Neurological Complications Of Sickle Cell Disease Research Articles

Molecular and environmental contributors to neurological complications in sickle cell disease.

Sickle cell disease (SCD) is an inherited hemoglobinopathy in which affected hemoglobin polymerizes under hypoxic conditions resulting in red cell distortion and chronic hemolytic anemia. SCD affects millions of people worldwide, primarily in Sub-Saharan Africa and the Indian subcontinent. Due to vaso-occlusion of sickled red cells within the microvasculature, SCD affects virtually every organ system and causes significant morbidity and early mortality. The neurological complications of SCD are particularly devastating and diverse, ranging from overt stroke to covert cerebral injury, including silent cerebral infarctions and blood vessel tortuosity. However, even individuals without evidence of neuroanatomical changes in brain imaging have evidence of cognitive deficits compared to matched healthy controls likely due to chronic cerebral hypoxemia and neuroinflammation. In this review, we first examined the biological contributors to SCD-related neurological complications and then discussed the equally important socioenvironmental contributors. We then discuss the evidence for neuroprotection from the two primary disease-modifying therapies, chronic monthly blood transfusions and hydroxyurea, and end with several experimental therapies designed to specifically target these complications.

A case series of hemorrhagic neurological complications of sickle cell disease: Multiple faces of an underestimated problem!

Sickle cell disease (SCD) is a group of hemoglobinopathies that vary in severity, the most severe form, homozygous sickle cell anemia, is often associated with neurologic complications. The incidence of various neurologic complications in SCD ranges from 6% to 30% in different series. Although the incidence of acute ischemic stroke and chronic cerebral ischemia is higher in SCD, about 20–30% of the neurological complications may be hemorrhagic in nature. Complications such as spontaneous subarachnoid hemorrhage, hemorrhagic stroke, extradural, and subdural hematomas have been described in the literature. The aim of this article was to report uncommon spontaneous hemorrhagic neurological manifestations of SCD. We have described three uncommon hemorrhagic neurological complications of SCD. One case had a parenchymal (intracerebral) bleed and presented with acute onset of parkinsonism, while two cases had an extradural hematoma (EDH), of which one patient had recurrent EDH at the same site which is hitherto not reported in the literature. Two patients survived, while one with recurrent EDH succumbed. Hemorrhagic neurological complications should be included in the list of differential diagnoses of neurological presentations in patients of SCD. EDH is an uncommon complication of SCD, while recurrent EDH is extremely rare. The condition should be suspected early in patients with SCD, as timely treatment often reduces the mortality.

Comprehensive Sickle Cell Disease Management Is Associated with Superior Grade Attainment and High School Graduation Rates

