The incidence of idiopathic intracranial hypertension in Israel from 2005 to 2007: results of a nationwide survey

European Journal of Neurology 2014 doi:10.1111/ene.12442 The incidence of idiopathic intracranial hypertension in Israel from 2005 to 2007: results of a nationwide survey A. Kesler a,b, N. Stolovic a, Y. Bluednikov c and T. Shohat c,d a Neuro-ophthalmology Unit, Department of Ophthalmology, Tel-Aviv Sourasky Medical Center, Tel Aviv; b Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; c Israel Center for Disease Control, Ministry of Health, Tel Hashomer; and d Department of Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Keywords: idiopathic intracranial hypertension, incidence, Israel Received 18 November 2013 Accepted 6 March 2014 Background and purpose: Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri, is a disorder related to increased intracranial pressure without clinical, laboratory or radiological evidence of an intracranial space occupying lesion or cerebral sinus vein thrombosis, predominantly affecting obese women of childbearing age. Our aim was to determine the incidence and clinical features of IIH in Israel. Methods: In a cross-sectional study, all medical records of patients discharged from the hospital with a primary diagnosis of IIH during 2005 2007 were reviewed. Results: Four hundred and twenty-eight patients with a new onset of IIH were diagnosed. The average annual incidence rate was 2.02 per 100 000 with an incidence of 3.17 per 100 000 for women and 0.85 per 100 000 for men. The incidence rate in females of childbearing age (18 45) was 5.49 per 100 000. The female to male ratio for >17 years old was 6.1:1 (252 females and 41 males) and 2.1:1 (60 females and 28 males) for ages 11 17. Obesity was documented in 83.4% of patients. Body mass index (BMI) data were available for 159 (37.1%) patients; of these, 59.1% had a BMI 30. Conclusion: The incidence of IIH in Israel has increased during the last decade. This finding could be related to the increasing rates of obesity. The association of IIH and obesity should be further explored especially with regard to the effect of weight reduction for primary prevention. Introduction Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri (PTC), is a disorder related to increased intracranial pressure without clinical, laboratory or radiological evidence of an intracranial space occupying lesion or cerebral sinus vein thrombosis, predominantly affecting obese women of childbearing age [1 3]. The association between obesity and IIH is well established; >90% of women and >60% of men who suffer from this disorder are obese [2 4]. The annual incidence of IIH in the general population has been estimated as 1 2 per 100 000 [2,5,6]. However, the incidence has risen to 3.5 12 per 100 000 in women aged 20 44 years, and to 7.9 21 per 100 000 amongst obese women in the same age group [3 5]. Correspondence: A. Kesler, Neuro-ophthalmology Unit, Department of Ophthalmology, Tel Aviv Sourasky Medical Center, 6 Weizmann St, Tel Aviv 64239, Israel (tel.: +972 3 6973868; fax: +972 3 6973867; e-mail: kesler@netvision.net.il). Idiopathic intracranial hypertension is relatively uncommon in men, with reported female to male ratios of 4.3:1 to 8:1 [3,7]. A recent large series confirmed that only about 10% of IIH patients are men [8]. Despite a high predilection in obese young women, IIH can occur in children, older adults, and in non-obese persons of either sex [6,9,10]. In 2001, our study relating to the incidence of IIH in Israel was published [5]. Subsequently, during the last decade, a rise in obesity has been documented worldwide. Since obesity is the only known risk factor for the development of IIH, here the incidence of IIH in the Israeli population from 2005 to 2007 was studied and whether the incidence rate of IIH had risen in our population was examined. Methods In Israel, patients with suspected IIH are routinely hospitalized in tertiary hospitals with neurology departments or in medical centers with a neuro-ophthalmology 1

