymptomatic papilledema from IIH have been treated with acetazolamide for relatively short durations, whereas others were not treated and the papilledema resolved. After confirming the diagnosis of IIH, it may be reasonable to follow some of these individuals without treatment. Alternatively, a short course of acetazolamide, a low sodium diet and weight loss program, if applicable, may be used. Frequent monitoring of the visual status and papilledema grade is imperative; although you 183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point can not make an asymptomatic patient better, you certainly do not want them to get worse. Alternatively, patients with a PMD of worse than 27 dB were excluded from the IIHTT. The rationale when designing the IIHTT was that these patients already had significant visual field loss and, in some cases, decreased visual acuity. Many might require more aggressive treatment (including surgery), and it would be unethical to withhold these therapeutic options. Another scenario on the "mild" end of the spectrum is the patient with headaches and papilledema but otherwise normal visual function. Headache management is the main concern in this cohort. Although headache disability in the IIHTT generally improved throughout the 6-month followup period, there was no benefit of acetazolamide over placebo in resolving headaches (2). Topiramate may be the preferred option in these patients, as it has mild carbonic anhydrase activity (similar to, but milder than, acetazolamide), may cause weight loss as a side effect, has Level I evidence of efficacy in the treatment of migraine, and tension-type headache (25). One open label study compared topiramate with acetazolamide for the treatment of IIH in adults (16). The cohort was heterogeneous with no limitations regarding visual function at study entry. Participants were of similar weight (the mean weight was 70 kg in the acetazolamide group and 73.5 kg in the topiramate group) with comparable degrees of papilledema and visual field loss. The treatment assignment was "randomized" although the randomization strategy was substandard (every other patient was treated with acetazolamide 1,000-1,500 mg/day, and the others were treated with topiramate starting at 50 mg daily and increased to 100-150 mg/day). One patient in the topiramate group was withdrawn because of rapid visual field deterioration. Of the remaining 40 patients, there was a statistically significant improvement in visual fields at 6 and 12 months, with no difference between treatment groups. Paresthesias occurred in both treatment groups with concentration difficulties and weight loss occurring more often in the topiramate group. The use of topiramate was an exclusion criterion in the IIHTT because of potential confounding effects with acetazolamide; the IIHTT evaluated visual parameters, weight loss, and headache disability as outcome measures, all of which may be impacted by topiramate. Other medications such as amitriptyline, nortriptyline, protriptyline, naproxen, gabapentin, and fluoxetine were recommended for headache prevention, if needed. Amitriptyline was used almost exclusively for headache prevention in the IIHTT. In practice, I find topiramate a useful adjunct to acetazolamide for the management of headaches in patients with IIH who do not improve with acetazolamide alone. However, I do not recommend it as the sole treatment for patients with visual loss as the evidence for its use is not strong. 184 Because the IIHTT did not include patients with a PMD worse than 27 dB at baseline, it does not provide guidance for those patients. Interestingly, the participants who had the greatest benefit from acetazolamide in the IIHTT had the most severe papilledema at baseline (Frisén Grades 3-5) (2). A risk factor for treatment failure (i.e., worsening of PMD beyond a predefined limit) in the IIHTT was central visual loss at presentation. Although no randomized trials have been performed in patients with moderate-to-severe visual loss, many years of clinical experience suggest that acetazolamide alone is often inadequate to restore or improve vision. Declining vision often precludes a gradual dose escalation of acetazolamide as was used in the IIHTT. Visual acuity loss in IIH may be due to macular edema and/or optic neuropathy. One study using spectral-domain optical coherence tomography showed that the maculopathy is generally reversible, with