Abstract Background: Sickle cell disease (SCD) in adolescents and young adults has been associated with low high school graduation rates. Complications of the disease may decrease school attendance, academic performance, and grade attainment. The graduation rate for patients with SCD enrolled in the Cooperative Study of Sickle Cell Disease (CSSD) was 71%. Poor educational outcomes might be due to a number of factors including socioeconomic status or days spent in the hospital due to illness. Neurological complications of SCD may also contribute. Stroke and microvascular ischemic events are detrimental to cognitive function and influence academic achievement and grade attainment. Patient and practitioner adherence to best practices, such as those described in the NHLBI 2014 guidelines vary widely, and the association of best practices with graduation rates has not been studied. We compared high school graduation rates of patients at Akron Children's Hospital Sickle Cell Disease Program (ACHSCDP) with national and local rates. Methods: We conducted a retrospective chart review of patients born between 1994 and 2000 who received care for all forms of SCD at ACHSCDP. Patients were identified through an onsite registry. Thirty-two patients were identified for chart review. We defined successful high school attainment as graduation from 12th grade, or having completed 11th grade by July 2018 and enrolled to begin 12th grade in Fall 2018, before or at 19 years of age. We determined successful high school attainment for patients at Akron Children's Hospital and assessed factors associated with success. Results: Patients born from 1994 to 2000 with sickle cell disease (SS, SC, SBeta-0, SBeta-+) were analyzed (n=32). Two patients transferred out of ACHSCDP prior to age 14 and were not included in our analysis. Of 30 patients studied, 14 were male and 16 were female. Twenty-six patients (86.7%) had graduated or were starting senior year as of July 2018. Of the 26 successful students, 12 (46.2%) had either an IEP or 504 (federally defined accommodation plan) in place. None of the 4 unsuccessful students had an IEP, however 1 student had a 504. Of the 26 successful students, 13 had HbSS, 1 had HbS/B o thal, 5 had HbS/B + thal, and 7 had HbSC. All 4 unsuccessful students had HbSS. Of the 26 successful students, clinical data from 4 years before graduation or 3 years before completion of the 11th grade revealed that the students were hospitalized an average of 5.77 days per year and visited the emergency department an average of 1.38 times per year. Of the 4 unsuccessful patients, data collected 4 years before the age of 19 revealed that the patients were hospitalized an average of 5.85 days per year and visited the emergency department an average of 1.37 times per year. Only one patient had a documented stroke, and this child successfully graduated from high school. Of the 26 successful students, 18 (69.2%) were enrolled in college after finishing high school and 3 students were in their senior year of high school. Discussion: In this cohort, a high percentage of patients (86.7%) graduated or were on track to graduate from high school. In the United States, approximately 90% of patients with SCD are African American. All patients analyzed here were African American. With this in mind, ACHSCDP patients' graduation rate compares favorably to estimated graduation rates across the US general population (84%), the U.S. African America population (76%), the U.S. sickle cell patient population (71%), the Ohio general population (84%), and the Ohio African American population (68%). The higher graduation rate among children at the ACHSCDP is associated with a multidisciplinary care model that prioritizes optimal hematologic care adhering to evidence based best practices including stroke risk screening and prevention, and use of hydroxyurea. In addition, team members assess for educations status and disease specific limitations at each encounter. A social worker advocates for educational needs. An outreach nurse makes school visits to educate staff and assist with implementation of federal accommodation plans. A teacher is available during inpatient stays to provide education in coordination with the patients' school. With comprehensive care, SCD is not a barrier to successful grade attainment, and academic distress in SCD patients should prompt re-evaluation of the patient's holistic medical care. Disclosures No relevant conflicts of interest to declare.

Sleep-disordered breathing and nocturnal hypoxemia in young adults with sickle cell disease

Sleep-disordered breathing (SDB) is reported in up to 69% of adolescents and children with sickle cell disease (SCD) [1], but data regarding the prevalence of SDB in adults with SCD are limited. In order to obtain a preliminary assessment of the frequency and degree of sleep-related hypoxemia and potential associations with cardiovascular function in adults with SCD, we conducted overnight sleep studies, 6-min walk tests, echocardiograms, and hematologic and chemistry panels, calculated the Pittsburgh sleep quality index (PSQI), and conducted fatigue- and health-related quality-of-life measurement in 20 young adults with SCD visiting a sickle cell clinic for routine care. Sleep apnea, defined as an apnea–hypopnea index (AHI) > 5 events/h, was found in 50% of patients. Traditional clinical indicators, such as obesity, the presence of snoring, and reported sleep complaints, did not reliably differentiate them. The patients with AHI > 5 had higher mean systolic blood pressure (p = 0.03), evidence of impaired left ventricular diastolic function (i.e., increased mitral valve E/A ratio, p = 0.05), a trend toward higher reduction in 6-min walk distances (p = 0.06), and lower health-related quality-of-life scores (p ≤ 0.01). Three of nine patients with more severe anemia (total Hb < 9.0) showed nocturnal hypoxemia in the absence of sleep apnea. As prolonged and frequent hypoxemic episodes likely increase risks for vaso-occlusive, cardiovascular, and neurologic complications of SCD, these results suggest that the prevalence and severity of SDB should be investigated further in studies of larger patient populations. If confirmed, these findings could identify opportunities to prevent or reduce nocturnal hypoxia and improve outcomes.

Uncommon Posterior Reversible Encephalopathy Syndrome in a Sickle-Cell Patient.

