Ferritin and Iron Burden in SAH sIRB

SAH, Dementia

Deferiprone

Ruptured cerebral aneurysms lead to subarachnoid hemorrhage (SAH),that has a high morbidity and mortality rate, the severity of which is predicted by the Hunt-Hess grade (HHG). SAH leads to iron (Fe) and hemoglobin (Hb) accumulation in the brain, which is toxic for neurons. Ferritin (iron reported in the brian) and iron overload leads to brain atrophy, specifically in the mesial temporal lobe (hippocampus, impairing patients' cognition. It is estimated that 50% of survivors have cognitive deficits. Most of the survivors of SAH could not return to work. Iron chelation therapy has been recently gaining ground as a therapeutic intervention in intraparenchymal hemorrhage and in SAH. However, there has not been any study that assess the iron deposition in the brain and the level of ferritin in the cerebrospinal fluid of SAH patients. The investigators propose to conduct a randomized trial using Deferiprone (oral chelating agent, De) + standard of care versus standard of care in patient with SAH to: 1. assess the level of ferritin (Ft) in CSF (CSF withdrawn from ventriculostomy tube), 2. assess functional outcomes measured by the Montreal Cognitive Assessment (MoCA) score, a score used to assess the level of dementia, mainly in Alzheimer disease patients. 3. quantify the the total iron deposition in the brain based on MRI

I) SIGNIFICANCE 1\) Significance and Incidence and Burden of the disease Intracranial aneurysm is a prevalent disease estimated around 2-5% of the population. Aneurysm rupture leads to aneurysmal subarachnoid hemorrhage , which have a tremendous impact on the patient's health, and a high mortality rate (\ 60%), with a large proportion of the survivors becoming functionally dependent. It accounts for 27% of all stroke-related years of life lost before age 65, and it has a predilection for a relatively younger age. Survivors have long term cognitive deficits and memory impairment in their productive years with major responsibilities with respect to work and family. Despite that, only one-third have neurological deficits. Most of the survivors could not return to work. Poor functional outcomes are related to iron and heme toxicity with resultant delayed cerebral ischemia , early brain injury , hydrocephalus and cerebral edema. As of today, there has not been any intervention that improves neurocognitive outcomes in these patients. The investigators postulate that iron chelation therapy can decrease the amount of Iron (Fe) deposition in the brain, reduce ferritin (Ft) in patients' cerebrospinal fluid (CSF) and potentially improve functional outcome. Our group was the first in the world to detect and quantify Fe concentration at the interface of brain aneurysms' wall and brain tissue using QSM-MRI sequence. This technique allowed us to detect microbleeds associated with sentinel headache in subjects with IAs and negative non-contrast head CT and negative lumbar puncture. In this proposal, the investigators will also use high-resolution MRI sequence to assess difference in volumes of amygdala and hippocampus and correlate that with CSF-ferritin. This will make our proposal the first go/no-go randomized double-blind placebo vs. deferiprone trial that attempts to establish Ft (a reporter of total Fe in the brain and CSF) as a biomarker of neurocognitive decline specifically in subarachnoid hemorrhage subjects and test the effect of deferiprone in decreasing the levels of Ft and therefore ameliorate the neurocognitive decline associated with this disease. If our hypothesis is validated, then this would set the stage for a phase 3 clinical trial and test our hypothesis in larger cohort of subjects. III) PRELIMINARY DATA (obtained with collaboration with our colleagues in Europe): To provide proof-of-concept of the effect of deferiprone on the levels of Ft in the CSF of subjects with aneurysmal subarachnoid hemorrhage (aSAH), Tthe investigators conducted a pilot study to analyze the concentration Ft in the CSF of subjects with aSAH and Hunt and Hess grade 1-3. Fourteen subjects were included (7 with only cisternal SAH but no intraventricular hemorrhage (IVH), and 7 subjects with cisternal aSAH and IVH). Their CSF (2-3 cc) were drawn daily (from day 0 to day14) and analyzed with Fe-ELISA kit. Then 4 subjects (2 with aSAH without IVH and 2 with SAH and IVH) were treated with 1000 mg of deferiprone twice orally for 14 days. The mean Ft level in subjects with aSAH without IVH was 900ng/ml vs. 420 ng/ml for those receiving deferiprone. The mean Ft level of patients with SAH and IVH was 1500ng/ml compared to 690 ng/ml in the deferiprone group. This small pilot study provided proof-of-concept that 1) aSAH increases the CSF-Ft in human, and this effect can be reduced significantly with deferiprone, and 2) aSAH associated with IVH increases furthermore CSF-Ft, which is also reduced significantly by deferiprone.

United States