Idiopathic intracranial hypertension (IIH) is characterised by increased cerebrospinal fluid pressure with an unclear aetiology. IIH affects predominantly young women, and is associated with serious consequences, including loss of vision, disabling headache, and loss of employment (1). Evidence is emerging that IIH patients also experience a range of cognitive impairments (2–7) that, despite effects on decreased quality of life and poor treatment outcomes (5), remain under-recognised and poorly understood. Whether cognitive changes are independent or a consequence of other features of the disorder, such as changes in visual processing, headache, mood disorders, weight and medication, is unknown.

Here we assessed cognitive changes in IIH using conventional neuropsychological measures and novel ocular motor tasks that examine visual processing changes associated with saccade generation (8). Ocular motor tasks were the simple prosaccade (PS) task, which requires a gaze shift toward a suddenly-appearing stimulus, reflecting simple sensorimotor processing, and the more complex antisaccade (AS) task that additionally implicates cognitive networks required to inhibit a saccade toward a suddenly-appearing stimulus and then move the eyes in the opposite direction (9). Task demands were modified using the interleaved AS-PS task that recruits a broader cognitive network, enabling assessment of the interaction between changes in visual processing and cognitive function more broadly (10). Relationships were assessed between cognitive impairments and common co-morbid IIH features, such as headache, mood, weight, waist circumference and visual processing changes.

All 22 participants were phenotypically typical of IIH and were tested at a mean of 2.7 months from diagnosis [standard deviation (SD) = 1.4]. Thirteen patients were managed with acetazolamide, 5 with topiramate and 4 were not on medications for IIH. Additional clinical characteristics and baseline demographics are shown in Table 1. Table 2 summarises group means and standard deviations for all tasks.

We reveal a range of cognitive impairments in IIH patients both on conventional neuropsychological and novel ocular motor tests of cognition. At baseline, as well as 3 and 6 months, IIH patients performed more poorly than controls on the Stroop test, indicating poorer inhibition of cognitive interference (21), on the SDMT, indicating reduced cognitive processing speed (20), and on the Digit Span and CVLT, indicating reduced working memory (22, 23).

At baseline, IIH patients found it more difficult to inhibit a saccade toward a suddenly appearing stimulus (AS error), irrespective of task difficulty. However, eye movements made directly toward a visual stimulus (PS) were comparable to controls for both tasks, at all time-points. For the more cognitively complex interleaved saccade task, AS latencies were significantly prolonged for IIH patients, suggesting reduced cognitive processing speed (8). At 3 months, IIH patients exhibited partial improvement for AS error and normal anti-saccade latencies. In five patients followed for 6-months, all ocular motor results were similar to controls, although these results must be interpreted with caution given the significant cohort attrition over time.

Although IIH patients reported high rates of headache, anxiety and depression, none of these factors predicted performance on any neuropsychological or ocular motor measure, at any time-point. Notably, rates of headache and mood disturbances remained similar over time. However, increased AS error rates were associated with changes in structures involved in afferent visual transduction (i.e., increased RNFL thickness). Increased RNFL thickness was not associated with performance on any other cognitive measure. Further, RNFL thickness reduced significantly over time, in-line with observed improvements in ocular motor results. On the contrary, poorer performance on neuropsychological assessments for IIH patients persisted at 6 months, suggesting that cognitive functions less reliant on visual processing are independent of the clinical features of the disorder. It is plausible that subclinical visual processing changes may not impact conventional tests of cognition or perceived visual functioning, but may be revealed using more direct testing of the visual processing system using ocular motor tasks.

With the exception of a single case report (28), all prior studies have reported cognitive impairments in IIH (2, 29–33). Yri et al. in a study of 31 IIH patients, described decreased processing speed and reaction times as well as cognitive flexibility deficits (2). When considered in combination with our findings of prominent inhibitory control deficits and impaired cognitive flexibility, it is conceivable that impaired frontostriatal function may underlie cognitive impairments in IIH (34).

Frontostriatal circuits support cognitive functions and neuroanatomically encompass the frontal cortex, thalamus and basal ganglia (35). Three of five major frontostriatal circuits are thought to mediate non-motor, cognitively driven behaviours, namely the dorsolateral prefrontal, medial orbitofrontal and lateral orbitofrontal circuits (36). The dorsolateral pre-frontal cortex is primarily responsible for executive functioning, which is comprised of cognitive domains impaired in our IIH cohort, such as inhibitory control, processing speed and working memory (37). Although IIH pathophysiology is not fully understood, there is a complex yet well-established relationship between IIH and obesity, with the pathology of obesity postulated to affect striatal networks (38).