Posterior reversible encephalopathy syndrome (PRES) refers to a clinicoradiological entity with characteristic features on neuroimaging and nonspecific symptoms comprising headache, confusion, visual disturbances, and seizures. This syndrome may occur in diverse situations, including the taking of cytotoxic and immunosuppressive drugs, hypertensive encephalopathy, and eclampsia. The lesions in PRES are thought to be due to vasogenic edema that occurs predominantly in the posterior cerebral hemispheres, and are reversible with appropriate management. We present herein the case of a female with sickle cell (SC) disease who presented with this syndrome without any of the common risk factors. A 57-year-old woman presented to the emergency room with confusion and behavioral changes of sudden onset. Her medical history included a SC disease and supraventricular tachycardia for which she was being treated with flecainide, atenolol, and aspirine. On the day before admission, the patient presented with a SC vaso-occlusive crisis with diffuse pain in both lower limbs. The examination upon admission revealed confusion, temporo-spatial disorientation, behavioral disorders, dysarthria, phasic disorders, a discrete right motor deficit, and psycho-motor slowing. She complained of leg pain, her blood pressure was 139/89 mm Hg, and there was no fever. Laboratory tests revealed normal renal function and serum electrolytes, but impaired liver function. Her hemoglobin and platelet count were 8.8 g/dL and 74,000/mm3, respectively, and her white blood cell count was elevated at 11,000/mm3. Lumbar puncture findings were normal; blood, urine cultures, and serology tests (HIV, human T-lymphotropic virus, syphilis, herpes, hepatitis C, leptospirosis, Lyme) produced negative results, hepatitis B, cytomegalovirus and Epstein-Barr virus serologies were in favor past healed infections. Brain MRI revealed multiple bithalamic, biparietal, bitemporal, bifrontal, and cerebellar subcortical high signal intensity lesions on T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted sequences (Fig. 1A). Apparent diffusion coefficient mapping revealed a high signal indicative of the presence of vasogenic edema. Control MRI performed after 15 days revealed complete resolution of the bithalamic lesions and all other lesions (Fig. 1B). The patient's clinical status also normalized spontaneously. Fig. 1 A: Brain axial fluid-attenuated inversion recovery MRI-sequence showing bithalamic, biparietal, and bifrontal hyperintense signals. B: MRI control performed 15 days later, showing disappearance of the presenting radiological features. The case described herein is thus far unique in that while lesions in PRES usually involve mainly the parieto-occipital lobes, in this case the lesions also involved both thalami, the cerebellum, and the temporal and frontal lobes. The diagnosis of PRES was confirmed by the radiological features disappearing at follow-up MRI performed 15 days later. The originality of this case also lies in the very rare cases of PRES described in SC patients being associated with severe acute chest syndrome, uncontrolled hypertension, renal failure, or pulmonary infection,1,2,3 which was not the case in the present patient. In those previously described cases, PRES was attributed to abrupt elevation of blood pressure, or blood volume. It is possible that our patient presented with relative hypertension, since SC patients generally have a lower blood pressure than non-SC controls. Reversible posterior leukoencephalopathy syndrome (RPLS) was described by Hinchey et al.4 in patients with hypertension, eclampsia, renal failure, or with immunosuppressor treatments. The syndrome includes headache, transient neurological symptoms, visual changes, seizures, or altered consciousness, with MRI revealing subcortical edema in the posterior regions of the cerebral hemispheres without infarction; these clinical and radiological findings are reversible with control of blood pressure or withdrawal of immunosuppressive therapy. Since the gray matter can also be involved, the term RPLS has been replaced by PRES. The pathophysiology of PRES remains a matter of debate. One hypothesis is that severe hypertension in these patients causes impaired cerebrovascular autoregulation, vasodilatation, and vasogenic edema, while another is that toxicity of immunosuppressive drugs (e.g., tacrolimus or cyclosporine) leads to impaired endothelial homeostasis. However, PRES appears ultimately to be related to endothelial dysfunction that leads to cerebro-vascular autoregulation impairment and vasogenic edema.2 Since endothelial dysfunction is thought to play part in the cerebrovascular disease observed in SC anemia, SC patients may have an increased risk of developing PRES.2 In addition to more classical neurological complications of SC disease, such as ischemic strokes, silent cerebral infarcts, intracerebral hemorrhages or seizures, PRES may also be evoked in patients presenting with acute neurological changes, even in the absence of risk factors, as in our case.

Subarachnoid hemorrhage in sickle-cell disease

The neurological complications of sickle-cell disease include cerebral intracerebral hemorrhage; subarachnoid hemorrhage (SAH) has been infrequently reported. Among 325 patients with sickle-cell disease followed at the University of Illinois between 1975 and 1989, 11 cases of SAH were identified. Aneurysms were found in 10 of these patients, three of whom had multiple aneurysms. All of the patients had some degree of anemia and nine underwent craniotomy without hematological or neurological complications. From this review it appears that SAH is not uncommon in sickle-cell disease patients and tends to occur at a younger age and with smaller aneurysm size than in the general population. With proper perioperative management, including exchange transfusions to reduce the proportion of hemoglobin S to less than 30%, these patients can undergo angiography and craniotomy without an increased incidence of complications. The techniques used in managing sickle-cell disease patients with SAH are discussed.