Improving diagnosis of High ICP in Cryptococcal meningitis (ICP-CRYPTO) - Abstract Raised intracranial pressure (ICP) is a common complication of cryptococcal meningitis (CM), affecting around half of patients, leading to increased morbidity and mortality. Lumbar punctures (LP) are used to diagnose raised ICP, by measuring cerebrospinal fluid (CSF) opening pressure (OP), and to treat raised ICP by therapeutic drainage of CSF. This reduces mortality but relief is often only temporary and high ICP frequently recurs during treatment, requiring further repeat LPs, sometimes daily. LPs are invasive, often painful procedures, and can lead to complications. A non-invasive test to identify patients with raised ICP would be highly advantageous as it would help identify patients at risk of ICP-associated complications, and significantly reduce the number of LPs performed purely for ICP monitoring reasons. Retinal imaging technologies show great promise and are now routinely used to detect and monitor raised ICP in other neurological conditions. These include Optical Coherence Tomography (OCT), which uses safe low- power laser to produce high-resolution, cross-sectional images of the retina, allowing for very accurate measurement of optic nerve swelling - a strong predictor of raised ICP; and fundoscopy, to identify retinal vessel changes associated with raised ICP. With the development of low-cost, portable OCT machines and lens adaptations that enable the use of mobile platforms for high-quality non-mydriatic fundoscopy, these assessments are now much more accessible to non-ophthalmologists and in resource limited settings. In this proof-of-concept translational proposal, we will evaluate whether mobile OCT and smartphone fundoscopy can be used to identify high ICP in CM patients at diagnosis and during treatment, and which non- invasive retinal imaging modality is better. To do this we will conduct a prospective cohort study in Kampala, Uganda, enrolling patients with HIV-associated CM. We will perform serial OCT and smartphone fundoscopy during inpatient treatment and compare these readings to opening pressure measured at LP. The proposal draws together expertise in retinal imaging and OCT analysis from Dr. Mollan’s group in Birmingham, with the clinical experience of a long-established and highly productive meningitis research collaboration between the University of Minnesota and the Infectious Diseases Institute, Makerere University (Uganda). This project has the potential to significantly impact the complex clinical care required to treat persons with HIV-associated cryptococcal meningitis, particularly in resource-limited settings. Using mobile retinal imaging as a non-invasive test for raised ICP would reduce the material resources, technical manpower, and possibility of adverse events that are associated with performing LPs. By demonstrating proof-of-principle and technical feasibility, the data from this R21 could then be leveraged into a larger diagnostic package of care used in a R01-funded randomized control trial for novel treatments and management strategies to reduce ICP in CM.
