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Obesity and Weight Loss in Idiopathic Intracranial Hypertension: A Narrative Review

Subramaniam, Suresh MD, MSc, FRCPC; Fletcher, William A. MD, FRCPC

Editor(s): Biousse, Valérie MD; Galetta, Steven MD

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Journal of Neuro-Ophthalmology: June 2017 - Volume 37 - Issue 2 - p 197-205
doi: 10.1097/WNO.0000000000000448
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Abstract

Idiopathic intracranial hypertension (IIH) is a condition of unknown etiology, which typically occurs in women of childbearing age (1). Over 90% of patients with IIH are obese or overweight. Weight loss is recognized as an effective treatment (2). We review the linkage of IIH with obesity, the pathogenesis of IIH with regard to obesity and the evidence for weight loss and weight-loss interventions in IIH.

OBESITY AND IDIOPATHIC INTRACRANIAL HYPERTENSION

Obesity presents a major public health challenge. In 2014, over two thirds of US adults were overweight, defined as a body mass index (BMI) ≥25 kg/m2 and one third was obese (BMI ≥30 kg/m2) (3). In 2008, the estimated annual medical cost related to obesity in the United States was $147 billion (4).

Evidence Supporting the Association of Obesity and Idiopathic Intracranial Hypertension

Several epidemiological studies have shown a strong association of IIH with obesity. Approximately 70%–80% of IIH patients are obese and over 90% are overweight (5–9). In the United States, the annual age-adjusted incidence of IIH in women is 1–3 per 100,000. The incidence increases to 12–19 per 100,000 in obese women. Similarly, the overall prevalence of IIH in women is 11 per 100,000 but increases to 86 per 100,000 in those who are obese (10–13). Furthermore, the risk of developing IIH increases with increasing BMI and percent weight gain. The odds ratio increases from 19.5 with a BMI of 30–35 kg/m2 to 26 with a BMI >35 kg/m2 and from 3.6 with a 5%–10% annual weight gain to 15.2 with 11%–15% annual weight gain (14). Nonobese patients (BMI <30 kg/m2) also are at greater risk of IIH if they have a recent weight gain of 5% or more (14). After IIH resolves, the risk of recurrence increases with weight gain (15,16). A study of recurrent IIH found a mean weight gain of 6% before the recurrence (16), mirroring the mean weight loss at which IIH resolves. The BMI at the time of recurrence was typically greater than that at initial diagnosis.

The role of obesity in IIH development in males is less clear. Kesler et al (17) reported that only 25% of men in their IIH cohort were overweight compared with 78% of women. Digre and Corbett (18) also found that men with IIH were less obese, and also had more vision loss than women. In a study of 66 men and 655 women with IIH, Bruce et al (19) found no difference in BMI between men and women but men were twice as likely to suffer serious vision loss. Another difference was that 24% had obstructive sleep apnea compared with 4% of women. Men with IIH may be at a greater risk for severe vision loss and obstructive sleep apnea (20) but whether they are less likely to be obese remains unclear.

Visual Outcomes in Idiopathic Intracranial Hypertension as a Function of Obesity

IIH patients with higher BMIs tend to have worse visual outcomes, especially if the BMI exceeds 40 kg/m2. A BMI ≥40 kg/m2 is more likely to be associated with severe papilledema at first neuro-ophthalmology visit than those with a lower BMI. Szewka et al (7) showed a trend towards more severe vision loss in patients with BMI >40 kg/m2. Each 10-kg/m2 increase in BMI confers a 1.4 times increased risk of severe vision loss. IIH patients with BMI >40 kg/m2 also have a higher prevalence of visual field defects (21).

Postulated Mechanisms of Idiopathic Intracranial Hypertension Development in Obesity

The pathophysiology of IIH is unclear and the mechanism by which obesity contributes to the development of IIH is poorly understood. Several mechanisms have been proposed but none are able to account for all features of the disease.

An increase in the rate of cerebrospinal fluid (CSF) production has been proposed to cause IIH but the results of the few relevant studies have been inconclusive. Using data from ventricular infusion studies, Donaldson (22) calculated that the rate of CSF secretion was elevated in 5 patients with IIH. Using data from velocity-sensitive magnetic resonance imaging mapping, however, Gideon et al (23) found no significant difference in CSF production in IIH patients and controls.