2 A. Kesler et al. unit for further evaluation (Appendix). All the medical records departments in Israel at the time of the study were computerized. Lists of all patients discharged from the hospital with a primary diagnosis of IIH or PTC (ICD9 code 348.2) during 2005 2007 were generated. The medical records of all these patients were reviewed. Data on age at onset of symptoms, gender, population group (Jews or Arabs), country of birth, height, weight, body mass index (BMI), comorbidities, imaging reports and results of lumbar puncture were collected. Only cases in which the primary diagnosis of IIH was based on the modified Dandy criteria [1,4] and only newly diagnosed patients were included in the study. Patients with IIH without papilledema (normal optic disc) were ascertained but not included in the analyses. Patients with BMI > 30 were considered obese. When BMI was unavailable, the physician s diagnosis of obesity was used. The incidence of IIH in obese females and males aged 18 45 was calculated by dividing the number of obese patients in this age group by the estimated number of obese individuals in the Israeli population of the same age. The denominator was the number of individuals aged 18 45 (data from the Central Bureau of Statistics) multiplied by the prevalence of obesity in this age group [data published by the Israeli Center for Disease Control (Health in Israel)], performed separately for males and females. The study was approved by the Institutional Review Board Committee in each hospital. Statistical analysis Incidence rates for IIH were calculated as follows: numerator, all newly diagnosed patients with IIH during 2005 2007; denominator, the average Israeli population for those years as published by the Central Bureau of Statistics. Age, gender and population specific rates were calculated. A comparison between characteristics of symptomatic patients and asymptomatic patients was performed using the chi-squared test and the Student s t test when applicable. Comparisons between the age of onset, signs and symptoms of obese patients and non-obese patients were performed using the Student s t test for continuous variables and the chi-squared test for categorical variables. For this comparison, only patients with a documented BMI were included. Analysis was performed separately for patients >17 years and those 17 years. Results Data were collected from 19 medical centers including all hospitals with a neurology ward (except for a very small hospital that referred patients with IIH to a tertiary medical center nearby) and those with a neuroophthalmology unit. During 2005 2007, 919 patients were diagnosed with IIH; 491 did not meet the Dandy criteria or the first diagnosis was made prior to 2005. During these years, 428 patients experienced a new onset of IIH: 149 patients in 2005, 131 in 2006 and 148 in 2007. The total Israeli population for these 3 years was 21 163 900. The average annual incidence rate was 2.02 per 100 000 [95% confidence interval (CI) 1.83 2.21]. Incidence rates by population group, gender and specific age groups are shown in Table 1. No differences were shown in the incidence between Jews and Arabs and between different ethnic groups amongst Jews. Females had significantly higher rates compared with males. The highest incidence rate was observed in females of fertility age (18 45 years). In the young age group, females 11 17 years had significantly higher rates compared with males (4.93 vs. 2.19 per 100 000 respectively, P < 0.001). A majority of cases (339, 79.2%) were females (female to male ratio 3.8:1). In patients >17 years, the female to male ratio was 6.1:1 (252 females and 41 males), and 2.1:1 (60 females and 28 males) in patients aged 11 17. The mean age at diagnosis was 25.39 13.04. Age of diagnosis was significantly higher in females compared with males (26.40 12.25 and 21.6 15.20, P = 0.001). This was also found in the younger age group (12.75 3.71 in females and 10.42 4.94 in males, P = 0.006) but not in the older group (>17), where age at diagnosis was higher in males than females (34.62 12.48 and 31.17 10.50 respectively, P = 0.06). Most patients (407/428, 95.1%) were symptomatic. In both adults and adolescents, the most common symptom was headache (81.8% and 80.7%, respectively). Amongst adults, symptoms included blurred vision (50.9%), nausea and vomiting (25%), double vision (13%), dizziness (8%) and tinnitus (7.3%). Amongst adolescents, nausea and vomiting (32.6%), blurred vision (28.9%), double vision (15.6%) and dizziness (11.1%) were the most common complaints. Diagnosis of IIH was made inadvertently following a routine ophthalmological examination in 21 (4.9%) asymptomatic individuals. Patients >17 years were significantly more often symptomatic compared with the younger age group (odds ratio 3.80, 95% CI 1.54 9.09, P = 0.001). Females were significantly more often symptomatic compared with males (odds ratio 3.06, 95% CI 1.25 7.52, P = 0.01); 80.3% of symptomatic patients were females compared with

