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Show Evidence of Multidomain Mild Cognitive Impairment in Idiopathic Intracranial Hypertension Dinah Zur, MD, Elvira Naftaliev, MD, Anat Kesler, MD Background: Idiopathic intracranial hypertension (IIH), a dis-order of unknown etiology, may occur in all age groups, but is most common in young obese women. Goals of treatment are to preserve vision and alleviate symptoms, including intractable headache, pulsatile tinnitus, and nausea. Cog-nitive function is not addressed routinely during clinical evaluation of IIH patients. The aim of our study was to test whether there is cognitive impairment in IIH patients and to evaluate the nature and characteristics of cognitive func-tions. Methods: Design-Prospective cross-sectional observa-tional study; Setting-Institutional;Study population-Thirty consecutive IIH patients (3 men and 27 women), mean age at time of testing was 34.4 years; Procedures-All par-ticipants completed a cognitive test battery; Outcome measures-Impairment of non-verbal memory, executive function, visual spatial processing, attention, motor skills, problem solving, and information processing speed in IIH patients. Results: Mean scores for all domain index scores were below average for age and education. The global cognitive score, attention, and visual spatial indices had the lowest scores. Conclusions: Our results indicate that patients with IIH have mild cognitive impairment. All domain measures apart from memory showed a statistically significant difference from normal individuals, indicating that there is a form of multidomain cognitive impairment in IIH. The relationship between cognitive impairment and chronically elevated intracranial pressures and its role in contributing to patient morbidity requires further study. Journal of Neuro-Ophthalmology 2015;35:26-30 doi: 10.1097/WNO.0000000000000199 © 2014 by North American Neuro-Ophthalmology Society Idiopathic intracranial hypertension (IIH) is a disorder of unknown etiology affecting predominantly obese women of childbearing age (1) The diagnosis is established accord-ing to the modified Dandy criteria (2). Scarce information exists as to the psychosocial impact and quality of life (QoL) of individuals with IIH. Consistently, a higher incidence of depression and anxiety has been reported in IIH patients compared with age- or weight-matched controls or neuro-ophthalmologic controls (3-5). Patients with IIH may complain of thought and concentration difficulty. However, there have been few studies of formal cognitive evaluation of this population. Sørensen et al (6) found a mild general intellectual impair-ment, mostly on verbal tests (6). Kaplan et al (7) published a case study showing depression and subjective complaints of concentration and memory deficits despite normal neuropsychological scores. A retrospective study reported impaired function in memory, learning, visuospatial skills, and language in 10 patients with IIH (8). Yri et al (9) conducted a prospective study showing cognitive impair-ment in newly diagnosed IIH patients. Considering the results of these reports and our impression that IIH influences cognitive functions, we evaluated cognitive functions in IIH patients who were not in the acute phase of the disease. METHODS Subjects Participants were recruited from the Neuroophthalmology Unit, at the Tel Aviv Medical Center, Tel Aviv, Israel. Thirty consecutive adult male and female patients diagnosed with IIH scheduled for routine clinical follow-up were offered to participate in this prospective study. Patients in the acute phase of the disease were not enrolled; the time of diagnosis or of a relapse had to be at least 2 months before cognitive testing. Patients with history of a major psychiatric disorder, major depression, any neurological disorder except IIH or use of psychotropic drugs were excluded. Department of Ophthalmology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Anat Kesler, MD, Department of Oph-thalmology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel; E-mail: kesler@netvision.net.il 26 Zur et al: J Neuro-Ophthalmol 2015; 35: 26-30 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Testing Procedure All participants completed a NeuroTrax battery of tests for mild cognitive impairment, which uses custom software installed on the testing computer (10). The computerized battery of tests used in this study (testing time: 30 minutes) sampled non-verbal memory, executive function, visual spatial processing, attention, motor skills, problem solving, and information