progresses with age.8-12 Clinical stroke, the most recognized complication, is 1 manifestation of global neurologic insult.13 The prevalence of clinically overt stroke reaches 24% of patients by 45 years of age, with an adult peak at 29 years for both ischemic and hemorrhagic strokes. The incidence of first stroke is 500 to 1280 Conflict-of-interest disclosure: The author declares no competing financial interests. Off-label drug use: None disclosed. Hematology 2017 435 per 100 000 person years in sickle cell anemia (SCA) compared with 12 per 100 000 person years in African Americans younger than 35 years of age.11 Hemorrhagic stroke in SCD is 30 times greater compared with non-SCD patients. Recently, an analysis of the administrative patient data from California confirmed the extremely high rate of stroke in SCD adults, with 56% being ischemic stroke, 24% intracerebral, and 20% subarachnoid hemorrhage.14 The high rate of annual subarachnoid hemorrhage in SCD is related to the high prevalence of intracranial aneurysms, which are distinct from the moyamoya vasculopathy. The prevalence of aneurysms in sickle cell adults is not exactly known, but recent data indicate that approximately 10% of unselected young adults without overt neurologic problems (median age, 30 years) undergoing magnetic resonance imaging (MRI) screening for silent infarction had saccular aneurysms on incidental screening.9 Silent cerebral infarction Silent cerebral infarction is well studied in children with SCD and is associated with neurocognitive impairment and increased risk of CNS complications. The cumulative risk for silent cerebral infarction increases with age; by 18 years, 39% of patients have lesions. Recent data suggest that cumulative risk continues with age. Kassim, using standardized definitions and technology, reported a prevalence of silent infarction in 53% of adults with SCA with a mean age of 30 years.9 In a group of neurologically asymptomatic SCA adults without multiorgan dysfunction, Vichinsky et al found that 15% of the population with a median age of 32 had silent cerebral infarctions larger than 5 mm.12 Of interest, many of these patients had normal screening MRI scans as part of childhood collaborative studies, suggesting that a normal MRI scan in childhood does not preclude new lesions occurring with age. Atrophy Increasing studies indicate that adult patients with SCD have progressive global gray and white matter volumetric loss involving critical brain regions independent of clinical or silent infarction.10,12 Compared with controls, adults with SCA have volume loss in the frontal, temporal, and parietal lobes; basal ganglia; and thalamus. Volume loss is consistent throughout each of the subregions including the caudate, pallidum, putamen, and thalamus. Perfusion studies indicate that many of these areas of atrophy have decreased perfusion, particularly in small and terminal branches of arterial blood vessels.15 Recent studies confirm that corpus callosum atrophy and damage often accompanies these other findings. Quantitative diffusion-tensor imaging in adults indicate fiber tract density damage and evidence of axonal injury in the corpus callosum compared with controls.16 Neurocognitive function Comprehensive assessment of neurocognitive function in neurologically intact adults with SCA indicates clinically significant impaired neurocognitive performance compared with controls.10,12,17,18 Important differences in neurocognitive performance on the Wechsler Adult Language Scale-III verbal IQ, picture IQ, and full-scale IQ indexes, as well as on tests of memory, language, learning, attention, retrieval, and overall executive functioning are observed. Additional differences in neurocognitive testing between patients and controls were noted on processing speed, working memory, global cognitive function (full-scale IQ), and the majority of measures of executive function (Delis-Kaplan Executive Function System), and selective attention. These neurocognitive abnormalities are independent of lacunar infarcts but are amplified by lesions. In general, silent infarction causes a steep decline in cognitive function over time and is a risk factor for early dementia. Because this study excluded complications and risk factors associated with neurocognitive decline, the results likely underestimate the level of cognitive difficulties experienced in the general adult population with SCA. Overall, one could expect these patients to have challenges in skills of daily life such as planning, employment, financial management, medication adherence, utilization of community resources, and social functioning.19 In adult patients with SCD, there are several clinical, environmental, genetic, and laboratory risk factors for neurocognitive decline and brain injury that increase with age. The clinician should be aware of these, correct those that are modifiable, and screen all high-risk patients for consideration of therapeutic interventions. Optimal screening and management of smoking, hypertension, cardiac disease, arrhythmias, diabetes, thrombophilia, hyperlipidemia, and obesity are important. Comorbid chronic renal and lung disease requires early multidisciplinary intervention. History of intermittent hypoxia or acute fall in hemoglobin should raise concern of neurocognitive injury or stroke risk. Any