Weight gain and obesity increase the risk of IIH, while modest amounts of weight loss can lead to disease resolution (39). In our cohort, weight and waist circumference did not predict cognitive performance. Similarly, Yri et al. found that IIH patient body mass index (BMI) did not predict cognitive performance (2) suggesting that cognition appears to be influenced by the presence of, rather than the magnitude of weight excess in IIH. However, obesity by itself, or when present in other neurological diseases, has been associated with a number of adverse cognitive outcomes (40, 41) and larger cohorts may be needed to resolve this association. Functional Magnetic Resonance Imaging (fMRI) suggests that obesity and binge-eating disorder is associated with decreased striatal responses to food, yet heightened frontostriatal responses to food cues (42). This supports the hypothesis that frontostriatal changes in obesity may facilitate decreased inhibitory control (43).

A further potential pathophysiological factor in obesity and IIH-related cognitive changes is the metabolically activity of adipose tissue, that can produce a range of adipokines and inflammatory cytokines (44). Such an inflammatory milieu may contribute to cognitive impairment by interfering with neuronal network function. This has been demonstrated in other conditions such as multiple sclerosis, where obesity independently contributes to cognitive dysfunction as assessed by clinical testing, biomarkers, and MRI (45). Obesity-related systemic inflammation as well as increased mechanical strain on frontostriatal networks from raised intracranial pressure may therefore both contribute to cognitive dysfunction in IIH (46). Since IIH patients exhibited no PS deficits, basic visual processing appears intact. Visual processing changes must therefore relate to the interaction of signals from the afferent visual pathway and widely distributed cognitive networks that are utilised in generating an AS (47). This is clinically relevant, since high rates of AS errors are associated with decreased concentration and high distractibility (48).

Surprisingly, we found no correlation between any ocular motor measure and neuropsychology test results in our study. This was especially surprising for tests of inhibitory control like the AS task and Stroop test. However, the Stroop test and AS task assess inhibitory control differently. Unlike the AS task, there are no absolute penalties for errors in the Stroop test (21), which records errors as a correct/incorrect binary variable. The Stroop test and AS task are also timed differently; the Stroop test is concluded when a time limit is reached, while the AS task measures the time taken to complete a task. While we might expect a relationship between saccade latency and deficits revealed by neuropsychological testing, as has been reported previously (49), this is conceivably confounded by high error rates due to impaired inhibitory control, excluding a large number of trials from latency analyses for our IIH cohort.

Our study was limited by a relatively homogenous group of IIH patients, with mild to moderate clinical characteristics. Longitudinal testing was impacted by Covid19 restrictions, and a larger, more heterogenous cohort of IIH patients would help to confirm trends and clarify clinical associations identified in our study. Ideally controls would be weight matched to the IIH group in addition to being age and sex matched, since cognitive impairments may be associated with obesity (43). Further, ocular motor tasks less reliant on inhibitory control would be useful in future IIH research, identifying impairments obscured by the high AS errors in our study.

While our results were largely consistent with previous studies in IIH patients, we also revealed a unique subclinical cognitive profile in IIH, that elucidates the difficulties some IIH patients have with maintaining employment and engaging in lifestyle alterations (2, 39). Although it is increasingly acknowledged that cognitive impairments are likely in IIH, cognitive screening is absent from management guidelines (50). The Mini Mental State Examination (MMSE) has been proposed as a screening test (32), however it lacks sensitivity (24). The SDMT is quick, simple to administer and easy to score (20), and could be considered as an alternative screening test for IIH-specific cognitive changes, such as reduced information processing speed (2).

Weight, waist circumference, anxiety, depression, and headache do not appear to underlie cognitive impairments in mild to moderate IIH but need to be studied in larger cohorts. Here, RNFL elevation was associated with ocular motor deficits, that might represent subclinical change in visual processing and cognition and future inclusion of more severely affected IIH patients would be of interest. Exploration of frontostriatal pathways, given impairments of inhibitory control, processing speed, and working memory, may provide insights into IIH pathophysiology. Our work adds to the importance of the inclusion of cognitive screening in IIH management to enable targeted neurorehabilitation and employment support, leading to improved patient care.

Statistical analysis was performed by WW and MC.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Alfred Health Human Research and Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

NS served on advisory boards for Merck and Roche, and has received travel support from Biogen.

AV served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck and Roche. She has received speaker's honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia.

OW receives discretionary research funding from Merck, and is an Associate Editor for Frontiers in Neuro-Ophthalmology.

JF receives funding for other research from Biogen and Genzyme.

WW: recruitment, data acquisition, data interpretation, drafting, and revision of manuscript. MC: data acquisition, data interpretation, study supervision, and revision of the manuscript. NS: recruitment and revision of the manuscript. AV, OW, and JF: design and conceptualisation of the study, study supervision, and revision of the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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