processing speed. Outcome parameters for tests or test levels included accuracy, reaction time (RT), standard deviation (SD) of RT, and a composite score ([accuracy/RT] · 100). Nor-malized subsets of outcome parameters were averaged to produce 7 summary scores. The outcome parameters con-tributing to each index score were included. The Global Cognitive Score (GCS) was computed as the average of the index scores. NeuroTrax index scores and GCS, computed using the same methodology, have been used in other studies (11-13). The test results of the participants were compared with normative data in the NeuroTrax database. The normative sample is stratified according to age and education, and normalization of patient scores is accord-ing to the appropriate stratification. Normalization occurs automatically with upload of the test results to the NeuroTrax server. All individuals in the normative sample were tested in their primary language and diagnosed as cognitively healthy-as diagnosed by expe-rienced clinicians as part of academic research studies using MindStreams performed at a variety of research sites (14-17). The following are brief descriptions of the NeuroTrax tests included in our study. Non-Verbal Memory Eight pictures of simple geometric objects were presented, followed by a recognition test, in which 4 versions of each object were presented, each oriented in a different direction (Fig. 1A). Participants were required to remember the ori-entations of the originally presented objects. Go-No Go Test A series of large colored stimuli were presented at pseudorandom intervals (Fig. 1B). Participants were in-structed to respond as quickly as possible by pressing a mouse button if the color of the stimulus was any color except red, for which no response was made. Stroop Interference The Stroop is a well-established test of response inhibition (18) (Fig. 1C). The NeuroTrax Stroop test consists of 3 phases. Participants were presented with a pair of large colored squares, one on the left and the other on the right side of the screen. In each phase, the participants were instructed to choose as quickly as possible which of the 2 squares was a particular color by pressing either the left or right mouse button, depending on which of the 2 squares is the correct color. Visual Spatial Processing Computer-generated scenes containing a red pillar were presented (Fig. 1D). Participants were instructed to imagine viewing the scene from the vantage point of the red pillar. Four alternative views of the scene were shown as choices. Staged Information Processing Speed This test comprises 3 levels of information processing load: single digits, 2-digit arithmetic problems (e.g., 521), and 3-digit arithmetic problems (e.g., 3+221). For each of the 3 levels, stimuli were presented at 3 different fixed rates, incre-mentally increasing as testing continues. Participants were instructed to respond as quickly as possible by pressing the left mouse button if the digit or result was less than or equal to 4 and the right mouse button if it was greater than 4. "Catch" Game The Catch game is a motor screen assessing cognitive domains distinct from those in other NeuroTrax tests (Fig. 1E). Participants had to "catch" a rectangular white object falling vertically from the top of the screen before it reached the bottom of the screen. Pressing on the mouse button moved a rectangular green "paddle" horizontally so that it could be positioned directly in the path of the falling object. The test required hand-eye coordination, scanning, and rapid responses. Problem Solving Pictorial puzzles of gradually increasing difficulty were presented (Fig. 1F). Each puzzle consisted of a 2 · 2 array containing 3 black and white line drawings and a missing element. Participants had to choose the best fit for the fourth (missing) element of the puzzle from among 6 pos-sible alternatives. NeuroTrax Summary Measures To minimize differences in age and education and to permit averaging performance across different types of outcome parameters (e.g., accuracy, RT), each NeuroTrax outcome parameter was normalized and fitted to an IQ-style scale (mean: 100, SD: 15) in an age- and education-specific fashion. Normative data consisted of test data stored on the NeuroTrax central server for individuals classified as cognitively healthy in controlled clinical trials conducted at academic centers. Normalized subsets of outcome parameters were averaged to produce 7 summary scores as follows, each indexing a different cognitive domain. Data Analysis All statistics were computed