The incidence of IIH in Israel 3 Table 1 Average annual incidence of idiopathic intracranial pressure in Israel during 2005 2007 (per 100 000) Number of patients Population size Incidence 95% CI Total population 428 21 163 900 2.02 1.83 2.21 Population group Jews 339 16 978 400 1.99 1.78 2.57 Arabs 89 4 185 600 2.12 1.68 2.57 Age group 17 years 123 7 041 500 1.75 1.44 2.05 >17 years 293 14 123 200 2.07 1.84 2.31 Gender Males 89 10 457 800 0.85 0.67 1.02 Females 339 10 706 100 3.17 2.83 3.50 Males 0 10 20 2 333 200 0.86 0.48 1.23 Females 0 10 27 2 214 900 1.22 0.76 1.68 Males 28 1 277 300 2.19 1.38 3.00 11 17 years Females 60 1 216 000 4.93 3.68 6.18 11 17 years Males 33 4 163 500 0.79 0.52 1.06 18 45 years Females 227 4 134 200 5.49 4.78 6.20 18 45 years Obese 24 549 948 4.36 2.62 6.11 males 21 45 years (estimate) Obese females 21 45 years (estimate) 127 392 550 32.35 26.73 37.98 Country of origin (for Jews) Israel 89 5 621 700 1.58 1.25 1.91 Europe and 104 6 088 900 1.71 1.38 2.03 America Asia 53 2 073 600 2.55 1.87 3.24 Africa 56 2 576 700 2.17 1.60 2.74 57.1% of asymptomatic patients. No significant association was found between population group and symptoms (P = 0.2). In 357/428 patients (83.4%) a reference to obesity appeared in the medical records; 48.1% were described as obese. Information on BMI was available in 159 (37.1%) patients only; of these, 59.1% had a BMI 30. Time to diagnosis was significantly longer for those 17 (145.0 259.9 days) compared with the adult group (96.4 170.3) (P = 0.03). No statistical difference was found in opening pressure between females and males (368.93 and 349.24 mm respectively, P = 0.08) and between the pediatric group and the adult group (362.4 vs. 349.2 mm, P = 0.22). Eighteen patients (4.2%) were diagnosed with IIH without papilledema (signs of increased intracranial pressure, normal neuroimaging and high opening pressure with normal constituents). Seven patients (38.9%) were 17 years old. Discussion In this nationwide cross-sectional study, clinical and demographic information on patients with IIH was obtained from 19 medical centers including all hospitals with a neurology ward (except for a very small hospital that referred patients with IIH to a tertiary medical center nearby) and those with a neuro-ophthalmology unit in Israel. The average annual incidence rate in the general population was 2.02 per 100 000, two and half times higher than the rate found in Israel in 1998 1999 [5]. This increase was observed in females (1.82 per 100 000 in 1999 to 3.17 in the present study) and was much more profound in males (0.1 per 100 000 to 0.85 in the present study). However, since the present study and the previous one differ in their methodology, there are some concerns as to the magnitude of the difference. Both studies were conducted in all the relevant medical centers at the time of the study. In 1998 1999 there were 15 medical centers and in 2005 2007 three new centers were opened. In both studies these centers served the whole population. The definition of IIH was similar in both studies. The main difference between the studies is the method by which patients were ascertained. In 2005 all medical records departments were already computerized, which allowed patient ascertainment through the ICD9 code of the primary diagnosis. The study conducted in 1998 1999 relied on the reporting by chairmen of the relevant departments and could therefore have resulted in some underestimate of the true incidence of IIH. However, since the diagnosis of IIH is not common and on average there were only about eight patients per year in each medical center under-reporting is unlikely to explain a difference of 250%. Our findings corroborate previous studies showing that the highest incidence rate of IIH was amongst obese females of childbearing age [5,9,11,12] and that females were significantly more often symptomatic than males [13]. Noteworthy in the present