Several experimental and clinical studies of IIH suggest a disturbance of absorption of CSF at its interface with venous compartments (22–25). One hypothesis is that occult microthrombosis occurs within the dural venous sinuses in the vicinity of arachnoid granulations, impeding CSF absorption. Two studies of IIH patients (26,27) found a high prevalence of prothrombotic abnormalities, including antiphospholipid antibodies, abnormal protein S levels, Factor 5 Leiden, and prothrombin 20,210 mutations. One of the studies, however, showed that the prothrombotic conditions were more common in nonobese IIH patients (26) and the other study (27) controlled for age but not for obesity (a known risk factor for thromboembolism) (28,29). Occult thrombotic obstruction to CSF absorption also has been suggested to explain the link between IIH and polycystic ovarian syndrome (PCOS) (30–33). A study of 25 patients with both IIH and PCOS (34) showed a high prevalence of thrombophilic abnormalities. Thirty-eight percent had homozygous methylenetetrahydrofolate reductase mutations and 29% had thrombophilic increased lipoprotein A levels. Both abnormalities were 3 times more common in patients than in controls. Thrombophilic concentrations of factor VIII also occurred in 14% of the patients but in none of the controls. A weakness of this study again was that the controls were not matched for BMI. Also, we found no pathological reports of venous sinus microthombi in IIH.

Obesity also elevates intra-abdominal pressure (35,36), which increases pleural and cardiac filling pressures and impedes venous return from the brain. The resulting increase in intracranial venous pressure may reduce CSF absorption. Increased abdominal pressure also may limit the expansion of spinal canal CSF spaces and alter CSF homeostasis (37,38). It has been proposed that obese patients who develop IIH do so by virtue of having greater central obesity due to accumulation of adipose tissue around abdominal organs. When IIH patients have been compared with obese controls, no predisposition to central obesity has been found (39) and, however, Kelser et al (40) showed that IIH patients have greater adiposity below the waist rather than above the waist. Also, other conditions associated with increased central venous pressures, such as primary pulmonary hypertension, are not reported to cause IIH.

Hormonal factors may play a role in causing IIH. Adipocytes secrete the hormone leptin, which regulates appetite, food intake, and body weight. Leptin levels are normally proportional to total body fat content (41). An absence of leptin or leptin resistance can lead to uncontrolled feeding and weight gain (42). In a case-control study, higher serum leptin levels were found in 15 IIH patients when compared with an age- and BMI-matched control group (43). The hyperleptinemia may be a secondary effect, however, since leptin is found in higher levels in subcutaneous fat compared with visceral fat and the distribution of obesity in IIH favors subcutaneous fat deposition (44). Leptin also enters the CSF through the choroid plexus (45,46) but may be impeded by elevated CSF pressure, creating a “leptin resistance state.” Leptin is also prothrombotic through its action on a platelet leptin receptor (47), possibly leading to venous sinus microthrombosis.

Ball et al (48) found that IIH patients had higher CSF leptin levels compared with controls after correction for age, gender, and BMI and suggested that obesity in IIH may occur as a result of hypothalamic leptin resistance.

Sodium homeostasis also may be impaired in IIH patients. Dietary sodium intake may influence body weight, subcutaneous fat, and leptin levels (49). A study of 30 women with IIH (50) found that 77% had orthostatic peripheral edema compared with none of 22 obesity-matched controls. Eighty percent of IIH patients also had abnormal orthostatic retention of sodium or water. The impairment of saline and water excretion was similar to that of a group of nonobese patients with idiopathic orthostatic edema, suggesting a common pathogenetic mechanism. Five of 12 IIH patients treated with a diuretic lost weight (up to 9 kg) and had less diurnal weight gain but diuretics were not given to obesity-matched controls to determine whether this effect was specific to IIH.