permanent visual loss related to the severity of optic neuropathy (26). Additional treatment options for visual loss due to optic nerve dysfunction include optic nerve sheath fenestration, cerebrospinal fluid (CSF) diversion procedures (shunting), temporizing CSF diversion (lumbar drain), systemic corticosteroids, and cerebral venous sinus stenting if a stenosis and pressure gradient are identified. Each of these procedures has potential benefits and limitations, and there are no randomized trials comparing these treatments with each other or to maximal medical therapy. Although it is more of a long-term treatment strategy, weight loss is generally accepted as an effective treatment, particularly for reducing papilledema and improving visual function. Newborg (27) first reported 7 female and 2 male obese patients with IIH who were treated with a modified rice diet (400-1,000 kcal/day) with fluid and sodium restriction. Although no visual function parameters were measured, fundus photography demonstrated improvement or resolution of papilledema; the duration of the study is not mentioned. A retrospective review of 48 consecutive patients analyzed data from 15 obese women (mean body mass index [BMI]: 40.7 kg/ m2) (28). Treatment was limited to weight loss and acetazolamide. An average of 3.3% weight loss correlated with a one-degree improvement in papilledema grade, and loss of 6.2% of body weight was associated with resolution of papilledema. Eleven patients had improvement in papilledema within 24 weeks, and 10 of the 15 patients had complete resolution of papilledema. Another retrospective study of 58 women stratified patients based on whether weight loss of at least 2.5 kg was achieved during any 3-month interval (29). Papilledema and perimetry improved more rapidly in patients who lost weight. A report of 8 obese (mean BMI: 29 kg/m2) patients with IIH with chronic headaches, good visual acuity, and enlarged blind spots on visual field testing, who underwent gastric surgery for weight loss showed an average Kaufman and Friedman: J Neuro-Ophthalmol 2017; 37: 182-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point weight reduction of 57 ± 5 kg (30). There was a reduction in CSF opening pressure, headache, pulsatile tinnitus, and papilledema when seen in follow-up between 4 and 72 months, postoperatively. Several surgical complications occurred, and it is not indicated whether or not the study was retrospective or prospective (although it appears to be retrospective). A prospective cohort study in the United Kingdom recruited 25 women with IIH to participate in a 3-phase protocol, in which they had no intervention, followed a very low calorie diet (3 months), and were followed up after the dietary intervention was completed (31). Papilledema was assessed by clinical examination, optic nerve ultrasound, and optical coherence tomography. Most participants had mild (Frisén Grade 2) papilledema and mild visual loss with a mean PMD of 23.8 dB. Data were collected regarding headache phenotype, disability, and analgesic use. The dietary intervention was a meal replacement liquid diet providing 425 kcal/day plus at least 2 L of fluid daily. Forty-four percent of patients were on a stable dose of acetazolamide throughout the study, and 20 women completed the entire study. Papilledema, ICP, and symptoms of IIH improved, although 8 women continued to have disabling headaches after the dietary phase. The mean weight loss was 17.5 ± 8.0 kg (P , 0.001) which was maintained in the 3-month follow-up phase. None of the dietary studies to date have included a control group and some also allowed patients to take acetazolamide. The interval of follow-up was not constant in the gastric surgery study, sometimes assessed many years later, making it difficult to sort out the effect of intervention from the natural history of IIH. However, as weight gain is clearly associated with both the development and recurrence of IIH, dietary management makes intuitive sense (32). Lastly, some patients do not tolerate or are allergic to acetazolamide. Other diuretics have not been rigorously studied for the treatment of IIH. For those patients unable to tolerate acetazolamide, chlorthalidone is a useful adjunct therapy for patients who also have orthostatic (idiopathic) edema, incorporating a low sodium diet and moderate fluid restriction (33). Spironolactone, amioride, and triamterene may