with SPSS statistical package version 15.0. Neurocognitive test scores were converted into z-scores and compared with 0 (i.e., average) Zur et al: J Neuro-Ophthalmol 2015; 35: 26-30 27 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. using a one-sample t test to evaluate whether performance differed from average for age and education. An indepen-dent sample t test was run comparing treated patients with non-treated. Pearson correlations were used to evaluate the relationship of neurocognitive test scores with years of edu-cation and duration of disease. Statistical analysis was per-formed by the Statistical Laboratory School of Mathematics, Tel Aviv University, Tel Aviv, Israel. Standard Protocol Approvals and Patient Consent This prospective study was approved by the local institu-tional review board. Written informed consent was ob-tained from all patients participating in the study. RESULTS Participants Thirty consecutive IIH patients participated, 3 men and 27 women. Mean age at the time of testing was 34.4 ± 10.6 years (range, 19-68 years). Mean disease duration was 5.7 ± 4.1 years. Body mass index (BMI) was available for 27 patients; mean BMI was 32.1 ± 5.8 kg/m2. At the time of testing, all patients were at least 2 months from diagnosis, a relapse or a lumbar puncture. Eight patients were being treated with acetazolamide; 22 patients did not receive treatment to lower intracranial pressure (ICP). None of the patients had persistent impairment of visual acuity or visual fields. Mean years of education was 14.2 ± 2.0. Demo-graphic data are shown in Table E1, Supplemental Digital Content, http://links.lww.com/WNO/A118. All patients denied suffering from severe or chronic headache when they were included in the study. When informed consent was obtained from the participants, the test supervisor explained the objective of the study. As part of the pre-study screening, all 30 patients confirmed that they had noticed some cognitive decline after having been diagnosed with IIH. However, they had not mentioned it to the treating physician, as they attributed it to daily circumstances of life rather than IIH. None of our patients took medication for anxiety or depression and none of them complained about an anxiety state or disturbances of sleep, depressed mood, lack of appetite, loss of weight, or other signs of depression. None of the patients suffered from sleep apnea. Domain Measures Mean scores for all domain index scores were below average for age and education (See Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A119 and Fig. 2). The GCS, attention, and visual spatial indices had the low-est scores with 20.63 to 20.73 SDs below average. A t test showed statistically significant differences from average for all domains but memory, which did not reach statistical significance (P = 0.162). The GCS and attention index were most impaired (P = 0.01). Results of all domains are shown in Table E3, Supplemental Digital Content, http://links.lww.com/WNO/A120. Results did not differ between patients who did or did not take acetazolamide at the time of testing (for Global FIG. 1. NeuroTrax testing modalities. A. Non-verbal memory. B. Go-No Go test. C. Stroop interference. D. Visual spatial processing. E. "Catch" game. F. Problem solving. 28 Zur et al: J Neuro-Ophthalmol 2015; 35: 26-30 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. score P = 0.1870). The cognitive domain measures and GCS were not correlated with age, years of education, BMI, or duration of disease (See Supplemental Digital Content, Table E4, http://links.lww.com/WNO/A121). DISCUSSION Our results indicate that patients with IIH have mild cognitive impairment. All domain measures apart from memory showed a statistically significant difference from normal individuals, indicating a form of multidomain cognitive impairment in IIH. Study of cognition in IIH patients is limited (6,8,9,12). Kharkar et al (8) reported retrospective results of 10 IIH patients and, similar to our results, found borderline def-icits in memory, learning, executive function, and visuo-spatial skills and language were impaired. Yri et al (9) evaluated patients within 7 days of diagnosis of IIH, who were tested the second time after 3 months of treat-ment. Similar to our results, they found a multidomain impairment. Processing speed and RT were most pro-foundly impaired. In the study of Yri et al, attention scores and visuospatial memory improved at follow-up, whereas the others stayed unchanged. This improvement was mainly explained by the test-retest effect. Our results also