Other factors proposed to play a role in the pathogenesis of IIH include inflammation and cortisol dysregulation. Obesity has been shown to be associated with chronic low grade inflammation and an abnormal pro-inflammatory cytokine profile (51,52). In a study of 26 IIH patients, however, profiles of inflammatory cytokines other than leptin did not differ from those of obese controls (48). Also, levels of inflammatory markers correlate more strongly with indices of central obesity than BMI (51) and central obesity is less marked in IIH patients than an obese cohort without IIH (40). Obesity also is associated with dysregulation of the intracellular enzyme, 11beta-hydroxysteroid dehydrogenase (11β-HSD1). 11β-HSD1 mediates local cortisol availability and also may affect CSF production and homeostasis through its expression in choroid plexus epithelium and arachnoid granulation tissue (52–55). Sinclair et al (56) studied 25 IIH patients before and after a 3-month very-low-calorie diet and found a reduction in global 11β-HSD1 activity after weight loss. They suggested that elevated 11β-HSD1 may represent a pathogenetic mechanism in IIH. However, a similar reduction in global 11β-HSD1 activity was also seen in 31 obese women without IIH after weight loss (57).

THE EVIDENCE FOR WEIGHT LOSS IN THE TREATMENT OF IDIOPATHIC INTRACRANIAL HYPERTENSION

Weight loss is advocated in the treatment of IIH based on the association of IIH with obesity and the results of retrospective studies and uncontrolled trials (58–61) (Table 1). In 1974, Newborg (58) reported 9 IIH patients treated with Kempner's rice/reduction diet, comprising a daily allowance of 400–1,000 calories, 750–1,250 mL fluid, and less than 100 mg sodium. Within 3 months, the patients lost 13%–38% of body weight and had resolution of papilledema. Visual function was not reported. Kupersmith et al (59) reviewed the charts of 58 IIH patients treated with weight loss and diuretics. Papilledema resolved in 74% of the 38 patients who lost weight compared with 40% of those who did not lose weight. The mean time for patients to improve one papilledema grade was 4 months if they lost weight compared with 6.7 months if they lost no weight. The improvement of visual field also was 3 times faster with weight loss (4.6 vs 12.3 mo). Johnson et al (60) retrospectively analyzed 15 IIH patients at 24 weeks or less after treatment with a weight reduction diet and acetazolamide. Ten patients (67%) had complete resolution of papilledema after an average weight loss of 6%. None of the patients who failed to lose weight improved despite similar treatment with acetazolamide.

T1
TABLE 1.:
Weight loss studies in patients with idiopathic intracranial hypertension

Sinclair et al (61) prospectively treated 25 women for 3 months with a very low energy diet (425 cal per day). Before the trial, the patients had stable IIH with a mean duration of 39 months. Eleven patients also were taking acetazolamide. After 3 months, the 20 patients who completed the study had lost an average of 15.7 kg. Cerebrospinal fluid pressure fell by an average of 8 cm H2O and headaches and papilledema improved. There was no correlation, however, between amount of weight loss and change in intracranial pressure. The weight loss and other outcome measures were maintained at 3 months after stopping the diet.

Based on the data reviewed above and the shared experience of physicians who treat IIH, there is general consensus that moderate weight loss often leads to the resolution of IIH. A randomized controlled trial of weight loss therapy would be useful but the existing consensus may make such a trial impossible.

The Role for Bariatric Surgery in Idiopathic Intracranial Hypertension

Bariatric surgery is a proven weight-loss method for morbidly obese patients and is effective at reducing excess body weight over the long term (62). There are no prospective studies of its use in IIH but it may be helpful in selected patients (63–66). In a literature review in 2011, Fridley et al (63) found 62 reported cases of IIH treated with bariatric surgery, comprising mostly gastric bypass surgery. Of the patients for whom data were available, 92% had resolution of IIH symptoms, 97% had resolution of papilledema, and 92% had complete or nearly complete resolution of visual field deficits. The mean decrease in CSF opening pressure on lumbar puncture after surgery was 25 cm H2O.

The optimal timing and indications for bariatric surgery in IIH are unknown. It may be appropriate for obese patients who continue to have moderate or severe IIH despite medical treatment, and for IIH patients who fail surgical treatment (optic nerve sheath fenestration, CSF diversion). A recent review of bariatric surgery can be found in this journal (67).