be helpful for those patients who are allergic to acetazolamide and thiazide diuretics. In summary, IIH is not "one size fits all" in regard to clinical manifestations or treatment options. Acetazolamide had a statistically significant but relatively modest clinical effect on PMD improvement in the IIHTT which may be a reflection of the degree of visual loss studied in the trial. Without additional randomized studies, it is uncertain which therapies are best suited for minimally affected patients or those with more severe visual loss. Rebuttal: Dr. Kaufman Although I agree with Dr. Friedman that the IIHTT showed only a modest beneficial effect in a specific group of patients, this study's findings must still be considered carefully by clinicians when managing this disease. Dr. Friedman's therapeutic suggestions in the atypical and more aggressive cases are really based on anecdotal reports and her personal experience. Although the IIHTT looked only at a specific patient cohort, there is a place to use acetazolamide in atypical groups of patients with IIH. This medication may not be the primary therapy, but it still has an important role to play. I would like to emphasize that while making decisions regarding patient management, physician judgment remains paramount. And this remains true even when a management pathway is subjected to a rigorous clinical trial such as the IIHTT. Dr. Friedman correctly points out that alternative treatments may be needed when caring for patients unlike those studied in the IIHT. However, in patients who fall within the inclusion criteria of the IIHTT, unless physician judgment clearly dictates something atypical has emerged (such as drug allergy or drug failure), following the outline of clinical care produced by the IIHTT seems prudent. Rebuttal: Dr. Friedman It appears that Dr. Kaufman and I agree that the results of the IIHTT provide the standard of care for treating patients with IIH with mild visual loss with PMD between 22 and 27 dB. It has been estimated that the degree of visual loss experienced by patients enrolled in the IIHTT only account for about one-third of all patients with IIH. Therefore most patients with IIH have either better or worse vision than Kaufman and Friedman: J Neuro-Ophthalmol 2017; 37: 182-186 those included in the clinical trial, and other treatment strategies may be more appropriate for them. A proposal for a surgical treatment trial for patients with IIH and moderate-to-severe visual loss has been submitted to the NEI. This study would enroll patients who have received maximal medical treatment of acetazolamide with diet (and furosemide, if needed). They would either undergo optic 185 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point nerve sheath fenestration or ventriculoperitoneal shunting. I am hopeful that such a study will be funded to help us treat our more severely affected patients than those studied in the IIHTT. Conclusion: Drs. Lee and Van Stavern The results of the IIHTT delivered Level 1 evidence for management of patients with IIH. However, applying the results of any clinical trial to an individual involves judgment on the part of the clinician, taking into account the specific details of each patient, including visual field loss, symptoms of intracranial hypertension, and medical comorbidities. The IIHTT provides a framework for evidence-based decision making about patients with IIH and mild visual loss. This is a first step in creating evidence-based paradigms in the treatment of patients with IIH, leading to improvement in clinical outcomes. REFERENCES 17. Lubow M, Kuhr L. Pseudotumor cerebri: comments on practical management. In: Glaser JS, Smith JL, eds. Neuro-ophthalmology. Vol IX. St. Louis, MO: CV Mosby, 1976:199-206. 18. Tomsak RL, Niffenegger AS, Remler BF. Treatment of pseudotumor cerebri with Diamox (acetazolamide). J Clin Neuroophthalmol. 1988;8:93-98. 19. Talan J. A randomized trial confirms efficacy of acetazolamide for idiopathic intracranial hypertension. Neurol Today. 2015;15:15-16. 20. Wall M. Idiopathic intracranial hypertension. Neurol Clin. 2010:593-617. 21. Thambisetty M, Lavin P, Newman N, Biousse V. Fulminant idiopathic intracranial hypertension. Neurology. 2007;16:229- 232. 22. Lueck C, McIllwaine G. Interventions for idiopathic intracranial hypertension. Cochrane Database Syst Rev. 2005;20:CD003434. 