study is the high incidence found in adolescents: 1.75 per 100 000 for 17 years old. However, when age and gender were considered, the incidence rate was 2.19 per 100 000 in males and 4.93 per 100 000 in females aged 11 17. Lower rates were reported in other studies. In Canada, the incidence rate was 0.9 per 100 000 in children and adolescents aged 2 15. When age and gender were considered, a higher incidence was found in females aged 12 16, 2.2 per 100 000 [14]. A recent German study found that the annual incidence for adolescents 17 years was 0.5 per 100 000 [15]. Female to male ratio for IIH in prepubertal IIH patients was 1.4. After puberty, a distinct female

4 A. Kesler et al. Country, year [reference] Total Female Female/male Females 18 45 Libya, 1986 [19] 1.7 3.6 1:0 10.3 74 USA, 1988 [3] 0.9 Iowa 8:1 3.5 67 1.1 Louisiana 4.3 3.5 69 USA, 1993 [20] 0.9 Minnesota 1.6 8:1 3.3 70 Libya, 1993 [21] 2.2 4.3 Japan, 2000 [22] 0.03 UK, 2001 [23] 0.51 0.86 Israel, 2001 [5] 0.94, 0.57 1.82 14:1 4.02 57 Italy, 2004 [24] 0.28 Spain, 2007 [25] 5.4 9:1 UK, 2011 [26] 1.56 2.86 14:1 Israel (present study) 2.02 3.17 3.8 5.49 59 Percent obesity Table 2 Incidence rates of idiopathic intracranial pressure in various studies (per 100 000) predominance emerged (2.2:1) as reported in other studies [16 18]. Obesity (identified by BMI) was observed in 59% of the study group. No significant differences were found between males and females. Information on BMI was available for only 37% of the patients, and this makes it difficult to draw a firm conclusion regarding obesity as the main contributor to this increase in incidence. However, our findings are in agreement with other studies (Table 2) [19 26]. Over the last decade, the prevalence of obesity in western countries has more than doubled [13]. It is possible that the increase in the incidence rate in the present study is attributed to the increasing rates of obesity in Israel. In 2002, the self-reported prevalence of obesity in Israel was 12.2% in males and 12.8% in females, with an increase of 32.8% in males and 19.5% in females to 16.2% and 15.3% in 2010 [27]. Our figures are generally higher than those reported in other countries (Table 2). The delay in diagnosis of IIH observed in the present study in subjects 17 years underlines the need for increased awareness of IIH in adolescents. Since 1972, when Lipton and Michelson [28] reported the first case of IIH without papilledema, several authors have reported patients with headache and IIH without papilledema [29]. In our study, 4.2% were diagnosed with IIH without papilledema; of them 61% were >17 years old. Conclusion In conclusion, IIH is a serious condition strongly associated with obesity and can cause severe visual loss. The findings in the present study suggest an increasing incidence that could be related to the obesity epidemic. It is important to explore whether weight loss can prevent IIH in susceptible individuals. Acknowledgements The authors thank Mrs Phyllis Curchack Kornspan for her editorial services. Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest. References 1. Ahlskog JE, O Neill BP. Pseudotumor cerebri. Ann Intern Med 1982; 97: 249 256. 2. Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic intracranial hypertension. Neurology 2002; 59: 1492 1495. 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. Radhakrishnan K, Ahlskog JE, Garrity JA, Kurland LT. Idiopathic intracranial hypertension. Mayo Clin Proc 1994; 69: 169 180. 5. Kesler A, Gadoth N. Epidemiology of idiopathic intracranial hypertension in Israel. J Neuroophthalmol 2001; 21: 12 14. 6. Bruce BB, Biousse V, Newman NJ. Update on idiopathic intracranial hypertension. Am J Ophthalmol 2011; 152: 163 169. 7. Kesler A, Goldhammer Y, Gadoth N. Do men with pseudomotor cerebri share the same characteristics as women? A retrospective review of 141 cases. J Neuroophthalmol 2001; 21: 15 17. 8. Bruce BB, Kedar S, Van Stavern GP, et al. Idiopathic intracranial hypertension in men. Neurology 2009; 72: 304 309. 9. Galvin JA, Van Stavern GP. Clinical characterization of idiopathic intracranial hypertension at the Detroit Medical Center. J Neurol Sci 2004; 223: 157 160. 10. Kesler A, Bassan H. Pseudotumor cerebri idiopathic intracranial hypertension in the pediatric population. Pediatr Endocrinol Rev 2006; 3: 387 392.