WEIGHT LOSS IN THE IDIOPATHIC INTRACRANIAL HYPERTENSION TREATMENT TRIAL

Study Design of the Idiopathic Intracranial Hypertension Treatment Trial

The idiopathic intracranial hypertension treatment trial (IIHTT) was a randomized, double blind, placebo-controlled study of acetazolamide therapy in IIH (68). The main objective was to evaluate whether acetazolamide was beneficial in improving vision in IIH patients with mild vision loss when added to a low-sodium weight-reduction diet. Patients were enrolled if Humphrey 24-2 perimetric mean deviation (PMD) in the worse eye was between −2 and −7 dB. The primary outcome variable at 6 months was the change in PMD. Secondary outcomes included weight loss and changes in papilledema, quality of life and headache disability. One hundred sixty-five IIH patients were enrolled; 161 were women. The mean age was 29 years. All patients received a lifestyle modification program, including diet, and were randomized to treatment with either acetazolamide (maximum 4 g per day) or placebo.

Weight Loss Intervention in the Idiopathic Intracranial Hypertension Treatment Trial

The weight loss program in the IIHTT was designed by the New York Obesity Nutrition Research Center (NYORNC). It was implemented through a patient workbook based on a 52-week outpatient program, comprising dietary, exercise, and behavioral interventions (Fig. 1). Weight loss education and counseling were provided over the telephone by trained coaches. The weight loss goal was 6% at 6 months and 10% at 12 months, with a weekly goal of 1–2 lbs.

F1
FIG. 1.:
Components of weight loss program designed for the idiopathic intracranial hypertension treatment trial (68) by New York Obesity Research Nutrition Centre.

Daily caloric needs were estimated based on age, gender, height, weight, and activity level. A balanced diet was designed to provide 20% of calories from protein, 25%–30% from fat and the remainder from carbohydrates. Patients were encouraged not to add salt to meals and informed of low sodium options. The exercise goal was 30–60 minutes of moderate-intensity exercise (or 20–60 minutes of vigorous-intensity exercise) daily for at least 5 days per week. Patients were advised on aerobic and resistance exercise, walking tips, and working out at a gym or at home. The behavioral intervention comprised cognitive behavioral therapy (CBT), which is an established treatment for obesity (69–74). CBT covered goal setting, relapse prevention, motivation, managing cravings and urges, good sleep hygiene, and lifestyle balance.

Results of the Idiopathic Intracranial Hypertension Treatment Trial: The Role of Weight Loss

The PMD showed significantly more improvement at month 6 in the acetazolamide group compared with the control group (68). Patients treated with acetazolamide lost more weight over 6 months (mean loss 7.5 kg; 7.8%) than those given placebo (mean loss 3.5 kg; 3.5%). Compared with the control group, the acetazolamide group also showed a greater decrease in mean BMI (3.3 vs 1.3) and waist circumference (8.6 vs 3.9 cm). Also, 28% of the control group gained weight compared with only 13% in the acetazolamide group. Acetazolamide-treated patients had a significant improvement in quality of life measures, which may have allowed them to pursue weight loss more diligently. It is also possible that acetazolamide caused greater weight loss by reducing appetite.

Although patients treated with acetazolamide averaged over twice the weight loss to those on placebo, analysis suggested that the improvement of visual fields in the acetazolamide-treated group was not mediated by weight loss. The total effect of acetazolamide on PMD was estimated to be 0.75 dB, with only 0.03 dB attributed to the indirect effect of weight loss. The IIHTT was not designed, however, to address the effect of weight loss since both treatment arms received weight loss intervention. Most of the control group also lost weight and had a mean improvement in PMD. The consensus of the authors was that weight loss likely had a modest effect on improving visual outcomes in the IIHTT and should be advocated strongly as a component of IIH therapy.