23. Volpe NJ. Idiopathic intracranial hypertension: important questions answered with more to come. JAMA Neurol. 2014;71:678-680. 24. Aylward SC, Aronowitz C, Reem R, Rogers D, Roach ES. Intracranial hypertension without headache in children. J Child Neurol. 2015;30:703-706. 25. Lampi C, Maracek S, May A, Bendtsen L. A prospective, openlabel, long-term study of the efficacy and tolerability of topiramate in the prophylaxis of chronic tension-type headache. Cephalalgia. 2006;26:1203-1208. 26. Chen JJ, Thurtell MJ, Longmuir RA, Garvin MK, Wang JK, Wall M, Kardon RH. Causes and prognosis of visual acuity loss at the time of initial presentation in idiopathic intracranial hypertension. Invest Ophthalmol Vis Sci. 2015;56:3850-3859. 27. Newborg B. Pseudotumor cerebri treated by rice/reduction diet. Arch Int Med. 1974;133:802-807. 28. Johnson LN, Krohel GB, Madsen RW, March GA Jr. The role of weight loss and acetazolamide in the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Ophthalmology. 1998;105:2313-2317. 29. Kupersmith MJ, Gamell L, Turbin R, Peck V, Spiegel P, Wall M. Effects of weight loss on the course of idiopathic intracranial hypertension. Neurology. 1998;50:1094-1098. 30. Sugarman HJ, Felton WL III, Salvant JB, Sismanis S, Kellum JM. Effects of surgically induced weight loss on idiopathic intracranial hypertension in morbid obesity. Neurology. 1995;45:1655-1659. 31. Sinclair AJ, Burdon MA, Nightengale PG, Ball AK, Good P, Matthews TD, Jacks A, Lawden M, Clarke C, Stewart PM, Walker EA, Tomlinson JW, Raiz S. Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study. BMJ. 2010;341:c2701. 32. Ireland B, Corbett JJ, Wallace RB. The search for causes of idiopathic intracranial hypertension. A preliminary case-control study. Arch Neurol. 1990;47:315-320. 33. Friedman DI, Streeten DH. Idiopathic intracranial hypertension and orthostatic edema may share a common pathogenesis. Neurology. 1998;50:1099-1104. 1. Wall M, Kupersmith MJ, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keitner JL, Schron EB, McDermott MP; NORDIC Idiopathic Intracranial Hypertension Study Group. The idiopathic intracranial hypertension treatment trial clinical profile at baseline. JAMA Neurol. 2014;71:693-701. 2. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee, Wall M, Schron EB, Kupersmith MJ. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014;311:1641-1651. 3. Durcan FJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri: population studies in Iowa and Louisiana. Arch Neurol. 1988;45:875-877. 4. Corbett JJ, Savino PJ, Thompson HS, Kansu T, Schatz NJ, Orr LS, Hopson D. Visual loss in pseudotumor cerebri: follow-up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol. 1982;39:461- 474. 5. Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol. 2006;5:433-442. 6. Paterson R, Depasquale N, Mann S. Pseudotumor cerebri. Medicine (Baltimore). 1961;40:85-99. 7. Jefferson A, Clark J. Treatment of benign intracranial hypertension by dehydrating agents with particular reference to the measurement of the blind spot area as a means of recording improvement. J Neurol Neurosurg Psychiatry. 1976;39:627-639. 8. Pollay M, Fullenwider C, Roberts P, Stevens FA. Effect of mannitol and furosemide on blood-brain osmotic gradient and intracranial pressure. J Neurosurg. 1983;59:945-950. 9. McCarthy K, Reed D. The effect of acetazolamide and furosemide on CSF production and choroid plexus carbonic anhydrase activity. J Pharmacol Exp Ther. 1974;189:194-201. 10. Neblett CR, Waltz TA, McNeel DP, Harrison GM. Effect of cardiac glycosides on human cerebral spinal fluid production. Lancet. 1972;2:1008-1009. 11. Schott GD, Holt D. Digoxin in benign intracranial hypertension (letter). Lancet. 1974;1:312-313. 12. Hannerz J. Decrease of intracranial pressure and weight with digoxin in obesity. J Clin Pharmacol. 2001;41:465-468. 13. Haagensen J, Hoegerl C. Digoxin and a treatment for patients with idiopathic intracranial hypertension. J Am Osteopath Assoc. 2014;114:213-215. 14. Pagan FL, Restrpo L, Balish M, Patwa HS. Houffs. A new drug for an old condition? Headache. 2002;42:695-696. 15. Friedman DI, Eller PF. Topiramate for the treatment of idiopathic intracranial hypertension. Headache. 2003;43:592. 16. Celebisoy N, Gokcay F, Sirin H, Akyureki O. Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study. Acta Neurol Scand. 2007;116:322-327. 186 Kaufman and Friedman: J Neuro-Ophthalmol 2017; 37: 182-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.