The incidence of IIH in Israel 5 11. Giuseffi V, Wall M, Siegel PZ, Rojas PB. Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case control study. Neurology 1991; 41: 239 244. 12. Wall M, George D. Idiopathic intracranial hypertension. A prospective study of 50 patients. Brain 1991; 114: 155 180. 13. Friesner D, Rosenman R, Lobb BM, Tanne E. Idiopathic intracranial hypertension in the USA: the role of obesity in establishing prevalence and healthcare costs. Obes Rev 2011; 12: e372 e380. 14. Gordon K. Pediatric pseudotumor cerebri: descriptive epidemiology. Can J Neurol Sci 1997; 24: 219 221. 15. Tibussek D, Distelmaier F, von Kries R, Mayatepek E. Pseudotumor cerebri in childhood and adolescence results of a Germany-wide ESPED-survey. Klin Padiatr 2013; 225: 81 85. 16. Phillips PH, Repka MX, Lambert SR. Pseudotumor cerebri in children. J AAPOS 1998; 2: 33 38. 17. Bassan H, Berkner L, Stolovitch C, Kesler A. Asymptomatic idiopathic intracranial hypertension in children. Acta Neurol Scand 2008; 118: 251 255. 18. Babikian P, Corbett J, Bell W. Idiopathic intracranial hypertension in children: the Iowa experience. J Child Neurol 1994; 9: 144 149. 19. Radhakrishnan K, Shridharan R, Ashok PP, Mousa ME. Pseudotumor cerebri: incidence and pattern in North-Eastern Libya. Eur Neurol 1986; 25: 117 124. 20. Radhakrishnan K, Ahlskog JE, Cross SA, Kurland LT, O Fallon WM. Idiopathic intracranial hypertension (pseudotumor cerebri): descriptive epidemiology in Rochester, Minn 1976 to 1990. Arch Neurol 1993; 50: 78 80. 21. Radhakrishnan K, Thacker AK, Bohlaga NH, Maloo JC, Gerryo SC. Epidemiology of idiopathic intracranial hypertension: a prospective and case control study. J Neurol Sci 1993; 116: 18 28. 22. Yabe I, Moriwaka F, Notoya A, Ohtaki M, Tashiro K. Incidence of idiopathic intracranial hypertension in Hokkaido, the northern-most island of Japan. J Neurol 2000; 247: 474 475. 23. Craig JJ, Mulholland DA, Gibson JM. Idiopathic intracranial hypertension: incidence, presenting features and outcome in Northern Ireland (1991 1995). Ulster Med J 2001; 70: 31 35. 24. Carta A, Bertuzzi F, Cologno D, Giorgi C, Montanari E, Tedesco S. Idiopathic intracranial hypertension (pseudotumor cerebri): descriptive epidemiology, clinical features, and visual outcome in Parma, Italy, 1990 to 1999. Eur J Ophthalmol 2004; 14: 48 54. 25. Asensio-Sanchez VM, Merino-Angulo J, Martınez-Calvo S, Calvo MJ, Rodriquez R. [Epidemiology of pseudotumor cerebri]. Archivos de la Sociedad Espanola de Oftalmologia 2007; 82: 219 221. 26. Raoof N, Sharrack B, Pepper IM, Hickman SJ. The incidence and prevalence of idiopathic intracranial hypertension in Sheffield, UK. Eur J Neurol 2011; 18: 1266 1268. 27. Israel Center for Disease Control (ICDC). Health Status in Israel 2010. Publication No. 333. Israel: Ministry of Health, 2011(Hebrew). 28. Lipton HL, Michelson PE. Pseudotumor cerebri syndrome without papilledema. J Am Med Assoc 1972; 220: 1591 1592. 29. Vieira DS, Masruha MR, Goncalves AL, et al. Idiopathic intracranial hypertension with and without papilloedema in a consecutive series of patients with chronic migraine. Cephalalgia 2008; 28: 609 613. Appendix Participating centers (in alphabetical order) who allowed access to the data Assaf Harofeh Medical Center, Zerifin, Israel: Titler J, Barzilai Medical Center, Ashkelon, Israel: Milo R, Bnai Zion Medical Center Haifa, Israel: Weller B, Carmel Medical Center Haifa, Israel: Meer J, Edith Wolfson Medical Center, Holon, Israel: Lampel Y, Emek Medical Center, Afula, Israel: Jabaly Habib H, Hadassah University Hospital, Jerusalem, Israel: Ben Hur T, PhD, Kahana S, Hillel Yaffe Hospital, Hadera, Israel: Carasso R, Kaplan Hospital, Rehovot, Israel: Leiba H, Meir Medical Center Kfar Saba, Israel: Klein K, Rabin Medical Center, Petach Tikva, Israel: Kalish H,, Reich E, Rambam Medical Center, Haifa, Israel: Shiler Y, Rivka Ziv Hospital, Tzfat, Israel: Shahein R, Shaare Zedek Medical Center, Jerusalem, Israel: Koren Lubezky, Sheba Medical Center, Tel Hashomer, Israel: Chapman J, Soroka University Medical Center, Be er Sheba: Wirgin I, Tel Aviv Medical Center, Tel Aviv, Israel: Kesler A, Western Galilee Hospital, Naharia, Israel: Gross B,