MANAGING WEIGHT LOSS IN IDIOPATHIC INTRACRANIAL HYPERTENSION PATIENTS

Neuro-ophthalmologists typically play a major role in IIH management and are often the first to advise patients on the importance of weight loss. Patients may be more motivated if they are made aware that IIH often resolves with weight loss of only 6%–10% and, once resolved, often recurs after a similar weight gain. It is widely recognized, however, that self-directed measures are often ineffective in achieving weight loss. In a 2-year study of obese patients who directed their own weight loss after initial coaching, less than 20% had loss of at least 5% of their baseline weight (75).

Weight Loss Programs

Multidisciplinary care aimed at practical approaches to lifestyle modification is endorsed by the National Heart, Lung, and Blood Institute (NHLBI) and the North American Association for the Study of Obesity (76). In collaboration with the NHLBI, the American College of Cardiology and the American Heart Association recommend a diet of 1,200–1,500 cal per day for women and 1,500–1,800 cal per day for men (adjusted for body weight) and at least 150 min per week of moderate-intensity physical activity, for example, 20–30 minutes of walking daily at 4 mph (expending 4–5 cal per minute) (62). These measures should induce a caloric deficit of at least 500 cal per day and confer weight loss of at least 0.5 kg per week. Moderate intensity, on-site comprehensive lifestyle interventions, which provide 1–2 treatment sessions per month, typically produces mean weight losses of 2–4 kg over 6–12 months. High-intensity interventions (≥14 sessions over 6 months) typically produce greater weight losses and are associated with significant improvement in weight-related health conditions. Many commercial weight loss programs also are effective over the short term. A systematic review of 39 randomized controlled trials (RCTs) (77) suggested that several commercial programs were at least as effective as education and counseling.

A major challenge of obesity treatment is the maintenance of weight loss over the long term. To improve long-term adherence to weight management, comprehensive lifestyle modification programs typically combine diet and physical activity with cognitive and behavioral strategies. Behavioral therapy often includes the use of goal setting, self-monitoring, feedback, reinforcement, self-motivation, and incentives. In 2010, Christian et al (78) reviewed published lifestyle modification trials that included 1-year outcomes and found that weight loss of 5% or more was maintained in 54% of participants in high-intensity programs (total duration 13–52 hours, mean 37 hours), 29% in low-intensity programs (1–9 hours, mean 5 hours), and 20% in a self-help program. In a case-control study (79), 4 months after receiving 8 hours of cognitive behavioral therapy (CBT), participants had lost an average of 3.1% of baseline weight, whereas the control group had gained 1.2%. Similarly, the control group in the IIHTT received CBT and lost an average of 3.5% of baseline weight over 6 months.

After an initial period of successful weight loss, however, most patients regain weight. In a RCT comprising 150 obese women (69), over 70% of participants receiving CBT or standard behavioral therapy had lost at least 5% of their initial weight over 44 weeks, as compared with 35% in a control self-help group. One year later, however, participants in both therapy groups had regained about 50% of the weight previously lost. After 3 years, they had regained almost 90%. Similarly, in a large RCT of weight maintenance over 30 months, after initial weight loss averaging almost 9 kg, Svetkey et al (80) found that both self-directed and behavioral intervention groups regained weight, especially over the first year. However, participants receiving a monthly personal contact intervention maintained an average of 5 kg of weight loss compared with 3.5 kg in the self-directed group, and a significantly higher proportion of the intervention group (42.2% vs 33.9%) maintained weight loss of 5% or more. A follow-up study at 60 months showed that the differences between groups were unchanged (whether or not the intervention had continued after 30 months) (81). A systematic review of RCTs (82) concluded that the overall mean additional weight loss attributed solely to behavioral interventions was 2 kg at 18 months, 1.5 kg at 24 months, and 0.85 kg at 30 months (but only 2 RCTs provided data beyond 18 mo). Very few RCTs of commercial weight loss programs extend beyond 12 months. A systematic review in 2015 (77) concluded that the Jenny Craig program provides 4.9% greater weight loss at 12 months as compared with education or behavioral therapy. Weight Watchers is the most cost-effective commercial program and provides 2.6% greater weight loss compared with education but whether it is better than behavioral therapy is unclear.