support Yri's findings, which showed no overall deficits in working memory, both in the acute and treated phase. Remarkably, Yri et al did not find a correlation between change in cognitive performance and difference in ICP from baseline. Arseni et al (19) found impaired memory in 24% of 85 IIH patients when tested with the Wechsler Memory Scale. Details of the nature and degree of mem-ory impairment were not described nor were other cogni-tive functions measured. Sørensen et al (6) reported normal neuropsychological test performance in 5 IIH pa-tients with a protracted clinical course. In a prospective study of 20 IIH patients, 10 with chronic headaches and 9 healthy controls, Kesler et al (20) used brief psychological instruments to assess hostility (8-item New-Buss scale), anxiety (State-Trait Anxiety Inventory), and depression (autobiographical memory test). Patients with IIH scored higher on anxiety and showed reduced recall of specific autobiographical memories com-pared with weight-matched controls. No difference was found within the IIH group between patients taking or not taking acetazolamide. Information regarding QoL and cognitive functions in IIH patients is limited: The impact of IIH on health-related QoL has been studied by Kleinschmidt et al (3) who reported a higher incidence of depression and anx-iety in IIH patients compared with weight- and age-matched control groups. Vision-specific health-related QoL was significantly lower in newly diagnosed IIH pa-tients compared with neuro-ophthalmologic controls. Kesler et al (5) found high levels of anxiety and stress in IIH patients. Depression and anxiety themselves are known to cause cognitive decline, impairing memory, executive functions, and learning (21). Accordingly, Air-aksinen et al (22) found significant impairment in epi-sodic memory and executive functions in anxious patients. The relationship between IIH and cognitive impairment is unclear. Neither structural change nor change in brain volume has been identified in IIH patients. Brain dysfunc-tion may be related to axonal flow as in optic nerve swelling or to mechanical compression as in normal pressure hydrocephalus (23,24). We speculated that elevated ICP may cause diffuse effects in a broad array of brain areas. We found poorer performance in all cognitive domains tested. Attention and visual spatial processing scores were lowest. Even though memory was below average, it did not reach statistical significance. Our results demonstrated that cognitive decline was not related to patient age, disease duration, BMI, or acetazolamide treatment. The absence of correla-tion with these other variables implicates that IIH itself may cause cognitive impairment. A limitation of our study is that we did not test patients for anxiety and depression, although none of the partic-ipants had a diagnosis of a psychiatric disorder. Yet, it is well known that anxious and depressive disorders are often unrecognized in the population. Hence, there may be a portion of patients that suffered from undiagnosed anxiety or depression and a possible impact on cognitive results cannot be ruled out. FIG. 2. Domain measures of neurocognitive scores. Mean, minimum, and maximum z-score relative to 0 (i.e., average for a cognitively healthy sample of similar age and education) for each of the neurocognitive summary scores. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design (D. Zur, A. Kesler); b. Acquisition of data (D. Zur, E. Naftaliev, A. Kesler); c. Analysis and interpretation of data (D. Zur, E. Naftaliev). Category 2: a. Drafting the manuscript (D. Zur, E. Naftaliev, A. Kesler); b. Revising it for intellectual content (D. Zur, E. Naftaliev, A. Kesler). Category 3: a. Final approval of the completed manuscript (D. Zur, E. Naftaliev, A. Kesler). Zur et al: J Neuro-Ophthalmol 2015; 35: 26-30 29 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. ACKNOWLEDGMENTS Statistical analysis was performed by the Statistical Labora-tory School of Mathematics, Tel Aviv University, Tel Aviv, Israel. REFERENCES 1. Ahlskog JE, O'Neill BP. Pseudotumor cerebri. Ann Intern Med. 1982;97:249-256. 2. Smith JL. Whence pseudotumor cerebri? J Clin Neuroophthalmol. 1985;5:55-56. 3. Kleinschmidt J, Digre KB, Hanover R. Idiopathic intracranial hypertension: relationship to depression, anxiety and quality of life. Neurology. 2000;54:319-324. 4. Daniels AB, Liu GT, Volpe NJ, Galetta SL, Moster ML, Newman NJ, Biousse V, Lee AG, Wall M, Kardon R, Acierno MD, Corbett JJ, Maguire MG, Balcer LJ. 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