Drug Therapy for Obesity

Anti-obesity drugs have played little or no role in the management of IIH and we found no trials of these drugs in IIH patients. Most anti-obesity drugs approved before 2012 were later removed from the market due to safety concerns. The only drug remaining and approved for long-term weight management was orlistat. Recently, however, research regarding weight regulation has accelerated (perhaps energized by the global obesity epidemic), leading to the development of new and more effective anti-obesity drugs. Such drugs likely will play an increasing role in the treatment of obesity and, eventually, IIH.

Orlistat is a pancreatic lipase inhibitor that impairs the absorption of fat. A systematic review of orlistat trials (83) suggested that, when added to a behavioral program and a lower fat diet, higher-dose orlistat causes on average 3.1% greater weight loss than placebo over 12 months and 2.7% greater loss over 4 years. The proportion of patients maintaining at least 5% weight loss on orlistat ranges from 35% to 73% and on average is 23% greater than placebo. Unpleasant gastrointestinal side effects may occur due to undigested triglycerides in the stool and over 90% of patients prescribed orlistat stop taking it within a year.

Between 2012 and 2014, 4 new drugs or drug combinations were approved in the USA for chronic weight loss management: locaserin, phentermine-topiramate, naltrexone-bupropion, and liraglutide. Lorcaserin, a selective 5-HT2C agonist that suppresses appetite (84), was studied in 3 RCTs. On average, 44% of patients on Locaserin had weight loss of ≥5% at 12 months as compared with 20.5% on placebo (83–88). Mild side effects include headache, dizziness, nausea, and fatigue. An extended release formulation combining phentermine, which is an amphetamine derivative, and topiramate, an antiepileptic known to promote weight loss, was approved for treating obesity after 2 large RCTs showed a large benefit at 12 months. Weight loss of ≥5% was observed in 45% of patients on the lowest dose, in 62% of those on the recommended usual dose, in 70% on the top dose and in 18.5% of those given placebo (89,90). Mild side effects commonly linked with phentermine-topiramate include paresthesias, palpitations. and increased heart rate. For women of childbearing age (most IIH patients), topiramate poses a potential teratogenic risk. A sustained-release formulation of bupropion, which inhibits noradrenaline and dopamine reuptake, combined with naltrexone, an opioid antagonist, has been studied in 4 RCTs (91–93). Patients were followed for up to 56 weeks. Weight loss of ≥5% was observed on average in 52% of patients on active drug as compared with 24% on placebo. The most common side effects include nausea, constipation, headache, and insomnia. Liraglutide is a long acting analogue of glucagon-like peptide-1, which has multiple antiobesity actions (94) and requires a daily subcutaneous injection. A 56-week double blind RCT enrolled over 3,700 patients (95). Weight loss of ≥5% was observed in 63% of the liraglutide group as compared with 27% of the placebo group. Mild or moderate nausea and diarrhea were the most frequent side effects and caused 6.4% of the patients to withdraw from the study. Another RCT enrolled 422 patients who had already lost ≥5% of their initial weight during a low-calorie-diet “run-in” (96). Over the following 56 weeks, 81% of patients on liguratide maintained weight loss of at least 5% as compared with 49% on placebo. Further weight loss ≥5% after enrollment was observed in 51% of patients on liguratide as compared with 22% on placebo. More information on these drugs and other promising obesity medications can be found in recent reviews (88,94,97).

Weight loss is an effective component of IIH management. Over the long term, lifestyle modification programs can provide a modest but significant improvement in maintaining weight loss. Selected commercial weight loss programs may also be helpful. As more data on long-term effectiveness, safety, and cost accumulate, anti-obesity drugs may play a future role in treating IIH.

STATEMENT OF AUTHORSHIP

Category 1: a. Conception and design: S. Subramaniam and W. A. Fletcher; b. Acquisition of data: S. Subramaniam and W. A. Fletcher; c. Analysis and interpretation of data: S. Subramaniam and W. A. Fletcher. Category 2: a. Drafting the manuscript: S. Subramaniam and W. A. Fletcher; b. Revising it for intellectual content: S. Subramaniam and W. A. Fletcher. Category 3: a. Final approval of the completed manuscript: S. Subramaniam and W. A. Fletcher.

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